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Monitoring illicit psychostimulants and related health issues
Brunt, T.M.
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Monitoring illicit psychostimulants and related health issues
Monitoring illicit
psychostimulants and related
health issues
Tibor Brunt
Tibor Brunt
Monitoring illicit psychostimulants
and related health issues
Tibor Markus Brunt
Cover design provided by redactie Nieuwsuur of NOS-NTR
Financial support for the printing of this thesis was provided by the
Trimbos-institute and the AMC.
Published by: Uitgeverij BOXPress, Oisterwijk
ISBN: 978-90-8891-355-6
Monitoring illicit psychostimulants and related health issues
ACADEMISCH PROEFSCHRIFT
ter verkrijging van de graad van doctor
aan de Universiteit van Amsterdam
op gezag van de Rector Magnificus
prof. dr. D.C. van den Boom
ten overstaan van een door het college voor promoties
ingestelde commissie,
in het openbaar te verdedigen in de Agnietenkapel
op vrijdag 2 maart 2012, te 12:00 uur
door
Tibor Markus Brunt
geboren te Amsterdam
Promotiecommisie:
Promotor:
Prof. dr. W. van den Brink
Co-promotor:
Dr. R.J.M. Niesink
Overige leden:
Prof. dr. D.J. Korf
Prof. dr. G.M. Schippers
Prof. dr. H. van de Mheen
Dr. J.G.C. van Amsterdam
Dr. R.J. Verkes
Faculteit der Geneeskunde
Contents
Chapter1:
Introduction
Chapter 2:
The Drug Information and Monitoring System (DIMS) in The
Netherlands: implementation, results and international comparison
Chapter 3:
The relationship of quality and price of the psychostimulants
cocaine and amphetamine with health care outcomes
Chapter 4:
An analysis of cocaine powder in the Netherlands: Content
and health hazards due to adulterants
Chapter 5:
Impact of a transient instability of the ecstasy market on
health concerns and drug use patterns in The Netherlands
Chapter 6:
Instability of the ecstasy market and a new kid on the block:
mephedrone
Chapter 7:
Linking the pharmacological content of ecstasy tablets to the
subjective experiences of drug users
Chapter 8:
General discussion
Appendices:
References
Nederlandse samenvatting & discussie
Dankwoord (words of praise)
Curriculum Vitae
List of publications
5
7
21
57
83
101
119
131
157
175
206
212
218
221
Chapter 1
Introduction
Introduction
Psychostimulants are an important class of psychoactive drugs which are
known to enhance mental and physical functioning. Although most of these
compounds were developed for clinical use, there has been an increasing
trend to use them for recreational purposes. The provision of additional
energy, improved concentration and increased self-confidence are among
the main reasons for the increased popularity of psychostimulants
(EMCDDA, 2010). Especially in Western societies, where the patterns of
nightlife have extended far beyond the midnight curfew and excesses in
social or sexual behaviour have become more and more normalized,
psychostimulants have become a major class of drugs of choice.
Additionally, where there is an ever-increasing feeling of pressure to
perform and achieve without room for failure (Compas et al., 1995).
Subsequently, the illegal manufacture and trade in these drugs have
become a large and globalized industry serving millions of illicit stimulant
users. For example, worldwide it was estimated that between 14.3 and
20.5 million people aged 15-64 used cocaine at least once and they
consumed 440 metric tons of cocaine in 2009 (UNODC, 2011). The global
estimated income in 2009 was 85 $ billion from retail sales.
Widespread use of illicit stimulants has been an ongoing political, legal,
economic and health issue. Most psychostimulants are not without health
risks and therefore, their worldwide consumption poses problems in terms
of medical treatment. This has prompted most countries to classify
psychostimulants under a controlled legal status and prohibit the
manufacture, distribution and possession of these substances. In scientific
terms, this strategy to reduce availability of illicit drugs is often referred to
as a “use reduction” approach in national drug policy (Caulkins & Reuter,
1997). On the other hand, many countries, like The Netherlands, have
adopted a health-based policy recognizing that drugs of abuse will be
available despite all possible legal efforts to prohibit their use (Mensink &
Spruit, 1999). This policy focuses on the prevention of drug use and on the
limitation of harm to users and society by offering specialized services to
9
drug users, and is often referred to as “harm reduction” policy. One of the
most famous examples of harm reduction is the syringe-exchange program
with injecting drug users, which originated in 1984 in Amsterdam as a
preventive measure to stop the spread of the hepatitis B and the HIV virus
among injecting drug users and has been adopted worldwide since for the
prevention of all blood borne diseases, including hepatitis and AIDS
(Hartgers et al., 1989). Since then, many other types of harm reduction
have been developed ranging from test services for recreational drug users
(Spruit, 2001) to heroin assisted treatment and safe injection rooms for
chronic, often treatment refractory drug addicts (Blanken et al., 2010; Kerr
et al., 2007). This thesis is about the results of a test service and
monitoring system in The Netherlands, the Drug Information and
Monitoring System (DIMS).
Drug testing: Drug Information and Monitoring System.
Drug use and the illicit drug market has taken an entirely different form in
the early 1990s with different drugs, different drug users and different drug
use patterns than in the previous decades (de Kort & Kramer, 1999).
Alongside traditional psychotropic drugs, new synthetic drugs emerged
with unknown effects and risks and most of these synthetic drugs could be
classified as psychostimulants. The new drugs were used in new settings
by a new group of users, very different from the traditional problematic drug
users or addicts (Parker et al., 1999). These users were not marginalized
or criminalized as a result of a lifestyle heavily revolving around drug use.
Basically, in most aspects, these drug users did not differ much from nonusers, with the exception of a higher propensity for novelty seeking and
impulsivity (Butler & Montgomery, 2004; Dughiero et al., 2001). Their
motivation for use was primarily recreational and the use was confined to
weekends at party‟s or clubs, and often in combination with the use of
alcohol or other drugs (Tossmann et al., 2001).
A new harm reduction program that originated in the 1990s in The
Netherlands was the Drug Information and Monitoring System (DIMS). This
program particularly focused on known and unknown psychostimulants that
emerged from the new subculture of recreational drug users (Spruit, 2001).
10
and the appearance of unexpected hazardous substances on the drug
market (Spruit, 1999). Within the framework of the DIMS, drug testing
facilities were organized in prevention agencies and addiction treatment
services throughout the country where users were able to hand in their
illicit drugs voluntarily to analyze composition and dosage. Whereas the
Dutch health policy emphasizes that the use of illicit drugs is never
harmless, it is now able to take decisive preventive actions if hazardous
substances appear on the illicit drug market that pose additional public
health risks. For instance, drug users will be alerted within the framework
of the prevention institutes, flyers are distributed at clubs or warnings are
published in the media (Keijsers et al., 2007). On the other hand, the DIMS
is a scientific monitor with information derived from drug users throughout
the country, the data are stored via a website into a large database, and
weekly data are available from the early 1990s until the present. This
thesis is largely based upon that dataset and shows the potential of
different health issues that can be investigated with it. The thesis is
focused on the three main psychostimulants that were handed in from the
beginning of the existence of DIMS: ecstasy or MDMA (3,4methylenedioxymetamphetamine), amphetamine and cocaine. These
substances constitute the vast majority of drug samples submitted to the
DIMS. Below we provide a brief summary of the chemical,
pharmacological, behavioral and toxic profiles of these different drugs.
Amphetamine.
Amphetamine is one of the earliest synthetic psychostimulants widely used
for non-medical (recreational) purposes (Rasmussen, 2009). Amphetamine
is often referred to as “speed” or “pep” by the drug users. It was first
synthesized in the nineteenth century by a chemist in Germany (Edeleano,
1887). It is a phenethylamine and is often sold as a white powder. It can be
ingested or snorted and appears in tablet form, spray or powder. In The
Netherlands, amphetamine is usually snorted (van Laar et al., 2010). A
dose varies from tens to several hundreds of milligrams depending on the
purity and the individual tolerance for the drug.
11
Amphetamine acts as a monoamine releaser. Its mechanism involves both
vesicular and plasma membrane monoamine transporters as targets for
monoamine release (Fleckenstein et al., 2007). It basically acts as a
substrate for monoamine transporters and it was hypothesized from animal
models that amphetamine is transported into the cell via the dopamine
transporter (DAT) which results in the exchange of dopamine (DA) in the
extracellular space (Fischer & Cho, 1979). Furthermore, amphetamine
increases intracellular Na+ and this also drives DA efflux (Sulzer et al.,
2005). Whereas DA induces strong feelings of euphoria, it also causes
dependence and neurotoxicity in the long run (Kita et al., 2009). Even more
potently, synaptic norepinephrine (NE) are increased by amphetamine
(Rothman et al., 2001). This could occur both via reuptake blockage and by
active release through an interaction with the NE neuronal transport carrier
(Florin et al., 1994). In a similar way, amphetamine releases serotonin (5HT) in certain parts of the brain (Jones & Kauer, 1999).
Before users found other purposes for it, it was originally used as
decongestant in the form of an inhaler (Rasmussen, 2009). However,
amphetamine‟s potent physical and mental stimulant effects were soon
discovered by many. During World War II it was used by the military to
combat fatigue and fear. Effects of a single dose may last for many hours
and may be succeeded by anxiety, fatigue, disinterest or tiredness. In the
years following the Second World War, many users experienced another
typical and hazardous drawback of the long term use of the drug: its high
dependence potential (Rasmussen, 2009). This led to a massive demand
for amphetamines and the drug started circulating the streets. Meanwhile
amphetamine was also being used by various groups for other purposes.
Truck drivers were taking the drug to stay awake, students to enhance their
concentration during study, many athletes believed it enhanced their
performance, it was given to racing horses and in some countries it was
even given to factory workers to keep them alert and awake (Rasmussen,
2009). In the late 1960s it was realized that the drug was a serious health
risk and it was banned worldwide. In The Netherlands amphetamine is a
controlled substance since 1976 (Buisman et al., 2000). At the same time,
amphetamine and its derivatives are used in clinical settings to treat certain
12
disorders, e.g. attention deficit hyperactivity disorder (ADHD), obesity and
narcolepsy (Fleckenstein et al., 2007).
In 2009 in The Netherlands, last month and life time prevalence of the use
of amphetamine in the general population between 15 and 64 was 0.2%
and 3.1%, respectively (van Laar et al., 2011). In the mid-nineties speed
was much more popular, especially among certain groups of partygoers
(hardcore techno) (ter Bogt, 1997; Nabben, 2010). Although amphetamine
use is currently relatively rare in The Netherlands, it seems to be a drug
with a steady group of users, unlike other parts of the world were the
amphetamine derivative methamphetamine (crystal meth) is much more
popular (UNODC, 2011). This substance, often smoked, is much stronger
and has a much longer lasting effect than (dex)amphetamine (Fleckenstein
et al., 2000).
Cocaine
Cocaine is a natural psychostimulant that occurs in and is extracted from
the leaves of the coca plant (Erythroxylon coca) in western South America.
Throughout the ages, rough coca leaves were chewed by the local
population to work under harsh conditions of high altitude and inadequate
diet (Gold, 1993). The cocaine alkaloid was first isolated in 1855, and
experiments with the coca leaves during the nineteenth century proved that
cocaine was a very effective local anaesthetic (Niemann, 1860). However,
coca leaves only contain about 1% cocaine and this is released slowly.
This generated interest from the clinical society to purify cocaine on a
larger scale for medical applications, like dental procedures or eye surgery
(Gold, 1993). It was soon found that cocaine also possessed potent
psychoactive effects, and it was used in experiments with a host of
psychiatric conditions (e.g. hysteria) (Galbis-Reig, 2004; Gold, 1993).
The mechanism of action of cocaine is well-known: cocaine binds to the
DA, 5-HT and NE transporter proteins (termed DAT, SERT and NET,
respectively) and prevents the re-uptake of these monoamines into the presynaptic neuron (Ritz et al., 1987). Inhibition of re-uptake subsequently
elevates the synaptic concentrations of each of these neurotransmitters.
Primarily, it is the alterations in the DA circuitry that make cocaine one of
13
the most addictive drugs (Hummel & Unterwald, 2002). However, cocaine
is postulated to work as a dirty drug and its action at the DAT does not
merely account for the addictive properties. More specifically, it is the
balance between aversive properties at the NET, modulating at the SERT
and rewarding properties at the DAT that determines its effects (Uhl et al.,
2002). An unfortunate side-effect of cocaine, its cardiotoxicity, can be
ascribed to the activation of coronary α-adrenergic receptors, resulting in
vasoconstriction (Lange & Hillis, 2001).
Like amphetamine, cocaine was also used in warfare (World Wars I and II)
and like amphetamine, the negative effects of cocaine became clear in the
course of the 20th century. Whereas its acute effects are of shorter duration
than amphetamine, cocaine has strong addictive properties (Epstein et al,
2006). Additionally, cocaine can cause cardiotoxicity, such as ischemia and
infarctions, even after incidental use (Lange & Hillis, 2001; Frishman et al.,
2003). Cocaine became banned worldwide during the late 60s, early 70s.
Cocaine is a crystalline white powder and is mainly used in two forms, as a
base or as a salt, which are smoked or snorted respectively (King, 2009).
When snorted, it is absorbed by the nasal mucosa, and when it is smoked
it enters the bloodstream through the alveoli of the lungs. Different groups
of users are associated with these two ways of cocaine administration.
Whereas the smoked form (i.e. crack) is almost exclusively used by
problematic and marginalised dependent users, the snorted form is mainly
used by recreational users ranging from successful businessmen to
students, often in combination with alcohol (UNODC, 2011, EMCDDA,
2010). The lifetime and last month prevalence of cocaine use in The
Netherlands was 5.2% and 0.5% respectively in 2009 (van Laar et al.,
2011). Of all clients in drug addiction treatment in The Netherlands,
cocaine abuse and dependence makes up for 29% of cases as the primary
substance of abuse, ranking second after heroin (36%) and above
cannabis (26%). About half of these patients are snorting the substance,
whereas the other half is smoking cocaine.
14
Ecstasy
Ecstasy or “XTC” is the popular synonym for a group of phenetylamines,
including 3,4-methylenedioxy-N-methylamphetamine (MDMA), 3,4-methylene-dioxyamphetamine (MDA), 3,4-methylene-dioxyethylamphetamine
(MDEA) and N-methyl-a-(1,3-benzodixol-5-yl)-2-butamine (MBDB). MDMA
is by far the most common of these substances on the illicit street market.
It was first synthesized in 1912 by Merck without a clear purpose for use
(Saunders and Shulgin, 1993). Although a potent psychostimulant,
MDMA‟s effects are very different from those of amphetamine or cocaine.
In addition to a rise in wakefulness, energy and stamina, it produces an
effect that was previously unknown to most drug users; an “entagogenic”
feeling, described as a feeling of empathy, love, and closeness to others
(Nichols, 1986). Later on, it was rediscovered by psychotherapists to use it
for conditions of anxiety and depression (Riedlinger & Riedlinger, 1994).
MDMA interferes with monoamine neurotransmitter transporters, mainly 5HT (Liechti & Vollenweider, 2001). MDMA enters the presynaptic nerve
cells by binding to the SERT and reversal of the 5-HT transport via the
transporter (Rudnick & Wall, 1992). Alternatively, MDMA is able to release
5-HT from the intracellular storage through interaction with the vesicular
transporter. This release of serotonin is enhanced through the reversal of
the SERT, so that very high 5-HT levels are reached in the synaptic cleft
(Baumgarten & Lachenmayer, 2004). In the same way, MDMA also
activates DA release, but it is the action at the 5-HT system that is partly
responsible for its unique entactogenic effects. In addition, the pituitary
hormone oxytocin is also released by MDMA, which might be responsible
for its prosocial effects in users (Wolff et al., 2006; Thompson et al., 2007).
The 5-HT system has been most frequently described as responsible for
possible long term MDMA neurotoxicity (McCann et al., 1994; Ricaurte et
al., 2000; Gouzoulis-Mayfrank & Daumann, 2006; Baumann et al., 2007).
Subacute changes include depletion of 5-HT associated with a feelings of
depression (midweek ecstasy blues), whereas long term changes include
apoptosis of 5-HT axon terminals and persisting hypoinnervation patterns
in several parts of the brain (Hatzidimitriou et al., 1999). The effect of
15
MDMA on DA release have been implicated in the severe hyperthermia
which can occur sometimes (Docherty & Green, 2010). Whereas most
evidence comes from animal data, human ecstasy users might also show
residual damage, especially when their lifetime consumption was extensive
(Reneman et al., 2001, de Win et al., 2006; McCann et al., 1998, 2000).
Despite its moderate applications in psychotherapy (Riedlinger &
Riedlinger, 1994; Mithoefer et al., 2011), MDMA never got officially
recognized by the medical profession and it gained an illegal status in the
United States in 1985. Meanwhile, Europe was just starting to uncover
MDMA‟s effects, and by the end of 1980 it had become no less than a
revolution in the recreational drug scene, with the drug dominating most of
the dance and club cultures over the following two decades (Reynolds,
1999; Nabben, 2010). In line with its specific effects, it was quickly dubbed
the “love drug”. In contrast with amphetamine and cocaine, ecstasy does
not seem to have a high addictive potential (Nutt et al., 2007,2010; van
Amsterdam et al., 2010). However, there are some associated negative
effects, such as hyperthermia and possible neurotoxicity (McCann et al.,
1998, 2000; Reneman et al., 2001, de Win et al., 2006). Hyperthermia has
often been reported in ecstasy-related incidents, mainly because it is used
in crowded environments while dancing exhaustively (Parrott, 2004a).
Ecstasy is normally sold in tablet form, in a wide variety of colours, shapes
and with many different logos. In can also be sold as a crystalline powder,
and it is typically orally ingested by the users. It is rapidly absorbed and
within 30-60 minutes its subjective effects are experienced for about 4
hours (de la Torre et al., 2004). Its mainstream use progressed almost
completely synchronous with the emergence of the house and techno
music and the rave culture (Saunders and Shulgin, 1993). Given its
popularity in the dance culture of the 1990s, ecstasy is typically associated
with young adults (aged 18-24) (EMCDDA, 2011; van Laar, 2011). In The
Netherlands, the lifetime and last month prevalence in 2009 were 6.2% and
0.4%, respectively (van Laar, 2011). The average age of recent use in The
Netherlands was 28 years. In the recreational nightlife setting, ecstasy still
ranks as the most popular drug of choice, after cannabis (Doekhie et al.,
2010).
16
Aims and outline of this thesis
The DIMS covers all provinces and all major cities in The Netherlands.
Drug samples are tested on a weekly basis and data are available from the
early 1990s until the present. This allowed for a detailed monitoring of the
situation of the street drug markets and possible relations to health issues
that concurrently were detected. The main aims of this thesis are to
demonstrate:
(1) that drug monitoring can be used to identify risky substances in illicit
street psychostimulants;
(2) that monitoring of psychostimulants can be used to resolve some basic
health issues, that are difficult or impossible to resolve with more traditional
techniques used in pharmacological sciences;
(3) that drug monitoring is important for harm reduction and prevention;
(4) that drug monitoring has added value as a tool to aid drug health policy,
both nationally and internationally.
The thesis starts with a brief historical context of the Dutch harm reduction
policy and the emergence of the DIMS. This development is described in
chapter 2, together with a general overview of the methods that are used
in the DIMS and the monitoring results of the three main psychostimulant
drug markets, i.e. ecstasy, amphetamine and cocaine. For comparison,
alternative international drug monitoring systems are summarized,
including some of their main results. Finally, this chapter underlines that
illicit markets for psychoactive substances are very dynamic and drug
monitoring is discussed from the perspectives of policy, prevention and the
drug users.
In chapter 3, monitoring data of the DIMS from the beginning of the 1990s
are used to explain the increase in two health care outcomes, i.e. addiction
treatment and hospital admissions. To this aim, time fluctuations in the
market dynamics of cocaine and amphetamine are studied. Time-series
regression analysis is performed to establish the causal relationship
between price and quality of these drugs and the two health outcomes.
Data of health outcomes are taken from two independent patient
17
registration systems in The Netherlands: National Alcohol and Drugs
Information System (LADIS) and National Medical Registration (LMR). This
chapter aims to prove that DIMS data can be used to investigate drug
related phenomena over time.
In chapter 4, DIMS data are used to describe the purity and the presence
of adulterants in cocaine that is sold on the street. Subjective effects of
cocaine can be seriously affected by the presence of these adulterants. To
this aim, records of users‟ experiences of the drug‟s effects are used to
compare experienced adverse effects of adulterated cocaine with
unadulterated cocaine and adulterants associated with adverse effects are
further described.
In chapter 5, DIMS data are used to study the effect of a transient ecstasy
shortage in The Netherlands. Illicit drug markets are at least as complex as
regular markets for consumer goods, and are subject to many other
external influences. For example, law enforcement and its influence on
import or export of illicit drugs that were cropped somewhere else, such as
cocaine or cannabis. In contrast, drugs such as ecstasy are purely
synthetic and manufactured in Western Europe, mainly The Netherlands.
For this psychostimulant, precursor chemicals to manufacture the drug are
of paramount importance and availability of these precursors can be
seriously hampered by strong prohibitive action by the legal authorities. In
this chapter, the shortage of ecstasy (or MDMA) is related to the behaviour
of ecstasy users who visit the DIMS. Health concern and drug use patterns
in the light of a deteriorated ecstasy market are investigated using timeseries analysis, comparing the situation before, during and after the
shortage of ecstasy.
In chapter 6, DIMS data are used to study to effect of ecstasy shortage on
the emergence of substitutes for MDMA in ecstasy tablets in an effort to
see whether DIMS is able to detect new substances of abuse entering the
market. In this chapter, the new substances are evaluated from the
viewpoint of subjective effects, potential for abuse and possible
consequences for public health.
18
In chapter 7, DIMS data are used to link the psychopharmacological
content of tablets sold as ecstasy to the subjective effects reported by
ecstasy users. Much psychopharmacological literature has been devoted
to the subjective effects of ecstasy reported by drug users and the relation
with possible psychobiological or environmental predictors of these effects.
However, studies that examine the relationship between the
pharmacological composition of ecstasy tablets and subjective effects are
rare. Using the DIMS data base, the effect of MDMA dose and the
presence of other psychoactive substances in ecstasy tablets are related to
the reported subjective effects of these ecstasy tablets. This hopefully
contributes to a better understanding of the wide range of subjective effects
ascribed to ecstasy.
Finally, in chapter 8 the results of this thesis are summarized and some
methodological issues are briefly discussed. Also, limitations and
concluding suggestions for future research are given.
19
Chapter 2
The Drug Information and Monitoring
System (DIMS) in The Netherlands:
implementation, results and
international comparison
Tibor M. Brunt and Raymond J.M. Niesink
Based on:
Drug Testing and Analysis (2011), 3 (9): 621-634
Abstract
The Ministry of Health of The Netherlands has made illicit drug testing for
drug users possible since the nineteen nineties, in order to prevent serious
health hazards associated with unexpected dangerous substances. This
system of illicit drug testing is called the Drug Information and Monitoring
System (DIMS). In nearly two decades more than 100,000 drug samples
have been handed in at the testing facilities that are part of the DIMS. This
review describes the methodology of the DIMS and overviews results of
the three main psychostimulant drug markets that have been monitored,
i.e. ecstasy, amphetamine (speed) and cocaine. Additionally, monitoring
results of hallucinogens are also described for the first time. For
comparison, alternative international monitoring systems are described
shortly and some of their results. Finally, drug monitoring is discussed from
the perspectives of policy, prevention and the drug users themselves.
Introduction: Dutch drug policy
From a historical point of view, drug policy and legislation on drug use in
The Netherlands is substantially different from that in many other countries.
The aim of Dutch policy is to reduce both the demand for and the supply of
drugs, and to limit the risks of drug use. One of the main features of Dutch
policy on drugs is harm reduction, i.e. preventing drug use and limiting
risks and harm to users and the people with whom they associate. This
policy is based on recognition of the fact that, in an open society, drugs are
quite simply available, and therefore (problematic) drug use is also
unavoidable [Mensink & Spruit, 1999]. In The Netherlands it is an offence
to produce, possess, sell and import or export drugs, although it is not
considered an offence to use them. Preventive strategies are aimed to
reduce the demand for drugs, while professional care limits the harm they
cause to users and the people they associate with. To cut off supplies the
authorities are cracking down on organized crime. Because in The
Netherlands drugs are primarily regarded as a health issue, the minister of
Health is responsible for the overall coordination of policy on drugs. The
23
central objective of the Dutch drug policy has already been formulated in
the seventies of the past century. As in many Western countries, the drug
problem in The Netherlands underwent a fundamental change at the end of
the 80‟s, beginning of the ninety nineties. In the slipstream of the
increasingly popular rave scene the popularity of synthetic drugs such as
ecstasy grew rapidly. Ecstasy became popular due to its non-addictive
properties and euphoric effect.
The Dutch drug policy in the early nineties was characterized by great
uncertainty about the substances being used, the user groups, and the
risks [de Kort & Kramer, 1999; Spruit, 1999]. Use of the new synthetic
drugs involved effects and risks that were different from those associated
with the traditional substances of abuse. Instead of addiction, the most
important risks became acute and chronic damage to the user's health.
However, the risks that these new substances posed to health varied
considerably, depending on their contents, the settings in which they were
taken and individual factors. The characteristics of the new drug users
were also very different from those of the traditional drug addicts [Parker et
al., 1999]. Users of synthetic drugs were not marginalized, deviant young
people who had adapted lifestyles revolving around drug use. The new
psychotropic substances were consumed on an incidental, recreational
basis by young people who did not differ from non-users in most respects.
In fact, the only similarity with the previous decade was that the drugs
being used were also psychoactive substances.
During the nineties and at present, besides using new synthetic drugs, the
new generations of recreational drug users also started to embrace more
traditionally abused drugs, like cocaine [Nabben, 2010]. Because of its
psychostimulant properties, not that different from amphetamines, and it
had an image of an associated successful and prosperous lifestyle.
Because cocaine use poses its own unique array of health risks, especially
when as casually used by the recreational users as synthetic drugs, and
cocaine
as
traditionally
adulterated
substance
with
various
pharmacological compounds, the widespread use of it has added an
additional concern to the health authorities in The Netherlands.
24
The Ministry of Health developed information material aimed at
discouraging young people from using ecstasy and other drugs associated
with the nightlife settings [Spruit, 1999]. Specific measures were
propagated to prevent or deal with problems caused by drug use at dance
venues, raves and clubs, such as good ventilation, the presence of first aid
teams and availability of free drinking water [Pijlman et al., 2003]. The
scale in which they were used and the specific risks that the range of new
recreational drugs brought about, such as the lack of certainty about their
dosage and composition, made the government decide to monitor this
market adequately [Spruit, 1999, 2001]. Illicit drug market monitoring was
deemed necessary for surveillance, in order to detect acutely hazardous
substances, dosages or situations at an early stage of appearance on the
drug market.
The Drug Information and Monitoring System (DIMS)
From the viewpoint of harm reduction and prevention, it was essential to
gain knowledge about the appearance of new risky substances on the drug
market and to take decisive preventive action. To enable the monitoring of
the rapid changes on the market for recreational drugs adequately, testing
services were set up where users could have the composition and dosage
of their XTC tablets and other drugs tested. These testing services,
provided within the framework of the national Drug Information and
Monitoring System (DIMS), offer valuable insights into the dynamic
recreational drug market, particularly for policy makers. Additionally, it
enables prevention activities to be expanded towards a group of drug users
that would normally not be reached. The testing facilities of the DIMS
network are usually embedded in the prevention departments of institutions
for the care of addicts. Traditionally, these departments have much
experience in prevention activities on the very problematic level of drug
addicts, recreational drug users were not seen by these institutions. Since
the foundation of the DIMS, users are frequently warned about the health
risks associated with recreational substances. The authorities will act
immediately when dangerous drugs are in circulation. Depending on the
severity of circumstances, the network of testing facilities will be alerted,
25
flyers are distributed at clubs and rave venues and/ or warnings are
published in the regional or national press [Spruit, 2001].
A nationwide network of test facilities at drug prevention institutions in
different places in The Netherlands takes part in the DIMS. Drug users
hand in ecstasy tablets or other preparations anonymously for a test. The
personnel working at these testing facilities are health and prevention
professionals, they communicate about the effects of the particular
substances and their associated risks. A few of the participating institutions
are merely receiving stations and directly send all the samples they receive
to the DIMS Bureau at the Trimbos Institute and do not offer the
opportunity for identifying any tablets at their own offices. However, most of
the testing facilities are able to identify some of the tablets at the moment
they are handed in by the drug user. This is referred to as 'office testing'.
“Office testing”
First the outward characteristics of tablets are registered, including
diameter, thickness, weight, colour, presence of a groove, light or dark
speckling (if present), and any logo visible (and its design). Second, a
Marquis reagent test is performed to find out whether a tablet contains any
ecstasy-like substances, amphetamine, a hallucinogenic compound, or
none of these. The next step is to determine whether information is already
available about the specific tablet based on these external characteristics
and results of the Marquis test. This is done with the help of an online
electronic database which is updated weekly by the DIMS Bureau. The
database contains features of all (ecstasy) tablets that have recently been
analyzed in a laboratory. Because of this weekly input of information on
tablets and because of the fact that ecstasy tablets are usually produced in
large batches, certain tablets can be determined and recognized through
this specially developed and weekly updated database on the DIMS
website,
the
„recognition
list‟.
The
average
MDMA
(3,4methylenedioxymetamphetamine) content and the variation of the tablet
are then known, and the tablet does not have to be analysed necessarily in
the laboratory. When the consumer decides to have the tablet analyzed in
the laboratory anyway, its analysis results can be used for validation of the
26
recognition list. This has shown a 99% reliability of the recognition list.
Therefore, this “office testing” recognition system provides the testing
facilities throughout the country with a tool to give the drug consumer an
immediate and accurate test result, without having to hand over the actual
tablet. On average, 30% of tablets are determined this way.
Tablets that are not recognized by this on-line determination system and
those about which doubt exist together with other drugs samples such as
powders, capsules and liquids are forwarded to the DIMS Bureau at the
Trimbos Institute. When possible, additional information, such as the place
of purchase, the price that was paid and the consumer's knowledge and
opinion of the product is added. Finally, at the testing facility, a unique
individual number is given to the drug consumer by which he or she is able
to communicate the particular drug sample‟s test result one week later. At
the DIMS Bureau itself, all samples received are registered, and details are
carefully re-examined for possible re-assessment of the determination that
was done by the testing facilities. Basically, all samples received by the
DIMS Bureau are then coded, packaged and transported to the laboratory
for full chemical analysis (see Figure 1 for a scheme of the DIMS system).
DIMS website
drugs
Test facilities/
DIMS network
Analysis results
consumer
DIMS-bureau
Laboratory
Figure 1. A schematic representation of the DIMS system.
Laboratory analyses
Qualitative and quantitative analyses of the drugs samples that have been
sent to the DIMS Bureau were performed in the laboratory of the Delta
Psychiatric Hospital (Deltalab, Poortugaal, The Netherlands), which
specializes in analyzing drug samples. A set of robust analytical methods
was used to identify known and unknown components, to quantify and
classify them. After crushing and homogenizing the sample, three separate
analytical techniques were used. First, thin layer chromatography
27
(Toxilab®A) was performed for identification. Therefore, a small part of the
sample (approximately 2 mg) was concentrated on a Toxidisc®, placed in
the chromatogram and developed according to the Toxilab®A procedure.
The analytes were identified by relating their position (RF) and colour to
standards through four stages of detection: a colouring stage I (Marquis
reagent), a washing stage II, an UV fluorescence stage III and finally a
colouring stage IV with Dragendorff‟s reagents. The Toxilab® methodology
including three reference samples provides a robust identification
[Goldschmidt, 2004]. An extensive library enables the chromatographer to
check on correct location of spots as well as the identification of new
substances.
Subsequently, the quantification of the main components (e.g.
amphetamine,
metamphetamine,
3,4-methylene-dioxyamphetamine
(MDA), 3,4-methylene-dioxyethylamphetamine (MDEA), N-methyl-a-(1,3benzodixol-5-yl)-2-butamine (MBDB), caffeine, cocaine and heroin) was
performed with gas chromatography - nitrogen- phosphorous detection
(GC-NPD). The samples were pretreated: after being crushed, 25 mg
sample was ultrasonified in 0.01 M HCl. An internal standard was added
(Chirald, Sigma-Aldrich, Zwijndrecht, The Netherlands); thereafter a liquidliquid extraction was performed with Toxitube®A, a diluted sample of the
extract was used for the cold-on-column injection on the GC-column
(WCOT-CP-Sil-8-CB, length 25 m, id 0.32 mm df 0.25 μm). The total
runtime was 12-28 minutes on a programmed time - temperature scale (75
- 280 °C) with nitrogen-phosphor-detector and helium as carrier gas. The
two methods were running independently and were used as a mutual
confirmation. In case of any discrepancies, or trace amounts requiring
quantification, a gas chromatography-mass spectrometry (GC-MS) method
was introduced as the tiebreaker. This generally needed to be done in
approximately 10% of the samples. GC-MS (Varian Saturn 4D, Varian
Medical Systems, Houten, The Netherlands) conditions were similar to GCNPD and substances were identified full scan (EI) with the NIST-library.
GC-MS was also used for quantification of certain uncommon substances
(e.g.
γ-hydroxybutyrate
(GHB),
γ-butyrolactone
(GBL),
paramethoxyamphetamine (PMA), para-methoxymethamphetamine (PMMA),
28
ephedrine, ketamine and lysergic acid diethylamide (LSD)). In exceptional
cases, identification was performed using advanced GC-MS and nuclear
magnetic resonance (NMR) spectroscopy structural analysis (e.g. 2,5dimethoxy-4-bromophenethylamine
(2C-B),
2,5-dimethoxy-4bromoamphetamine (DOB) and 4-methylthioamphetamine (4-MTA)).
Combining different routes for clarification and quantification leads to a
growing list of identified compounds in illicit drugs found over the years
(Fig. 2).
Yes
Identification retention time,
mass spectrum list
identified compounds
List identified compounds,
on the basis of certified
standards
No
Yes
List unknown compounds,
mass spectra stored in
database
Identification retention time,
mass spectrum list
unknown compounds
No
Yes
Previously unseen
unknown compound
Clarification with mass spectrometry or
NMR spectroscopy
Figure 2. A flowchart representing the procedure of clarification of
substances by the laboratory.
Drug users
An important difference between the DIMS and other ways of collecting
toxicochemical data on drug samples, such as drug seizures by the police,
is the fact that data are collected directly on the user‟s level and there is
contact with the users. With the DIMS, this means there is information
exchange between the personnel at the testing facilities and the users.
29
Most important information, such as personal adverse effects, or adverse
effects experienced by friends, with the drug sample in question is inputted
and saved in the DIMS database. Other important inputs in the database
are regional origin, date, source of purchase, price and reason for testing.
Other relevant information may be added by the testing personnel, but
anonymity of the drug user is always guaranteed, one of the main
conditions to keep the DIMS system trustworthy for drug users. The
information supplied by the users is often crucial in determining which
substance is associated with unexpected risks and in which part of the
country these risks may possibly occur. From the perspective of the
institutions for addiction and mental health care that provide the testing
facilities it is important to have one-on-one contact with young, recreational
drug users as target for their prevention and harm reduction activities.
There have been at least two studies that attempted to describe the users
that utilize the DIMS as a test facility for their drugs [Benschop et al., 2002;
Korf et al., 2003]. These suggested that users utilizing testing systems are
broadly similar to non-testing users. We can therefore consider the target
group of the DIMS system as a reasonable reflection of all recreational
drug users. The vast majority of drug users that visit the DIMS testing
services are youths or men with an ethnic Dutch background who are
engaged in paid employment or study. The group includes both
experienced users who take ecstasy every week and less experienced
ones who just take it occasionally. As well as taking ecstasy, they report
considerable experience with alcohol, tobacco and cannabis, and to a
lesser extent also with cocaine and other drugs. Most of them have no
experience with heroin or basecoke. The most common lifetime pattern of
ecstasy use involves increasing amounts taken up to a peak of use,
followed by a decline to a somewhat lower level. The average dose is two
tablets per occasion. If ecstasy is taken in combination with another
substance, it is usually alcohol, and, to a lesser extent, cannabis. Tablets
are usually bought from a friend or a known dealer some time before a
night out. Buying ecstasy, knowing the dealer is considered far more
important than obtaining tablets with a familiar logo or colour. Visitors of the
test facilities were also asked about the main reason why they have their
30
drugs tested. The majority answered curiosity about the results, followed
by health concern and circulating warnings about dangerous drugs. With
regard to the attitude towards prevention and harm reduction, the testing
systems were seen as a very reliable source of information and users also
appreciated this way of contact with prevention organizations [Benschop et
al., 2002; Korf et al., 2003].
The DIMS results are not, by definition, an exact representation of the
ecstasy market in The Netherlands. The DIMS monitoring system depends
on drug samples handed in by users, and will therefore not be an exact
reflection of the use and availability of drugs on the market. However, the
DIMS is a qualitative monitor that does not focus on the precise number
(quantity) of specific tablets or other drugs on the market, but on the
contents (quality, chemically and toxicologically) of drug samples.
However, a study comparing drug samples as delivered at the DIMS with
those obtained from police seizures at dance venues and rave parties,
showed that the DIMS results in fact provide a fairly accurate picture of the
total Dutch ecstasy market at consumer level [Vogels et al., 2009].
Monitoring results
Since the DIMS was set up in 1992, the Dutch illicit drug market has now
been monitored for almost two decades. In particular DIMS follows
movements of ecstasy, amphetamine and cocaine and to a lesser extent,
of synthetic hallucinogens on the market. Cannabis products,
hallucinogenic mushrooms and doping-related substances such as
anabolic steroids are not systematically monitored. For cannabis-related
products, DIMS has a different monitoring system [Pijlman et al., 2005].
Here we will discuss the DIMS results of the contents of ecstasy,
amphetamine, cocaine and LSD drug samples over the past 18 years.
More specific details for ecstasy may be found in Spruit, 2001 and Vogels
et al., 2009 and for amphetamine and cocaine in Brunt et al., 2009, 2010.
31
12500
10000
7500
5000
2500
0
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Not analyzed
Tablets recognized
Tablets analysed
Capsules
Liquids
Miscellaneous
Powders
Figure 3. Number of drug samples per year delivered at DIMS between
1993 and 2010. Data reflect pharmaceutical appearance.
100%
75%
50%
25%
0%
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Tablet
MDMA
Amphetamine
Other/unknown
Cocaine
Miscellaneous
Figure 4. Relative contribution of tablets, amphetamine, cocaine, XTCpowders and other drugs delivered at DIMS between 1993 and 2010 that
have been analyzed in the laboratory.
32
It is well-known that The Netherlands has been an important country for the
illegal production of amphetamine and ecstasy for many years [UNODC,
2008], and it seems reasonable to assume that most ecstasy and
amphetamine on the Dutch consumer market comes directly from this
illegal production. This contrasts with cocaine, which is exclusively
obtained through illegal imports. Large changes in the composition of
amphetamine and ecstasy are therefore often a direct reflection of changes
in production processes, such as shortages of precursors or other
chemicals. In contrast, changes in the composition of cocaine could be
explained by law enforcement activities affecting export and import.
As for the overall results of the monitor, a combined total of more than
100,000 drug samples have been handed in at the DIMS since 1992 until
July 2010. The vast majority of these samples were tablets, falling into the
categories “recognized” or “analyzed by the laboratory” (Fig. 3). Figure 4
shows the proportion of tablets, powders and other drugs (liquids,
capsules, papertrips) that have been analyzed in the laboratory between
1993 and 2010. Powders make up the largest part of the rest of the drug
samples, these comprise mainly MDMA-, speed- or cocaine powders.
Liquids, capsules or miscellaneous forms of drug samples only make up for
a very small percentage of the total.
Ecstasy
There is a difference between what in pharmacological literature is defined
as ecstasy and what is called ecstasy by drug users. Pharmacological and
chemical scientific literature defines ecstasy as 3,4-methylenedioxy-Nmethylamphetamine (MDMA) [Segen, 2002]. When epidemiological or
socio-scientific research refers to ecstasy, preparations are meant that are
known to the interviewees by that name. By no means everything that is
sold as ecstasy is MDMA [Vogels et al., 2009; Parrott, 2004]. In the
beginning of the nineties, MDMA, MDEA and MDA were the substances
most frequently found in tablets bought as ecstasy (Fig. 5).
MDMA, MDEA and MDA, often referred to as ecstasy-like substances, are
substituted methylenedioxyphenethylamines, a chemical class of
33
derivatives of the phenetylamine group, to which group also amphetamine
belongs. Apart from MDMA, MDEA and MDA, MBDB, or "Eden", also
belongs to the group of methylenedioxyphenethylamines (see Fig. 6 for
chemical structure formulas).
The use of MDMA in The Netherlands was first reported in 1985 [Konijn et
al., 1997]. MDMA induces the so-called entactogenic effect [Nichols, 1986].
MDMA and MDA hardly exert any hallucinogenic effects and MDA causes
nothing more than light illusory perceptions and distorted images. MDEA
has a stronger stimulating effect than MDA and MDMA, but a weaker
entactogenic effect.
The most common form of MDMA incorporated in ecstasy tablets is the
hydrochloride salt. It is a white powder that is easily soluble in water.
Ecstasy products on the market are seen typically as tablets with a
characteristic logo, less commonly as powders, capsules, liquids or
crystals. A typical ecstasy tablet contains between 80 and 100 mg of
MDMA. From the literature, it may be concluded that people take anything
from half a tablet to several tablets per evening or weekend [GouzoulisMayfrank et al., 2000; El-Mallakh et al., 2007]. If these figures are used as
a reference mark, the recreational doses taken by users amount to 0.5-4
mg/kg, distributed over many hours and sometimes several days. In some
cases, peak use can be as high as 10 mg/kg. What people take and how
much they take depends, however, on factors such as the effects they
want to achieve, their degree of experience and the actual, often unknown,
composition of the tablets.
34
Figure 5. Composition of tablets sold and bought as ecstasy handed in at
DIMS per year, a number of novel substances found are given at the top of
the figure, in order of appearance through time.
35
Figure 6. Chemical structures of the methylenedioxyphenethylamines:
MDMA, MDA, MBDB and MDEA.
Figure 5 summarizes the composition of tablets sold as ecstasy as
analyzed by DIMS in the laboratory throughout 1993-2010. The picture
shows that there have been two periods during which many tablets
contained other substances in addition to or instead of MDMA. In and
around 1997, many ecstasy tablets contained amphetamine and in and
around 2009 many tablets contained meta-chlorophenylpiperazine (mCPP)
instead of or in addition to MDMA. At the peak of the shortage of MDMA, in
October 1997, only 30% of the ecstasy tablets handed in at the DIMS
contained MDMA or a MDMA-like substance. The peak of shortage of
MDMA in 2009 was in March, with only 40% of all ecstasy tablets
containing MDMA.
MDEA and MDA, which were present in about 30% of the ecstasy tablets
before 1997, have virtually disappeared from the ecstasy market; MDEA
and MDA were never present in substantial amounts, since 1997.
Sporadically, nowadays, only small amounts of MDEA and MDA are found
in combination with MDMA in tablets. Apart from the marked decline in the
number of tablets containing MDMA-like substances, the periods around
36
1997 and 2009 are characterized by the appearance of other psychoactive
substances in tablets sold as ecstasy, e.g. MBDB, 2C-B, atropine, 4-MTA,
PMA around 1997 and mCPP and mephedrone around 2009 (Fig. 5). The
appearance of PMA was accompanied with a national warning campaign in
The Netherlands, since this is a much more hazardous substance as any
MDMA-like substance, with a steep dose-response curve [Jaehne et al.,
2007]. In the late 1990s, PMA appeared in ecstasy tablets all over the
world and caused numerous emergencies and even deaths [Kraner et al.,
2001; Schifano et al., 2003a; Dams et al., 2003; Refstad, 2003].
Between 1996 and 2001 less than 50% of the ecstasy tablets contained
more than 70 mg MDMA; the same applies for 2009, when only 42% of the
tablets sold as ecstasy contained more than 70 mg MDMA per tablet.
Before 1997 and between 2000 and 2009, more than 50% of the ecstasy
tablets contained more than 70 mg MDMA per tablet.
Speed
In the nineteen thirties amphetamine was marketed as a nasal inhaler to
shrink mucous membranes under the trade name BenzedrineTM. Early
users of the Benzedrine inhaler discovered that it had a euphoric stimulant
effect, which resulted in becoming one of the earliest synthetic stimulants
widely used for non-medical (recreational) purposes [Rasmussen, 2009].
Speed and pep are the street names for amphetamine, like XTC and
ecstasy are street names for MDMA. In The Netherlands, amphetamine is
a controlled substance since 1976 [Buisman, 2000]. The proportion of the
people in The Netherlands that recently used amphetamine, as well as the
lifetime prevalence of the general population of twelve years and older, is
quite low and relatively stable, in 2005 0.3 and 2.1 percent respectively
[van Laar et al., 2010]. In the mid-nineties of the last century there has
been a temporary increase of amphetamine abuse. In that period, speed
became especially popular among certain subgroups of partygoers. They
often distinguished themselves from others by music preference (hardcore)
and dress [ter Bogt, 1997; Doekhie et al., 2009]. Because amphetamine
(speed) is much cheaper than cocaine (coke), it was previously also known
as "coke for the poor". Methamphetamine is closely related to
37
amphetamine. In Thailand, tablets containing methamphetamine are sold
as Yaba [APAIC, 2010]. Yaba is much stronger and is much longer acting
than amphetamine. In The Netherlands, recreational use of amphetamine
is much more common than abuse of methamphetamine; in fact,
methamphetamine use is very uncommon.
Unlike MDMA, amphetamine has no entactogenic properties. The
recreational user of amphetamine seeks the mental and physical
stimulation which it produces. The desired effects usually last up to four
hours and as the effects begin to wear off may be succeeded by a period
of restlessness, anxiety, fatigue, disinterest or tiredness [Rasmussen,
2009]. Some users seek the stimulating properties of amphetamine for
other purposes. Those in monotonous occupations may abuse
amphetamine in the workplace and students may use the drug to decrease
tiredness, enabling studying for long periods of time [Rasmussen, 2009].
Amphetamine is a member of the phenethylamine family. As an illicit drug,
amphetamine is mostly found as a sulfate salt, which is a white powder,
easily soluble in water. Although amphetamine appears in tablets with
logo‟s similar to ecstasy, on the street amphetamine is mostly sold in
powder form and like cocaine, it is often snorted [van Laar et al., 2010].
When snorted or ingested, a dose may vary from several tens to several
hundreds of milligrams depending on the purity and the individual tolerance
for the drug.
Between 1992 and July 2010, 8,239 powder samples bought as speed
have been handed in at the DIMS. In about 85% of these samples, the
amount of amphetamine was high enough for quantification. Thus, over the
years, 15% of the speed powders did not contain a quantifiable amount of
amphetamine. Between 1997 and 2001, the percentage of samples that
did not contain quantifiable amounts of amphetamine was over 20 percent,
reaching a peak of over 40% in 1999. Until 1996, the number of speed
samples delivered to the DIMS was hardly high enough to describe the
speed market. Since 1996, the number of samples increased to over 10
samples per month from 1996 until 1999, and since 2000 on average more
than twenty samples per month were handed in. In 2008 and 2009, more
than sixty samples per month were received at the DIMS.
38
The analyzed speed powders that were handed in between 1995 and
2010, with detectable amounts of amphetamine, contained on average
30% pure amphetamine (30.2 ± 0.2%; mean ± SEM). Between July 1998
and April 2001, the mean amount of amphetamine decreased to less than
20% with an absolute low in January 2000 of less than 5%. Simultaneously
with the decrease in amphetamine concentration, the amount of caffeine in
speed powders increased (Fig. 7). The purity of speed, expressed as the
mean percentage of amphetamine, seems to follow an inverse relationship
with the percentage of caffeine over time, with the mean percentage of
amphetamine in a powder being high, the percentage of caffeine being low
and vice versa.
80
60
40
0
1993-3
1994-1
1994-3
1995-1
1995-3
1996-1
1996-3
1997-1
1997-3
1998-1
1998-3
1999-1
1999-3
2000-1
2000-3
2001-1
2001-3
2002-1
2002-3
2003-1
2003-3
2004-1
2004-3
2005-1
2005-3
2006-1
2006-3
2007-1
2007-3
2008-1
2008-3
2009-1
2009-3
2010-1
20
Amphetamine
Caffeine
Figure 7. Mean percentage of amphetamine and caffeine in speed
powders per year (quartiles indicated by scaling lines on axis). Only
powders containing quantifiable amounts of amphetamine (>1%) have
been included.
39
A similar phenomenon as in 1999 occurred in 2008/ 2009, with declining
amphetamine percentages and increasing caffeine percentages. This time,
an absolute low was reached in December 2008, with a mean percentage
of amphetamine of 18% and a mean percentage of caffeine of 60%. The
amount of samples handed in did not drop, and neither did the percentage
of samples not containing quantifiable amounts of amphetamine.
The most common route of synthesis for amphetamine is by the Leuckart
method [Rasmussen, 2009]. This method uses benzylmethylketone (BMK,
1-phenyl-propanone) as a precursor. Around 1999 and in 2008 and 2009,
there were shortages of this amphetamine precursor in the illegal drug
production circuit. Therefore, it became extremely difficult to produce
amphetamine. The available speed powders hardly contained
amphetamine and were much more cut with caffeine. Caffeine is often
added to amphetamine at the production source, whereas other cutting
agents, such as glucose and other sugars are usually added elsewhere
[UNODC, 2008]. Unlike MDMA, a shortage of amphetamine on the illegal
drug market does not seem to cause the appearance of “new”
psychoactive compounds in speed powders. However, the transient
shortage of amphetamine in 2008/2009 caused the appearance (and
disappearance) of two psychoactive substances: 4-fluoroamphetamine and
4-methylamphetamine (not to be confused with methylamphetamine),
substances that had not been seen in speed powders before (see Fig. 8 for
chemical structure formulas).
40
Figure 8. Chemical structures of amphetamine, methamphetamine, pfluoroamphetamine and p-methylamphetamine.
Cocaine
Cocaine is a natural product extracted from the leaves of Erythroxylon
coca. Cocaine has a psychomotor stimulant effect similar to that of
amphetamine. Cocaine base and the hydrochloride salt are white powders
[King, 2009]. In recreational use, cocaine is typically snorted whereby it is
absorbed through the nasal mucosa.
Since 1993 DIMS received cocaine powders; in the early nineties, on
average between 5 and 10 samples per month, but in subsequent years
this number quickly increased. Since 2004, more than 50 samples per
month were handed in. Of the powders that were sold as cocaine
averagely 10% did not contain quantifiable amounts of cocaine. The
remaining powders contained 56 ± 0.3% (mean ± SEM) pure cocaine. In
the nineties (1993-1999), the average purity was higher than in the past
decade (2000-2010), 66.3 ± 0.7% (mean ± SEM) versus 54.9 ± 0.8%
(mean ± SEM) respectively. Often adulterants are added to increase
weight, and sometimes other, mainly less costly substances are added to
make up for lost potency [Fry & Levy, 2009]. Alternatively, adulterants are
added to camouflage the decrease in potency of the cut up cocaine,
41
usually other local anesthetics, which produce the same numbness to the
gums as cocaine, thereby creating the false impression to the consumer of
high purity. The cocaine powders that were handed in at DIMS were cut
with a variety of substances: inert compounds (mannitol, maltose, inositol,
flour, starch), synthetic local anesthetics (lidocaine, benzocaine, procaine,
tetracaine) and other pharmacologically active substances (caffeine,
phenacetine, levamisole, hydroxyzine, diltiazem) [Brunt et al., 2009].
75
50
25
0
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
No pharmacologically active substances
Pharmacologically active substances
Figure 9. Mean percentage of cocaine (purity) in cocaine powders
containing pharmacologically active adulterants and samples not
containing pharmacological adulterants. Only powders containing
quantifiable amounts of cocaine have been included.
Approximately 10% of all cocaine samples contained a synthetic local
anesthetic. The average amount of pure cocaine in these samples (44.6 ±
0.9%; mean ± SEM) was significantly lower than in the samples not
containing a synthetic local anesthetics (57.0 ± 0.3%; mean ± SEM).
42
Similarly, cocaine cut with other pharmacologically active substances also
contained less pure cocaine (38.8 ± 0.4%; mean ± SEM) than cocaine
powders that did not contain these substances (62.1 ± 0.3%; mean ± SEM)
(see Fig. 9). Apparently, all of these adulterants were added for
compensatory purposes as mentioned above. Table 1 summarizes the
major pharmacologically active substances found in DIMS cocaine
powders during the last five years (2005-2009). Atropine was found in
2005, and again in 2007. The presence of atropine in cocaine was
accompanied by several hospitalizations and even fatalities in both
occasions, in The Netherlands and across the border (Italy, France,
Germany, Belgium) [EMCDDA, 2007; Braida et al., 2008]. In situations as
these, it is a vital part of the surveillance function of the DIMS to
immediately orchestrate a national mass media warning to warn the
(potential) users and furthermore, to alert the international network of early
warning systems throughout the EU.
Table 1 Psychoactive compounds most commonly found in DIMS cocaine
powders (2005-2009).
Phenacetin
Levamisole
Caffeine
Lidocaine
Procaine
Diltiazem
Hydroxyzine
Benzocaine
Diphenhydramine
Tetracaine
Atropine
Present in % of
samples
Mean ± S.E.M.
38
21
15
8
7
6
3
0.4
0.1
0
0
25.5 ± 1.3 (n=956)
7.4 ± 0.3 (n=338) 1)
9.0 ± 2.6 (n=502)
n.q.
n.q.
n.q.
n.q.
n.q.
n.q.
n.q.
2.0 ± 3.0 (n=5)
N.q., not quantified; n,number of samples quantified;
43
1)
Data from 2010.
LSD and other hallucinogens
Of all hallucinogens, lysergic acid diethylamide (LSD or “acid”) is the most
prevalent handed in at the DIMS. LSD samples are usually papertrips,
taken from greater formats of colourfully decorated paper. The LSD is
impregnated into the paper at a certain concentration, which does not have
to be equally spread among individual papertrips taken from one original
sheet of paper. The other form in which LSD is handed in at the DIMS is as
microdot. This is a minute tablet, usually weighing less than 10 mg, without
logo or much other specific characteristics. Most microdots are coloured
uniformly black.
In The Netherlands, LSD is used by small subpopulations of users and in
other settings as the mainstream clubs or events where ecstasy or cocaine
are used. One subpopulation is often referred to as the “psychonauts”; the
experimental drug users that are interested in exploring new psychological
avenues in the brain as well as going out and listening to dance music
[Schifano et al., 2003b]. This dance music is often another style (e.g.
psytrance, a psychedelic type of dance music) than the more mainstream
dance music played at big clubs or events [Nabben, 2010]. Because LSD
is used in the busy and noisy setting of a dance party, the dosages used
nowadays tend to be considerably lower (20 – 125 μg) than the dosages
that were reported in the 1960s and 1970s (300 – 2000 μg; [Henderson &
Glass, 1994]). This reduces the risk of a negative mental experience or
“bad trip”, while undergoing LSD‟s specific effects.
At the DIMS, first numbers of LSD samples were handed in around 1999.
In that year, only 6 samples were handed in that were sold as LSD. This
increased to 10 samples in 2000 and 12 in 2001. From 2002 and onwards
the amount of LSD samples handed in at the DIMS became more and
more substantial, with a peak of 99 samples in 2003 and a 66 samples for
the first half year of 2010. Based on these numbers, something can be said
about the LSD market, at least on an annual basis. Around 80% of the
samples that were sold as LSD contained the hallucinogenic substance
(Fig. 10). An exception was 2002, when only 26% of all LSD samples
contained the hallucinogen, in the rest of the samples the concentration
44
was either not quantifiable or traces of other compounds were found, such
as methamphetamine or DOB. In 2007, some papertrips were handed in
containing fentanyl, a very potent synthetic opioid, which led to a special
warning campaign, directed at the small target group of LSD users. The
average concentration LSD ranged from 20 μg to 96 μg/ unit (unit meaning
either papertrip or a microdot) (Fig. 10). However, the variation in LSD
concentration was substantial: from 1 – 500 μg/ unit. This wide spread in
concentration between units probably represents two extremes of the
market: the low dosages, probably being used at nightlife settings, such as
dance parties and raves, whereas the higher dosages might come from the
more experienced users that take LSD in a more secluded, private setting
[Erowid, 2010a].
Fentanyl
DOB
2C-B
120
100
80
60
40
20
% of samples contained LSD
average (in μg/unit)
0
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
Figure 10. Percentage of samples containing LSD of all samples that were
sold as LSD and the average concentration of LSD per trip (papertrip or
microdot), 3 substances found in samples sold as LSD are given at the top
of the figure, in order of appearance trough time.
There were only a few other hallucinogens handed in at the DIMS with 2CB being the most prevalent one after LSD. Initially 2C-B was sold as small
tablets, with concentrations between 1-15 mg 2C-B per tablet. During the
45
second half of the 2000s, 2C-B was frequently found in tablets sold as
ecstasy and these tablets highly resembled ecstasy tablets, with different
logo‟s, shapes and colours. Recently, 2C-B was also encountered in LSD
papertrips (Fig. 10). Concentrations 2C-B rarely exceeded 5 mg per
sample (tablet or papertrip). Other hallucinogens that have been found by
the DIMS were on sporadic basis and comprised 2,5-dimethoxy-4ethylthiophenethylamine (2C-T-2 and 2C-T-7), N,N-Dimethyltryptamine
(DMT),
5-methoxy-diisopropyltryptamine
(5-MeO-DiPT)
and
Dextromethorfan (DXM), among others.
Other drug markets and monitors
Illicit drug testing in order to gain insight in certain drug markets for health
or even law enforcement purposes is nothing new. Usually, information
concerning the contents of illicit street drugs comes from the various
national forensic institutes that are situated in most countries. These
forensic institutes often receive parties of drugs that have been seized by
the police, either at customs, clandestine production facilities or directly
from consumers at local events. Actually, this is no different in The
Netherlands, were the National Forensic Institute provides important
information about the drug market in addition to the DIMS system. The
presence of two independent systems offering quantitative and qualitative
information about the state of the illicit drug market makes for an ideal
situation to compare and validate results. It also adds to a more complete
picture of the illicit drug market and allows to specify which parties of drugs
were distributed domestically and which were probably meant for export.
Regardless the advantages, most countries do not have an additional
direct costumer-derived information source of the illicit drug market,
besides the seized samples.
However, besides The Netherlands, there are other nations assembling
illicit drug market data from additional sources than the forensic institutes,
like the French National Identification System for Drugs and Other
Substances (SINTES) in France, a combination of police and customs‟
seizures and samples obtained directly from the consumers by social field
workers [Giraudon et al., 2007]. TICTAC in the United Kingdom, which
46
utilizes amnesty bins from large clubs and venues in some major British
cities to describe the chemo-analytical contents of the drugs in these bins
[Ramsey et al., 2001; Kenyon et al., 2005]. There is the “on-the-spot”
dancefloor High Performance Liquid Chromatography (HPLC) analysis by
the Check-It team from Vienna, Austria, and in Switzerland there is the
Safer Party© initiative, collecting samples from the users directly through
fieldwork contacts [EMCDDA, 2009; Helmlin, 2010]. Their analysis
procedure is based on an automated HPLC for the separation process
[Helmlin, 2010]. These HPLC systems are equipped with DAD/UV-Vis
Spectrometers (DAD=Diode Array Detector) and autosamplers and
analysis results can be obtained within 20 minutes, making it useful for
testing on the dancefloor. In the United States there is the DanceSafe
website, they test drugs and make the test results public to the potential
consumer audience [Tanner-Smith, 2006; Dancesafe, 2010]. It more or
less seems to work according to the way the DIMS recognition list works
(see paragraph ”office testing” of this review), with the exception that the
drug consumer has to do the colouring test him-/ herself and combine the
result of this test with the tablet characteristics given on the website.
Finally, the National Drug and Alcohol Research Centre in Australia
provides a very elaborate system of monitoring the illicit drug markets, and
besides using the laboratory analysis information provided by the
Australian Crime Commission they use a wide network of drug users for
information on “perceived drug purity” for instance, collectively referred to
as the Illicit Drug Reporting System (IDRS) and the Ecstasy and Related
Drugs Reporting System (EDRS) [Matthews et al., 2009; Topp et al., 2004].
Whereas these initiatives have all contributed to the knowledge of the
composition of the illicit drug markets throughout the world, by far, most
international chemo-analytical data were reported by the different national
forensic institutes [Cole et al., 2002; Simonsen et al., 2003; Camilleri &
Caldicott, 2005; Sharma et al., 2005; Teng et al., 2006].
Because of the large differences in types of drug sample monitoring
methodologies between the various countries around the world it is virtually
impossible to make an one-on-one comparison between countries on
market variables, such as purity, price or contents. Large institutes, such
47
as the EMCDDA and the UNODC, provide some insight into the variety of
the different global illicit drug markets [UNODC, 2010; EMCDDA, 2009],
but the quantity and extent of coverage still differs considerably between
countries. Nonetheless, figures 13-16 aim to provide some insight into
international comparison between the three main illicit drug markets
previously discussed in this review, i.e. ecstasy, cocaine and
amphetamine. Important to bear in mind is that not all countries provided
information on every substance, for instance amphetamine is barely
monitored outside of Western-Europe, but methamphetamine instead.
Also, the analytical methods of the different international laboratories might
differ considerably, which of course impacts on the results as well.
Therefore, the results are more indicative of global trends than they are
exact comparisons.
Figure 11. Percentage of analysed tablets containing MDMA-like substances in 6
countries between 2004-2008; sources: [Dancesafe, 2010; EMCDDA: National
reports 2005-2009, 2010]. Average content of ecstasy in mg/ tablet in 5 countries
between 2004-2008; sources: [EMCDDA: Statistical bulletins 2004-2009, 2010;
48
NDARC, 2010]. Average amphetamine purity in 5 countries between 2004-2008;
sources: [EMCDDA: Statistical bulletins 2004-2009, 2010]. Average cocaine purity
in 8 countries between 2004-2008; sources: [EMCDDA: Statistical bulletins 20042009, 2010; NDARC, 2010; USDEA: Cocaine, 2010].
*In Western Australia average content was expressed as percentage of MDMA/
tablet.
Comparing the different monitoring results in recent years to those of the
DIMS, it is evident that every country shows its own unique drug market
composition and dynamic (Figure 11). Roughly, and not surprisingly, the
different Western European ecstasy markets show more resemblance to
each other as to Eastern Europe or Western Australia for instance (Fig 11).
The different Western European “speed” markets also show resemblance,
but the amphetamine purity in all of them is considerably lower than it is in
The Netherlands (Fig 11). In contrast to the ecstasy markets, the different
cocaine markets show a less clear pattern of resemblance between
Western European countries. The markets in the US and Western Australia
are in fact very comparable with many European markets (Fig 11). This
makes sense, since the source of cocaine (Latin America) is the same in
all considered countries.
Additionally, new psychoactive additives are also reported by many
countries, providing an alternative source of comparison between drug
markets (Table 2). To keep matters simple, only the cocaine and ecstasy
markets are compared, since these two markets are most known for
emerging new substances/ adulterations anyway. The United States are
compared to two major Western-European countries, France and
Germany, to provide some degree of cross-Atlantic comparison. As is
shown, the ecstasy markets show a lot of similarities between these
countries divided by the Atlantic. However, the United States seems to
have its own specific compounds appearing in ecstasy tablets, such as
dextromethorphan (DXM) or phentermine for instance. On the other hand,
phenethylamines like MBDB or MDHOET were not seen in the United
States ecstasy market. As for cocaine adulterants, there is once again a
more uniformous spread among all three countries, confirming cocaine as
the import product it is to all these countries [UNODC, 2010]. Interesting
49
from a global diversion point of view, however, are the different time-points
that the adulterants arose in the different countries. As with the purity data,
it is important to bear in mind that the drug testing systems between these
countries might probably differ in a number of aspects.
50
Table 2. New psychoactive substances detected on the ecstasy- and cocaine markets
in 2004 – 2009 in Germany, United States and France
2004
2005
2006
2007
2008
2009
Germany
Ecstasy
market
2C-I,
MBDB
Ephedrine,
MBDB
BZP
mCPP
mCPP,
BZP
Mephedrone
, PMA
Lidocaine,
phenacetin,
caffeine,
procaine
Phenacetin
, lidocaine,
caffeine,
diltiazem,
procaine,
levamisole,
hydroxyzine,
bezocaine
Phenacetin,
lidocaine,
diltiazem,
caffeine,
procaine,
hydoxyzi
ne,
Levamisole,
benzocaine,
amphetamine
Phenacetin,
lidocaine,
diltiazem,
caffeine,
procaine,
hydroxyzine,
levamisole
phenacetin
, lidocaine,
levamisole
-
Ephedrine,
DXM,
fentanyl,
mCPP, 5Meo-MiPT
Ephedrine,
DXM,
ketamine
, mCPP,
phentermine,
MDDMA,
procaine
mCPP,
modafinil,
ketamine
, nicotinamide,
procaine,
BZP
mCPP, BZP,
ketamine,
phentermine,
2C-I, 5-MeoDMT,
TFMPP,
procaine
mCPP,
2C-B,
BZP,
ketamine,
DXM,
FPP,
mephedrone, 5Meo-DMT,
TFMPP,
diphenhydramine
, procaine
Diltiazem,
Hydroxyzine,
methylephedrine
Procaine,
caffeine,
Diltiazem
,
procaine,
caffeine
Diltiazem
,
procaine,
caffeine,
hydroxyzine,
benzocaine,
creatine
Diltiazem,
procaine,
caffeine,
levamisole,
nicotinamide
Caffeine,
levamisole
, lidocaine
France
Ecstasy
market
MBDB, 5Meo-Dipt
mCPP,
MDHOET
4-MTA,
ketamine
, mCPP,
TFMPP,
BZP
BZP,
ketamine
, TFMPP,
2C-B,
mCPP
mCPP, BZP
4-fluoro
amphetamine,
mephedrone
Cocaine
Phenacetin
Phenacetin
Phena-
Levam-
Levamisole,
-
Cocaine
market
United States
Ecstasy
Ephedrine,
market
DXM, BZP,
TFMPP,
creatine
Cocaine
market
51
market
, lidocaine,
procaine,
Atropine*
, lidocaine,
procaine,
Atropine*
cetin,
lidocaine,
procaine,
caffeine
isole,
phenacetin,
phenadiltiazem,
cetin,
caffeine,
diltiazem, hydroxyzine,
caffeine,
lidocaine,
Hydroprocaine
xyzine,
lidocaine,
procaine
MBDB, N-Methyl-1-(1,3-BenzoDioxol-5-yl)-2-Butanamine; TFMPP, 1-(3trifluoromethylphenyl)-piperazine; BZP, benzylpiperazine; MDDMA, 3,4methylenedioxydimethylamphetamine; DXM, dextrometorphan; MDHOET, 3,4methylenedioxy–N-(2-hydroxyethyl)amphetamine; 4-MTA, 4-methylthioamphetamine; 2C-I,
2,5-dimethoxy-4-iodophenethylamine.
*Detected in drugs obtained from intoxicated hospitalized patients.
Sources USA: [Dancesafe, 2010; United States Drug Enforcement Administration:
Microgram Bulletins, 2010].
Sources France & Germany: [EMCDDA: National reports, 2010; EMCDDA: EWS final
reports, 2010].
52
Discussion
Illicit drug market monitoring is recognized as a surveillance tool for the
benefit of public health [Ritter, 2010; Katz et al., 2010], somewhat
analogous to agencies concerned with inspecting product quality of foods
or medicines, that are well-spread throughout all countries over the world.
Similar to warnings about food poisonings, drug monitors try to keep track
of acutely hazardous substances found in illicit drugs and issue warnings to
take a rapid course of action. The monitoring results of the DIMS have
provided valuable qualitative information on changes in the content of drug
samples in The Netherlands throughout the years. The DIMS results were
used for national and international risk assessments and major warning
and prevention activities. In this capacity it functions almost directly at the
level of the potential drug consumers and this ensures quick delivery of the
prevention message. Secondly, it attempts to accurately follow drug market
processes in time. This is in contrast to the forensic institutes which do not
usually aim at public health related matters, nor strive to monitor processes
through time.
During nearly two decades of monitoring street drugs, the DIMS has shown
that the different psychostimulant markets are very dynamic and new
psychoactive substances and additives are emerging frequently.
Interestingly, the rise of new substances often co-occurs with the shortage
of a specific illicit drug of abuse. This applied to amphetamine, 4-MTA and
PMA, found in ecstasy tablets, during the 1990s or mephedrone and
mCPP during the last couple of years. Mephedrone, actually, is rather a
special case as recent literature has made clear [Winstock et al., 2011;
Measham et al., 2010; Brandt et al., 2010a; Brandt et al., 2010b; Brunt et
al., 2010]. It was sold through various websites, as plant fertilizer,
especially in the UK [BBC, 2009]. Although in The Netherlands it was found
as a replacement for MDMA in ecstasy tablets, mephedrone seems to be a
part of a far more greater whole: “legal highs”, referring to drugs sold
through the internet that mostly do not have a legally controlled status. This
phenomenon seems to be persistent, because, after the ban of
mephedrone in a number of countries, a new generation of post53
mephedrone products were already signalled [Brandt et al., 2010a]. These
products can be produced in laboratories anywhere around the world and
their sale via the internet will make legislation more complex, thereby
changing the face of drug trade radically. Besides these new psychoactive
substances, also novel adulterants, such as levamisole, could provide new
challenges for health care and policymaking [Chang et al., 2010; Zhu et al.,
2009; Buchanan et al., 2010; Bradford et al., 2010].
In the UK, massive use of mephedrone among youth caused such a stir,
that it was banned earlier in 2010 [Morris, 2010]. It has been banned in
many other EU member states at the moment and a risk assessment
procedure has already been conducted by the EMCDDA and the European
Medicines Agency (EMA), on the basis of a EMCDDA-Europol report
[EMCDDA, 2010], which may possibly lead to a ban in the remainder of the
EU member states. Following the continuing rise of new psychoactive
substances on the drug markets, described in this review, such collective
European efforts to ban substances seem to have increased in frequency
over time. Other substances that underwent the same fate and got banned
were BZP, 4-MTA, PMA, MBDB, among others [EMCDDA, 2009;
EMCDDA Risk assessments, 2010]. But it is the monitoring systems that
are at the core of these Pan-European policy initiatives.
Whereas the special drug policy of The Netherlands makes a system like
the DIMS possible, other countries have made great efforts of their own to
create intelligible insights into their drug markets. Some of these efforts
resulted in similar systems like the DIMS, whereas others derive drug
market information in a different way [Giraudon et al., 2007; Ramsey et al.,
2001; Kenyon et al., 2005; Tanner-Smith, 2006; Matthews et al., 2009;
Schifano et al., 2006a; Mounteney & Haugland, 2009; Legleye et al.,
2008]. As suggested in this review, it is apparent that analytical testing
procedures for drug samples probably differ between many countries,
reflecting on the results. Several factors could be of importance: ways of
extraction, measuring to the base or salt form, purity definitions,
quantification method used, etc. Nevertheless, on various drugs of abuse,
very similar results over time were reported by different countries [UNODC,
2010; EMCDDA, 2009]. This provides interesting avenues of investigation,
54
like import, export, routes of dispersion or sources of adulteration for
example. Recently, perhaps one of the most striking new chemo-analytical
methods of measuring drug market information that has been reported by
several research groups is the detection of drugs of abuse, their
metabolites and adulterants in public wastewater by HPLC-tandem mass
spectrometry [Huerta-Fontela et al., 2007; Kaspryk-Hordern et al., 2009;
van Nuijs et al., 2009; Shao et al., 2009; Zuccato et al., 2008; Chiaia et al.,
2008]. In this way, drug markets can be monitored without the involvement
of anyone participating in the illicit drug circuit, from users to producers. But
this method rather measures consumption itself and is better developed for
large, non-specified, bulk analyses from certain areas. User-specific or
sample-specific data are impossible to gain by this method. These
methods might be useful in assessing the scale of temporal and spatial
illicit drug use in the future.
Finally, there is the question of the benefit of a monitoring system for the
drug users themselves. Despite the fact that most recreational drug users
are relatively well-informed about the risks, they are often willing to accept
them nonetheless [Gamma et al., 2005; Murphy et al., 2006; Morgan et al.,
2010]. So how could a system like DIMS possibly aid in prevention or harm
reduction? There are at least two arguments to be made in favour of a drug
analysis and testing system in this context. Firstly, it has been suggested
that individual directed harm-reduction advice serves the needs of existing
users better than simply promoting abstention [Gamma et al., 2005]. In this
sense, the one-on-one contacts the users have with the personnel at the
DIMS testing offices, combined with factual information concerning their
drug purchase and other drugs circulating the streets largely meets the
information needs of drug users. Additionally, young drug users often
dismiss government messages as tendentious and untrustworthy and more
persuaded by personal contact with well-informed peers or professionals
[Gamma et al., 2005; Murphy et al., 2006; Falck et al., 2004; Allott et al.,
1999; Toumbourou et al., 2007]. It has to be noted, however, that the reach
of a drug testing system such as the DIMS is limited to a fraction of all
(potential) drug users.
55
Conclusion
Monitoring the market of illicit drugs creates a platform on which to base
policymaking and public health preventive activities, as well as for research
purposes. This review of the DIMS system and other drug testing systems
has made clear that the market for psychoactive substances of abuse is
continuously moving, underlining the necessity to continue the systematic
monitoring of this market. Future challenges for the DIMS could lie in
developing ways to monitor the internet- and doping drug markets, as
these seem to be developing rapidly and good insights into these markets
are lacking.
56
Chapter 3
The relationship of quality and price
of the psychostimulants cocaine and
amphetamine with health care
outcomes
Tibor M. Brunt, Margriet van Laar, Raymond J.M. Niesink
and Wim van den Brink
Based on:
Drug and Alcohol Dependence (2010), 111(1-2): 21-29
Abstract
A major component of the illicit drug market can be subcategorized as the
psychostimulant drug market, with cocaine and amphetamine as popular
constituents. In the Netherlands, an increase in both health care outcomes
addiction treatment and hospital admissions was noted for both
psychostimulants amphetamine and cocaine throughout a period of 17
years (1992-2008). Both cocaine price and quality showed a decrease in
the Netherlands during the studied period. We used time-series regression
analysis to investigate whether price or quality of the drugs were
associated with health care outcomes. Drug seizures were also added to
the time-series regressions, in order to check for possible effects of drug
availability and supply. Price and quality of cocaine were strongly
associated with both health care outcomes. Price of amphetamine also
showed a decrease during these 17 years, but was associated with an
increase in addiction treatment only. Other amphetamine market variables
did not show any relationship with the health care outcomes. It could be
stated that following basic market logics does not apply equally to all
psychostimulants of abuse. Other factors might play a role, such as the
addictiveness or desirability of a specific drug in question. This finding is
supportive of the dynamics of the illicit psychostimulant market affecting
actual use and thereby health care outcomes.
Introduction
Over the years, the European market of illicit psychoactive drugs has
become increasingly diverse. Drugs with various appearances are
distributed on the street, such as powders, tablets, capsules, paper trips,
liquids and aerosols. A major component of the illicit drug market can be
subcategorized as the psychostimulant drug market. Among the main
drugs that are distributed on this market are cocaine and amphetamine
(Shearer and Gowing, 2004). Amphetamine is an illicit substance that is
found both in tablets and in powders, and is mostly referred to by the
consumers as "speed". Although this substance has been frequently found
59
in tablets, it seems that the majority of amphetamine in Europe is sold in
powder form (Ramsey et al., 2001; EMCDDA, 2009). Cocaine
hydrochloride is a substance distributed exclusively in powder form
(UNODC, 2008; Van Laar et al., 2008). Both cocaine and amphetamine are
snorted, whereas amphetamine can also be taken orally. Cocaine can also
be injected and smoked. Especially the smokable form, often referred to as
crack or basecoke, is very prevalent among the chronic, marginalized drug
users, often in combination with or as substitute for opiates (EMCDDA,
2007).
The EU average of the last year estimated prevalence of cocaine use in
the general population in 2007 was around 1.2% (4 million) and for
amphetamine 0.6% (2 million) (EMCDDA, 2009). For the Netherlands,
these percentages were on the low end of the scale, with 0.6% for cocaine
and 0.3% for amphetamine (Van Laar et al., 2008). These
psychostimulants are snorted frequently among visitors of clubs and raves,
which is a younger age group than the users that smoke cocaine, usually
outside of these recreational settings (EMCDDA, 2007; Van Laar et al.,
2008).
In the Netherlands, the National Alcohol and Drugs Information System
(LADIS) reported an increasing prevalence of clients in addiction treatment
for cocaine- and amphetamine-related problems (Van Laar et al., 2008).
One third of all cocaine clients are snorting the substance, often in
combination with alcohol or other substances, the rest is smoking cocaine
or crack, often in combination with heroin as primary problem substance.
Regarding physical health, both psychostimulants are characterized by
specific clinical risks, such as cardiotoxicity, neuropathology and a whole
range of systemic complications (Lange and Hillis, 2001; Knuepfer, 2003;
McCann and Ricaurte, 2004; Glauser and Queen, 2007; Westover et al.,
2007; Bertol et al., 2008). Averaged for the period from 2002 to 2006,
approximately one third of hospitalized drug victims in the Netherlands
(34%) indicated having used cocaine (Van Laar et al., 2008). In most of
these cases cocaine was involved as secondary substance. This number is
surely an underrepresentation, since a lot of drug-related emergencies go
undetected. Regarding amphetamine, the percentage is considerably
60
lower, not exceeding ten percent of the total amount of drug victims in
hospitals.
Measurements of the stability of illicit drug markets can be important in
understanding specific changes in drug use, and subsequently changes in
drug-related health care outcomes, e.g. addiction treatment or drug-related
hospitalizations (Hyatt, Jr. and Rhodes, 1995; Darke et al., 2002;
Brownstein and Taylor, 2007; Callaghan et al., 2009). For instance,
previous studies have shown that the price of cocaine is an important
predictor for the level of drug-related medical emergencies (Hyatt, Jr. and
Rhodes, 1995; Caulkins, 2001, 2007; Dave, 2006). Generally, it was found
that when the price of cocaine decreased, the level of cocaine-related
medical emergencies increased as consequence of increased cocaine
consumption. In addition, quality of cocaine may play a role in the level of
drug use and could therefore be a predictor for health care outcomes as
well (Hyatt, Jr. and Rhodes, 1995; Schifano and Corkery, 2008).
The Dutch Drugs Information and Monitoring System (DIMS) monitors
trends in price, purity and adulteration of illicit drugs on the consumer level.
In this study, we used the DIMS data from 1992 to 2008 as indicator of the
market variables price and quality (in terms of purity and adulteration) of
the psychostimulants amphetamine and cocaine. We utilized time-series
regression methods to examine the relationship of market variables for
cocaine and amphetamine with health care outcomes over 17 years. For
this aim, we used the data available from the LADIS and the National
Medical Registration (LMR) as indicators of health care outcomes. We also
used the number of cocaine and amphetamine seizures to control for
possible changes in overall drug supply and availability (Weatherburn,
2003). The aim of this study is to shed some light on the impact of illicit
drug markets on health for prevention and policy purposes and may add to
the existing insights gained from countries with different national drug
policies than the Netherlands.
Methods
Consumer samples and market variables (DIMS data)
61
All drug samples were collected according to the methods described by
Brunt et al. (2009). Shortly, consumers hand in their drugs voluntarily and
free of charge to a test office, in order to find out if there is any unexpected
health hazard present in the contents of the drugs they have purchased.
This system is carried out on behalf of the ministry of health in The
Netherlands for preventive and monitoring purposes only. A detailed
description of the DIMS system can be found in a paper by Spruit (1999).
We used only the data available from consumers that snorted cocaine,
since we scarcely received samples from consumers smoking cocaine/
crack, which is not primarily within the scope of the communication and
prevention activities of the DIMS network.
Since consumers hand in illicit drug samples each week, we consider the
DIMS data as the best possible up-to-date indicator for the situation on the
illicit drug market in The Netherlands. Verification of the DIMS
representativeness has been done by comparing with 'seized samples' by
the police from various cafés, clubs and dance venues in The Netherlands
(Vogels et al., 2009). Market variables concerning quality of the drugs were
derived from laboratory analyses. Prices were based on consumer's
reports, experts in the field and governmental reports. Prices were adjusted
for purity to get a realistic picture of what was effectively spent on the illicit
drug in question (Caulkins, 2007). Prices were given in euro's, prices
before 2001 were recalculated from Dutch guilders (1 Euro = 2.23 Dfl).
Prices were inflation-adjusted per year.
Addiction treatment (LADIS data)
Addiction treatment information was obtained from the National Alcohol
and Drugs Information System (LADIS), a database managed by the
Organisation for Information Systems in Care (SIVZ). LADIS covers all
major addiction outpatient care services in The Netherlands. It
anonymously traces clients and new registrations throughout each year
(Van Laar et al., 2008). Clients can be subdivided according to substance
abuse profile with this database. Because we tried to directly relate cause
and effects regarding market variables and health care outcomes, we only
considered data from clients with primary problems associated with
62
cocaine or amphetamine, excluding those that exposed secondary
problems with these substances of abuse. Furthermore, we only included
clients that experienced problems with snorting the substance and left out
the group of cocaine/ crack smokers, which allows for equal comparison
with the DIMS data. We included all clients in addiction treatment per year,
combining newly registered and previously registered. Furthermore, we
corrected the number of clients in addiction treatment for population growth
in the Netherlands per year, taking the population in 1992 as reference
value.
Hospital admissions (LMR data)
Information concerning hospital admissions related to drug abuse was
obtained from the National Medical Registration (LMR). LMR is managed
by Prismant, the research and advisory agency for the Dutch Health Care
Service. Most general and academic hospitals in The Netherlands are
connected to the LMR. Information upon hospital discharge is sent to the
LMR and coding is according to World Health Organization (WHO)
international guidelines: ICD-CM (Clinical Modification of the International
Classification of Diseases). Hospital admissions in relation to cocaine and
amphetamine were defined as ICD-9 codes 304.2, 305.6 and 304.4, 305.7
respectively. Unfortunately, no distinction is made between smoked or
snorted cocaine in these hospital admissions. We also corrected the
number of hospital admissions for population growth in the Netherlands per
year, taking 1992 as reference value.
Adulteration
In this article we use the term "adulterants" and "adulteration". We hereby
refer to pharmacologically active substances which may alter the
characteristics of a drug in question. For instance, caffeine is regarded as
an adulterant on account of its mechanism of action as central nervous
system stimulant. This is in contrast to other components in
psychostimulant powders, such as sugars, which are not recognized as
adulterants, as they have no psychopharmacological effects. Adulteration
63
is measured in this article as the proportion adulterated (in %) of total
powders per year, purity is measured as the average percentage cocaine
or amphetamine in the powders.
Laboratory analysis
Laboratory analysis was performed using at least two analytical techniques
for quantification and qualification of the pharmacological drug substances,
Thin Layer Chromatography (TLC) and gas chromatography nitrogen
phosphorous detection (GC-NPD). First, samples are crushed and
homogenized, then TLC is used for identification (using the ToxiLab®A
procedure). The analytes are identified by relating their position (RF) and
colour to standards. Cocaine is typically identified with RF 0.78,
amphetamine with RF 0.38 and caffeine with RF 0.60. Marquis reagents is
used for the colour identification of amphetamine in stage I (vanishing
fluorescent yellow spot) and Dragendorff reagents is used for caffeine and
cocaine in stage IV (orange and brown spots, respectively). Quantification
of the sample is done using gas chromatography nitrogen phosphorous
detection (GC-NPD: Interscience GC8000/NP-800). An internal standard
was added to the solution (Chirald, Sigma-Aldrich, Zwijndrecht, The
Netherlands). In an optional third step, validation or identification with gas
chromatography-mass spectrometry (GC-MS: Varian Saturn 4D, Varian
Medical Systems, Houten, The Netherlands) is used. The NIST (National
Institute of Standards and Technology) library is used to identify the
various mass fragments.
Time-series regression analysis
In order to explore the causal relationships between the market variables
price, purity, adulteration and seizures the Granger causality method for
time-series regression was used. Granger causality originates from
econometrics, but has been applied increasingly in the biomedical field as
well (Lütkepohl, 2006; Ladroue et al., 2009; Peterson et al., 2009). In short,
it studies the relationship of one time-series with another. Y is said to be
Granger-caused by x if x helps in the prediction of y, or equivalently if the
64
coefficients on the lagged x‟s are statistically significant. To implement the
Granger causality test with multiple variables, we determined
autoregressive lags and estimated vector autoregression (VAR) models by
the ordinary least squares (OLS) estimation method. A VAR model
determines the regressive association of each vector at the appropriate lag
with another vector at the subsequent time of measurement t. Vector
autoregression includes regressions of one variable to the other as well as
the lags of autocorrelation that denote the impact of each variable on itself.
By minimizing the Akaike Information Criteria (AIC), the best parametric
model with optimal number of lags was chosen.
The time series were differenced to become stationary (detrended). This
led to causality tests using Granger approach with first-order differenced
VARs for each of the dependent variables (health care outcomes) tested.
Next, we checked for cointegration of variables with the Johansen
cointegration test (Johansen, 1995). This test provides evidence if one or
more variables in an equation model are cointegrated, which could lead to
spurious regression results in the VAR. Indeed, in both the case of cocaine
and amphetamine, market variables seemed to be cointegrated (which is
not an uncommon phenomenon when one deals with market dynamics).
Therefore, a special type of VAR was performed: the Vector error
correction model (VECM). This is the most stringent of Granger type timeseries modeling, in which an additional error-correction term is added as a
variable to the equation. The error-correction term denotes if there is a
Granger causality present in a regression. Finally it has to be noted that
Granger causality is not causality in an absolute sense of the word. In its
best sense it is linear prediction, with one variable predicting another.
Unfortunately, neither the LADIS or the LMR assembled data more
frequently until 2008, so neither monthly or quarterly data could be used,
so it has to be emphasized that this study uses annual time series and the
analysis therefore is conducted under the constraint of a small sample size.
With short time series, the power of certain time-series analysis tests
(ARIMA for example) is insufficient, which may lead to lower probabilities of
rejecting the null hypothesis or otherwise misleading results. We have
looked at the statistical power through various parameters of the models,
65
such as the effect size and likelihood inference as described by Johansen
(Johansen, 1995). Most of these measures were within the acceptance
range. However, other issues could still be argued, the implications of the
long sampling lag period (one year) are therefore briefly discussed in the
discussion section of this article. Granger causality with VARs and VECMs
was done with Stata software, version 11.
Results
Drug samples
From 1992 to 2008, DIMS collected 14,763 individual illicit psychostimulant
drug powders from anonymous drug consumers that were sold as either
"speed/amphetamine" or "cocaine ". Quantitative laboratory analysis on
purity and adulteration was based only on those powders containing the
actual psychostimulant (7,091 powders contained amphetamine and 6,248
cocaine).
Demographic profiles of clients in addiction treatment and admitted to
hospital
The average age of amphetamine clients in addiction treatment in 2008
was 28 years (25 to 28 years for 1992-2008), for cocaine clients it was 36
years (40 to 36 for 1992-2008). The ratio man/ woman for amphetamine
clients between 1992-2008 was about 4, the same ratio as for cocaine. For
the hospital admitted cases very similar profiles were seen. For users
snorting cocaine the general client registration profile between 1992 to
2008 is that they were of Dutch origin, with jobs and housed. Users of
amphetamine were also primarily of Dutch origin, housed but more often
without job incomes. For hospital admissions, such data weren‟t available.
Health care outcomes
The amount of clients in addiction treatment for primary problems
associated with snorting cocaine has been steadily increasing, about
fourfold between 1992 and 2008 (Fig. 1). In 2008, 25 people per 100,000
66
inhabitants in The Netherlands were in addiction treatment for cocaine
snorting related problems. Also, the amount of hospital admissions related
to cocaine abuse showed an increase from 1992 until 2008 (Fig 1).
The amount of clients in addiction treatment with primary problems
associated with amphetamine has increased over the period 1992 to 2008,
especially after 2001, albeit more modest than that for cocaine in the same
time period (Fig. 2). Hospital admissions related to amphetamine use show
a relatively constant picture, although since 2004 numbers have modestly
increased (Fig. 2).
67
Figure 1. Health care outcomes for cocaine.
68
Figure 2. Health care outcomes for amphetamine.
69
Market variables
Both average purity and price of cocaine gradually decreased from 1992 to
2008, with a maximum drop in purity of 70.8% to 52.8% and a maximum
drop in price from 135 to 73 euro/gram respectively (Fig. 3). At the same
time, the incidence of adulterated powders on the Dutch drug market
increased considerably, from 10% in 1992 to 58.2% of total cocaine
powders in 2008. All kinds of adulterants were present in cocaine powders,
such as caffeine, lidocaine, procaine, phenacetin and more (as previously
described in Brunt et al., 2009).
For amphetamine powders, the situation looks quite different. The purity
and adulteration of amphetamine showed a fluctuating pattern (Fig. 4). The
overall average purity of amphetamine between 1992 and 2008 balanced
around 30%, and about 50% of these powders were adulterated. The year
2000 shows a clear drop in average purity of amphetamine powders. In
amphetamine powders, the primary adulterant encountered throughout the
entire measured time period was caffeine. Only 0.5-3.5% (mean about
2.0%) of the amphetamine powders in the Netherlands contained
methamphetamine.
Relationship of market variables with health care outcomes
Firstly, we established that no bivariate relationships were found for any of
the variables in this study. Obviously, market variables should be
influencing health outcomes, and not the other way round. We used firstorder differenced time-series for cocaine, since these were all trends and
had to be stationarized first. With simple exploratory Granger causality
tests, all relationships between the market variables and the health care
outcomes turned out to be univariate.
All cocaine VAR models could be described as third-degree autoregressive
models VAR(3). Then we did cointegration analysis and 2 market variables
seemed to be cointegrating, so we decided on a VECM regression with 3
lags and cointegration rank 1. All cocaine time series were first-order
differenced to become stationary. Results from the VECM regression
70
analyses for the relationship between market variables and health care
outcomes are summarized in table 1.
71
72
10
120
3.4
Price (€ / gram)
Seizures (metric tons)
3.7
135
2
8.2
125
13.0
4.9
114
8.5
65.5 70.8 67.5
65
9.2
108
2.5
11.5
112
8.0
9
97
7.0
10.4
95
6.5
6.5
105
8.4
100
8
97
73
77
80
87
84
17.6 12.4 14.6 10.6 10.5 11.8
79
17.0 18.5 14.9 25.0 39.5 41.2 55.7 53.6 58.2
68.9 67.9 66.2 54.3 60.5 68.7 65.4 56.6 54.4 52.8 53.1 55.4
0
2
4
6
8
10
12
14
16
18
20
72
Figure 3. The market variables, cocaine price, purity, adulteration and seizures. Prices were adjusted for both
inflation and purity. Purity is given as mean purity per year, adulteration is given as the proportion (in %) of the total
cocaine powders per year.
67
Average purity (%)
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Level of adulteration (%)
0
20
40
60
80
100
120
140
160
73
32
23
267
Price (€ / gram)
Seizures (kilograms)
293
25
38
36
317
21
34.4
34.5
45
23
41.4
27.9
324
24
60.1
28.6
815
22
59.5
29.6
1450
21
47.7
30.7
855
29
50.8
23.7
293
59
60.5
10.6
579
19
42.2
32.4
481
15
33.9
37.5
843
17
50.1
33.1
533
18
56.9
34.9
1576
17
55.2
34.7
633
18
58.8
33.5
24
57
25.8
2800 2000
17
59.2
33.7
0
500
1000
1500
2000
2500
3000
73
inflation and purity. Purity is given as mean purity per year, adulteration is given as the proportion (in %) of the total
amphetamine powders per year.
Figure 4. The market variables, amphetamine price, purity, adulteration and seizures. Prices were adjusted for both
33
Level of adulteration (%)
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Average purity (%)
0
10
20
30
40
50
60
70
74
10.808
-11.679
-1.677
-0.154
Adulteration
Purity
Seizures
EC
0.544
0.006
0.002
0.012
0.028
p-value
-0.002
-0.795
1.919
-1.509
-0.385
Estimate
0.001
0.195
0.254
0.374
0.149
S.E.
3.158
11.776
-50.657
0.856
2.021
-2.071
-3.890
4.294
-4.030
-3.588
t-ratio
0.201
0.031
0.023
0.027
0.041
p-value
Hospital admissions
information criterion, EC: error correction term.
74
S.E.: standard error; regression coefficient estimates and t statistics for the vector-error correction models. AIC: Akaike
72.787
S.E. of regression
0.921
1.976
-0.644
-4.212
5.089
-3.563
-2.834
t-ratio
19.959
-115.730
2.604
0.037
2.124
3.278
2.332
S.E.
Addiction treatment
AIC
Log likelihood
R-squared
Durbin-Watson stat
-6.607
Estimate
Price
Market variables
Dependent variables
Table 1. Granger causality tests using vector-error correction for the interaction of cocaine health care
outcomes and market variables.
75
3.805
3.101
-0.057
-0.250
Adulteration
Purity
Seizures
EC
0.090
0.081
0.185
0.117
0.024
p-value
-0.005
-0.916
0.528
0.0522
-0.170
Estimate
0.002
0.394
0.267
0.300
0.085
S.E.
5.766
11.946
-55.677
0.388
1.269
1.576
-1.623
1.979
0.174
-0.685
t-ratio
0.190
0.143
0.119
0.870
0.531
p-value
Hospital admissions
information criterion, EC: error correction term.
75
S.E.: standard error; regression coefficient estimates and t statistics for the vector-error correction models. AIC: Akaike
53.197
S.E. of regression
0.824
2.520
-1.897
-2.324
1.435
1.732
-2.717
t-ratio
26.193
-182.445
0.030
0.155
2.651
2.658
2.129
S.E.
Addiction treatment
AIC
Log likelihood
R-squared
Durbin-Watson stat
-5.811
Estimate
Price
Market variables
Dependent variables
Table 2. Granger causality tests using vector-error correction for the interaction of amphetamine health
care outcomes and market variables.
Results indicate that all three DIMS market variables price, purity and
adulteration Granger cause (i.e. show an intrinsic univariate relationship)
both health care outcomes addiction treatment and hospital admissions. As
the table shows, the coefficient of the error-correction term (EC) is
significant in both equations. Thus, the error-correction term provides an
additional channel of causal relationship. In contrast, cocaine seizures can
be ruled out in these models as factor influencing health care outcomes.
Amphetamine time series were somewhat differently characterized using
initial exploratory analyses. Amphetamine health care outcomes were
described as second-degree autoregressive models. Health care outcome
time series were differenced to become stationary. Amphetamine market
variables time series were stationary, except for price (first-ordered
difference). As with cocaine, market variables showed cointegration, so
VECM regression with 2 lags and rank 1 was chosen. Results are shown in
table 2. In contrast to cocaine, no amphetamine market variables showed
any relationship with health care outcomes, except for some moderate
effect of price on addiction treatment. As can be seen for the EC term, the
model for causality of this market variable and addiction treatment just falls
out of the 95% significance level in the Granger sense.
Discussion
This study describes 17 years of monitoring the illicit psychostimulants
cocaine and amphetamine on the Dutch drug market. Changes in the illicit
drug market can be anticipated by monitoring and aid the development of
proper responses, such as the implementation of interventions on the level
of health care. Based on the time trends decribed in this study, the
situation concerning the drug market does not seem to differ much
between the Netherlands and many countries with a stricter drug policy.
The decrease in price of cocaine we describe is consistent with other
international reports (Caulkins, 2001; Dave, 2006; Schifano and Corkery,
2008; Costa Storti and De Grauwe, 2009). Likewise, there is support that
cocaine purity is declining throughout the years in Europe (EMCDDA,
2007; EMCDDA, 2009). For amphetamine, trends were less
straightforward, there is a large spread in price and purity in Europe (from
76
10 to 30 euros per gram retail price and 10% to 30% respectively in 2007;
EMCDDA, 2009). To our knowledge, adulteration has never been
described in this context. On one hand, adulteration can be considered as
a compensatory mechanism to substitute (lack of) the main
psychostimulant, on the other hand adulteration takes place independent
from this to continuously increase profits by selling more and more diluted
product. Additionally, the accessibility of potential adulterants nowadays
may have improved considerably (Pai et al., 2003).
Our cocaine health care outcome trends were also reflected by data from
most European countries (EMCDDA, 2007). Regarding the trends in
hospitalizations associated with cocaine use it is apparent from various
studies that cocaine plays an important role in drug-related hospitalizations
(Weber et al., 2000; Leikin et al., 2001; Glauser and Queen, 2007).
Unfortunately, studies on cocaine hospitalizations in Europe are rather
sparse, making international comparisons difficult (Vitale and van de
Mheen, 2006). Addiction treatment care for amphetamine abuse has
remained relatively stable during the period from 2002 to 2006 in most of
Europe (EMCDDA, 2009). Interestingly, the Netherlands (LADIS) showed
the highest increase of clients in addiction treatment for amphetamine
abuse during this period in Europe, although the relative proportion of
amphetamine clients to all drug clients remains small. Regarding trends in
hospitalizations concerning amphetamine, far less information is available
from literature than is the case for cocaine. In recent years, quite a lot of
data was assembled on hospitalizations after methamphetamine use
(Degenhardt et al., 2008), but this substance was only marginally available
on the Dutch drug market.
As our exploratory time-series regression results indicate, the
socioeconomics of cocaine use most likely plays a role in related health
care outcomes, such as addiction treatment or hospital admissions. This is
not an unique finding, several previous studies have reported this
relationship (Hyatt, Jr. and Rhodes, 1995; Caulkins, 2001; Caulkins, 2007;
Dave, 2006). Mainly cocaine price was found to be an important predictor
for hospital admissions. These studies mainly found (very high) negative
correlations between cocaine price and cocaine-related hospital
77
admissions. Conversely, utilizing econometric time-series modelling as
well, previous research demonstrated a decrease in drug-related health
care outcomes when the prices of drugs like cocaine or heroin increased
(Caulkins, 2001; Smithson et al., 2004; Dave, 2006). Fitting in with the
market logics; a decrease in the price of cocaine leads to increased
purchase and consumption pattern, whereas an increase leads to the
opposite (Darke et al., 2002; Sumnall et al., 2004; Williams et al., 2006).
Noteworthy is the fact that this has been explicitly described for a drug like
cocaine, whereas for amphetamine this has not been investigated (Goudie
et al., 2007).
The quality of cocaine also proved to be related to health care outcomes in
this study. This is in line with a number of studies from countries such as
the United Kingdom and the United States (Hyatt, Jr. and Rhodes, 1995;
Caulkins, 2001, 2007; Dave, 2006). However, other studies have predicted
hypothetical negative decision making in purchasing cocaine when quality
was perceived as being poor among potential users (Goudie et al., 2007;
Cole et al., 2008). Although this may seem contradictory, there may be
several arguments to explain this. Firstly, the decrease in price might be a
prevailing argument over the loss in quality in the purchase and
consumption of cocaine. Secondly, it could be argued that a decrease in
quality will lead to a compensatory increase in consumption to maintain the
desirable effects (Schifano and Corkery, 2008). In addition, adulteration of
cocaine has been known to be the cause of specific detrimental effects on
the consumer's health (Behrman, 2008; Brunt et al., 2009).
Despite many pharmacological similarities of both psychostimulants, the
dynamics of the market and socioeconomic behaviour do not show much
resemblance. This is a previously undescribed finding. Firstly, it has to be
stressed that the markets are influenced by completely different
trajectories. Whereas the cocaine market is influenced by illegal export and
import activities, amphetamine is manufactured in dispersed clandestine
laboratories throughout the world (UNODC, 2008; EMCDDA, 2009).
Another finding in this study is that the amount of drugs seized barely
seemed to be of any consequence to health care outcomes of either
psychostimulant. This suggests that measuring availability or supply in this
78
way might not relate to direct use or consumption. Of special interest in this
respect is a recent socioeconomic study done in Canada, were time-series
analysis indicated increases in methamphetamine-related hospital
admissions after federal regulation of availability of methamphetamine
precursors and chemicals, contrary to what was expected (Callaghan et al.,
2009). An explanation given for this was an adaptive strategy to this
regulation of producers in synthesizing the illicit psychostimulant, with an
increase in supply as consequence, instead of a decline. For instance, the
instability of the amphetamine market we observed in 2000 may well be
attributed to a shortage of its precursor, benzyl methyl ketone (BMK),
whereas a dilution of the cocaine market could be the result of disrupting
illegal import through increased law enforcement activities.
Regardless of the market dynamics, our results indicate there might be
other underlying mechanisms of importance in the relationship between
illicit drug markets and health care outcomes. Other factors might be of
consequence, such as addictiveness or desirability of a specific drug. For
instance, the fact that cocaine is more popular than amphetamine within a
larger group of problem users might be important in the valuation of price
decrements (Van Laar et al., 2008).
Limitations
Our study is hampered by some limitations. First of all, since only short
annual time series were available from health care monitoring systems in
The Netherlands we could not provide more detailed causality estimates or
seasonal variations for instance. Although Granger causality tests can be
quite straightforward and have been used increasingly for shorter time
series, there is a considerable risk of overestimation which should be
considered. However, a short time series does not necessarily mean that
statistical power is insufficient (for more detail about this, see Gelper and
Croux, 2006). The long sampling lag period (one year) enables us to spot
only the gross patterns. Details about short-term effects are missed,
whereas these will probably play an important part in cocaine related
health issues. More frequent reports from the monitoring institutes of health
would certainly provide a magnificent tool in order to state more about
79
cause and effect measures. Additionally, the inclusion of other variables
than the market variables would have provided more detail on the
specificity of the market variable effects on health care outcomes.
Variables such as incidence rates of cocaine and amphetamine use or the
level in which these drugs were used throughout the years. Whereas some
sources exist in the Netherlands that have described the incidence rate of
amphetamine and cocaine use, these figures are doubtful in that they lack
quantitative accuracy. There are reports of declining incidence rates for
both amphetamine and cocaine use over the period 1997 to 2005 at the
level of the general population, but others have reported an increased
popularity of cocaine during the same period (Rodenburg et al., 2007; Van
Laar et al., 2008). Furthermore, about the level of use (frequency and
amount) of cocaine or amphetamine in the Netherlands hardly anything is
known at all. Another issue that remains is the information given by the
LADIS and LMR databases regarding primary cocaine diagnoses. It cannot
be ruled out that the health care outcomes of a number of cases were
resulting from concomitant drug abuse. Cocaine snorting is often
accompanied by alcohol abuse, and this particular combination poses its
own risks (McCance-Katz et al., 1998; Pennings et al., 2002).
Conclusions
Our socioeconomic approach of the changes in psychostimulant related
health care outcomes over almost two decades gives an indication about
which illicit drug market variables could be of influence to the consumption
pattern of users and subsequently explain some of the increases in health
care outcome variables, most likely in much the same fashion as regular
product market variables play a role in consumption and health. Our study
also emphasizes the importance of judging different drug markets on their
own merits, as shown for psychostimulants with similar psychological
effects like cocaine and amphetamine. This underlines the necessity for
health authorities and policymakers to keep systematically monitoring the
market of illicit drugs (Brownstein and Taylor, 2007). Whereas Granger
causality is not totally exclusive, it does give a degree of certainty about the
relationship of one variable with another over time. Especially the fact that
80
Granger causality indicated univariate significant relationships between
cocaine market variables and related health care outcomes, despite the
long sampling period of one year, is an interesting finding which challenges
to investigate more detailed time series in future for this purpose.
81
Chapter 4
An analysis of cocaine powder in The
Netherlands: content and health
hazards due to adulterants
Tibor M. Brunt, Sander Rigter, Jani Hoek, Neeltje Vogels,
Peter van Dijk and Raymond J.M. Niesink
Based on:
Addiction (2009), 104(12): 798-805
Abstract
Aims To report on trends in the content and adulterants present in street
cocaine (powder) in The Netherlands and to describe the associated
hazards to the health present. Design and participants. Drug consumers
handed in samples of cocaine powder during 1999 to 2007 for analysis.
Reports were compiled of users‟ experiences with the samples received.
Measurements and analysis. Linear regression analysis was used to
assess the trend in adulterated cocaine powder across the study period,
and comparison of reported adverse effects of adulterated with those of
unadulterated cocaine by Fischer exact test. Findings. There was a
statistically significant upward trend in the occurrence of adulterated
cocaine powder over the years. Adulterated cocaine was more frequently
associated with reported adverse effects than unadulterated cocaine.
Phenacetin, hydroxyzine and diltiazem appeared to be three adulterants
contributing to these adverse effects. Conclusions. An increase in
adulterants was detected in the analysed cocaine powder between 1999 to
2007. This increase is associated with relatively more adverse effects with
cocaine use. The cardiac and hallucinatory effects that were reported more
frequently are not understood clearly. Adverse effects are likely to be due
to several factors, including interactions of adulterants with cocaine and the
route of administration.
Introduction
Cocaine is associated with various toxic effects on the human body,
especially on the cardiovascular system (Lange & Hillis, 2001;Pozner,
Levine, & Zane; 2005). On occasions, cocaine can cause ischemia and
infarctions within a few hours after ingestion. This may result in
hospitalization or even sudden death in both initiators and regular cocaine
users (Frishman, Del Vecchio, Sanal, & Ismail; 2003). Cocaine may also
cause cerebrovascular effects resulting in cerebral ischemia and stroke
(Buttner, Mall, Penning, Sachs, & Weis; 2003). Several studies have also
reported rhabdomyolysis (breakdown of skeletal muscles) after high dose
85
cocaine use, subsequently leading to renal failure (Horowitz, Panacek, &
Jourisles, 1997; Nolte, 1991). Many of these latter effects typically occur
after chronic and heavy use.
Cocaine is one of the most widespread used drugs worldwide (UNODC;
2007). The overall prevalence of cocaine use in the total adult population in
Europe is 3.7%, with at least 12 million Europeans having used this drug in
their lifetime (EMCDDA; 2007). The number of cocaine users has steadily
increased from 1992 until 2005 (UNODC; 2007). It is estimated that current
cocaine use (last month) in Europe is twice that for MDMA (ecstasy).
Intranasal ingestion (snorting) of cocaine hydrochloride is the most
common administration route among powder users; smoking or “basing”
cocaine is restricted to a relatively small group of problematic and
marginalized users (van Laar, Crutz, Verdurmen, van Ooyen-Houben, &
Meijer, 2008).
Although several laboratory studies have described the effects of cocaine
on the body and nature of cocaine dependence (Foltin, Fischman, & Levin,
1995; Epstein, Preston, Steward & Shaham, 2006), street cocaine usually
differs considerably from the pharmaceutical grade cocaine which is used
under laboratory conditions (EMCDDA; 2007; Foltin, Fischman, & Levin;
1995). However, adverse reactions and other serious health hazards may
occur, when a drug turns out to contain another pharmacologically active
component (adulterant). The Dutch Drugs Information and Monitoring
System (DIMS) monitors the contents of cocaine hydrochloride powder
(cocaine herein) sold on the street and also records users‟ experiences of
the drug‟s effects.
Previous research has identified caffeine, lidocaine, benzocaine, diltiazem,
procaine and phenacetin as adulterants in cocaine samples (McKinney,
Postiglione & Herold; 1992; Fucci & De Giovanni; 1998; Kenyon, Ramsey,
Lee, Johnston & Holt; 2005; Staack, Paul, Schmid, Roider & Rolf; 2007).
More recently, also hydroxyzine and levamisole were identified in seized
illicit cocaine shipments (Fucci; 2007; Behrman; 2008); and in one case,
poisoning with cocaine adulterated with atropine was described (Weiner,
Bayer, McKay, DeMeo & Starr; 1998). Lidocaine, procaine and benzocaine
are all common local anaesthetics (Sweetman; 2006). The other described
86
adulterants are prescription medicines with various applications: diltiazem
is used in cases of cardiac arrhythmias or ischemia (Apostolakos & Varon;
1996); phenacetin has been used as analgesic (Sweetman; 2006), but it
has been removed from the pharmaceutical market because of renal
toxicity and alleged carcinogenicity (Ames, Magaw & Gold; 1987); atropine
is also indicated for multiple clinical purposes, such as toxicity by nerve
agents or eye surgery (Geyermek; 1998); levamisole is used as
anthelmintic (medicines used to expel parasitic worms) and as adjuvant in
malignant disease (Sweetman; 2006). Adverse effects to most of these
substances are well described (see Table 1).
Using DIMS monitoring data, this report describes the contents of street
cocaine powder and possible additive health hazards posed by the
adulterants present. Data from users‟ self-reports are used to contrast
experienced adverse effects of adulterated cocaine with unadulterated
cocaine.
Table 1. Adverse pharmacotoxic effects of known adulterants.
Adulterants
Lidocaine
Main usea
Local anaesthetic
Possible adverse effectsa
Central nervous: nausea, vomiting,
dizziness, tremors, convulsions.
Cardiovascular: myocardial
depression, hypotension,
bradycardia, arrhythmias.
Procaine
Local anaesthetic
As lidocaine (see above).
Benzocaine
Local anaesthetic
As lidocaine (see above). Also,
methemoglobinemia is associated
with large doses.
Phenacetin
Analgesic
Chronic use associated with
nephrotoxicity leading to incontinence
and back and flank pain.
Caffeine
CNS stimulant
Chronic use associated with
withdrawal symptoms, including
headache, irritability.
87
Hydroxyzine
Sedative,
anxiolytic. Also
used as
antihistamine.
Dizziness.
Levamisole
Anthelmintic and
After acute intake: nausea, diarrhoea
adjuvant in
and dizziness.
malignant disease. After prolonged intake: muscle pain,
headache, fever, insomnia, dizziness
and convulsions.
Diltiazem
Calcium channel
blocker. Used in
cardiovascular
disease.
Adverse cardiovascular reactions,
including angina, bradycardia,
hypotension and arrhythmia may
occur. Also fainting, nausea, vomiting
and diarrhoea.
Atropine
Antimuscarinic
agent. Various
clinical
applications:
treatment of
brachycardia,
inducing mydriasis
in eye surgery.b
Central nervous: amnesia,
disorientation, visual hallucinations,
ataxia, psychoses and eventually
coma.
Peripheral: tachycardia, mydriasis,
restlessness, urinary retention,
disturbed speech and swallowing. b
Methods
The DIMS network
DIMS is a large network of institutions for mental health and addiction care
within The Netherlands. The coordinating and steering centre is at the
Netherlands Institute of Mental Health and Addiction in Utrecht. The
participating institutes are located throughout the country and they offer a
laboratory drug testing service to individuals who wish to evaluate the
content of street drugs in their possession. Drug users hand in their drugs
anonymously and they are invited to report their experiences with the drugs
they hand in, if any. Personnel working in these offices are trained in
providing information on drugs and the feedback of laboratory results to the
88
individual consumers. Centrally, information about drugs is compiled in a
database and laboratory results are reported via a secure website which is
only available to those participating in the DIMS system.
An important record in the DIMS database is the user‟s report on what
information was given at the time of purchase concerning the nature of the
product (i.e. in the present context, DIMS can report on whether what was
sold as cocaine does indeed contain cocaine as the main active
ingredient). This is important information from a public health perspective.
Through laboratory analysis, potentially dangerous substances are
identified and communicated throughout the DIMS network. In this fashion,
information is quickly gathered and appropriate measures can be
undertaken, such as warning campaigns (Keijser, Bossong & Waarlo,
2007; Spruit; 2001). Additionally, DIMS has a surveillance function and
reports on trends and new substances in the street drug market.
Drug testing
The DIMS testing function is conducted by various testing offices. Drug
consumers hand in their drugs and receive the laboratory results one week
later. Because of this weekly update of information on drugs with various
appearances, test offices can sometimes recognize certain drugs on the
spot through the database on the DIMS website. This mainly applies to
tablets, capsules and squares of paper presumed to contain hallucinogens.
A number of main psychoactive ingredients in powder samples are
established through the Marquis reagent test (Jeffrey; 2003). For example,
this reaction will turn colourless/pink if the drug contains cocaine.
Cutting agents and adulterants
The term cutting agent is often used synonymously with adulterants in the
scientific literature. In both cases, the substances may be used to increase
profit by diluting the pure cocaine with cheaper alternatives. However,
while cutting agents refer to pharmacologically inactive substances with a
similar appearance as cocaine (e.g. sugars such as inositol and mannitol),
89
adulterants are pharmacologically active substances which may modify the
characteristics of cocaine. Topical anaesthetics may be used to create the
same oral numbness that pure cocaine causes, so the customer will get
the impression of high-quality cocaine whereas in actuality, the user is
receiving a diluted product. In this article, only adulterants will be
discussed.
Laboratory analysis
The laboratory analysis for DIMS proceeds as follows: samples are first
crushed and homogenized, then Thin Layer Chromatography (TLC) is used
for identification (using the ToxiLab®A procedure). The analytes are
identified by relating their position (RF) and colour to standards through
four stages of detection. Cocaine is typically identified with RF 0.78. To
confirm TLC results, the sample is determined using a gas chromatography
nitrogen phosphorous detection (GC-NPD) procedure (Interscience
GC8000/NP-800). A solution is prepared using an internal standard
(Chirald). Cold on column injection is then used, with a temperature
program detector temperature 300 °C and with Nitrogen-PhosphorDetector and Helium as the carrier gas. In the case of a discrepancy
between these two methods of analysis, identification with gas
chromatography-mass spectrometry (GC-MS) was used (the GCconditions are similar to GC-NPD). The NIST(National Institute of
Standards and Technology)-library is then used to identify the various
mass fragments. This procedure is optimized for detecting pharmacological
active compounds, such as medicines or illicit drugs.
Data analysis
The distribution of reported adverse effects between adulterated and
unadulterated cocaine by drug users, and the associations between
different adulterants and reported adverse effects were analyzed by
Fischer‟s exact test. Trend in the adulteration of cocaine over the years
was determined with linear regression analysis. SPSS version 15.0 was
used for all statistics (SPSS Inc, Chicago, Ill).
90
Results
A total of 3230 samples of powder sold as cocaine were handed in for
analysis by DIMS between 1999 and 2007. Some 2824 (87.4%) contained
cocaine. These samples were used for the analysis of adverse effects,
since the comparison could be made between cocaine with or without
adulterants. The 406 samples that did not contain cocaine as component
were taken to be false samples.
Trends in the content of cocaine powders
Trends in the content of powder sold on the street as cocaine during 1999
and 2007 are show in Figure 1. Only a small proportion of the samples sold
as cocaine actually contained another component that was not cocaine.
They consisted of either no pharmacological active components
whatsoever (such as sugars), or other pharmacological active components
than cocaine, such as amphetamine or caffeine. There is a clear trend for
more detected adulterants in the cocaine samples tested over time.
Regression analysis shows a significant trend by year from 1999 to 2007
(6.6% annual increase (95% confidence interval, 5.9-7.3%), P<0.001).
Whereas in 1999 the proportion of adulterated cocaine was 6.5%, this
increased to 57% in 2007.
Over the years the diversity of adulterants found in cocaine has increased
considerably. The percentages of the most frequent types are shown in
Table 2. Mainly, phenacetin seems to be a preferred adulterant in cocaine
throughout the years. But other adulterants likewise appear more
frequently, such as procaine, caffeine and novel adulterants such as
diltiazem and levamisole. By contrast, the presence of the local anaesthetic
lidocaine is declining over the years. Rather than percentages, the
absolute numbers (n) of samples containing atropine are given in Table 2
to illustrate the contrast between adulterants with acute and secondary
health hazards. In 2004, atropine appeared on the Dutch cocaine market,
which was a reason to alert the authorities and orchestrate a national mass
media warning campaign. Atropine is very toxic at low doses and in
combination with cocaine life-threatening situations may occur. This
91
situation repeated itself in 2005 and 2007 when again several cocaine
samples were identified containing atropine.
Reported adverse effects of cocaine powders by drug users
The reported effects were interpreted from a perspective of physiological or
psychological health as either adverse or not. Of the 2824 users that
handed in their cocaine samples, 172 reported adverse effects and 487
reported otherwise (for instance pleasant or non-specific effects). The
remainder did not report anything. The reported adverse effects varied in
seriousness from nausea to cardiac effects; in some instances resulting in
emergency care hospitalization. A subdivision into the categories of these
adverse effects is shown in Table 3.
92
93
7.3
8.0
17.0
67.7
4.1
7.4
6.5
82.0
% of other pharm. active substances
% of no pharm. active substances
% of adulterated cocaine
% of unadulterated cocaine
69.8
18.5
4.3
7.4
2001
(165)
74.8
14.9
3.6
6.7
2002
(202)
70.1
25.0
1.8
3.1
2003
(228)
52.0
39.5
2.4
6.1
2004
(375)
50.9
41.2
2.7
5.2
2005
(638)
38.6
55.7
2.4
3.3
2006
(630)
39.9
53.6
3.0
3.5
2007
(735)
93
Figure 1. Trends in powders sold as cocaine, subdivided into four categories: powders containing unadulterated
cocaine, adulterated cocaine, other pharmacologically active substances and powders containing no
pharmacologically active substances.
2000
(135)
1999
(122)
year 0%
( n=)
20%
40%
60%
80%
100%
94
2.5
n
4.0
-
-
n
Caffeine
Hydroxyzine
Diltiazem
Levamisole
-
n
-
5.6
-
-
14.0
2.8
2.1
2001
(143)
%
-
n
-
4.6
-
-
8.7
1.7
7.4
2002
(175)
%
-
n
-
3.7
-
-
8.3
3.7
16.8
2003
(217)
%
3
n
1.0
0.6
5.5
1.0
1.0
5.2
4.8
35.6
2004
(343)
%
3
n
2.0
1.0
7.8
0.5
0.5
4.8
3.4
38.3
2005
(588)
%
-
n
6.6
4.5
10.9
2.0
0.5
8.2
12.0
48.0
2006
(593)
%
94
Atropine is not given in percentages, but absolute number of samples. This substance is acutely toxic and
warning campaigns were immediately initiated when this substance was encountered in cocaine samples.
#
Atropine
-
-
-
Benzocaine
-
15.0
5.0
3.8
1.0
Lidocaine
Procaine
#
1.3
1.6
2000
(80)
%
Phenacetin
Adulterants
Year 1999
(n=) (108)
%
7
n
12.0
11.6
15.8
4.4
0.2
6.4
8.3
40.6
2007
(683)
%
TABLE 2. Adulterants that were found in cocaine powders in percentages. One or more adulterants can be present in
one powder.
95
309
47
137
115
Caffeine
Hydroxyzine
Diltiazem
Levamisole
0.0
0.1
0.5
0.2
0.1
1.1
4.9*
10.6**
3.8
1.2
0.2
3.0
1.3
7.7**
5.4* 4.3
34
Adverse effects Nausea
All
0.1
0.2
0.4
0.6
1.4
0.3
2.4
0.4
36
Headache
2.9
9.3**
0.1
4.3
2.1
1.4
7.7**
10.8**
54
Cardiac
effects
0.6
0.1
2.4
1.8
1.1
0.4
0.0
0.0
16
Allergic
reactions
95
Associations were determined using the Fischer‟s exact test. Significance is shown as * P < 0.05. ** P < 0.01.
195
248
Lidocaine
Procaine
996
Frequency
Phenacetin
Adulterants
All
Categories
2.5
14.0**
12.0*
0.1
1.68
2.02
4.8*
4.0
34
Hallucinations
Table 3. Reported adverse effects in cocaine powders and their associations with the main adulterants are given in
Chi-square values. Adverse effects are subdivided in five major categories.
Distribution of the adverse effects was compared between adulterated and
unadulterated cocaine samples. Benzocaine and atropine were not
included in this comparison, since the percentages were too low for reliable
statistical analysis. Reports of adverse effects were more likely when
adulterated cocaine was taken than unadulterated cocaine, as can be seen
in Table 3 ( 2=5.4, P=0.02). Phenacetin, hydroxyzine and diltiazem were
associated with a higher likelihood of reported adverse effects in drug
consumers
( 2=7.7,
P<0.01;
2
=4.9,
P=0.04;
2
=10.6,
P<0.01,
respectively). Levamisole, caffeine, procaine and lidocaine were not
associated with an increased likelihood of adverse effects ( 2=3.8, P=0.06;
2
=1.1, P=0.3;
2
=3, P=0.1,
2
=0.1, P=0.8 respectively).
With respect to the nature of different adverse effects reported, cardiac
effects (such as chest pain and abnormal heart beat) were associated with
adulterants present in cocaine powders ( 2=10.8, P<0.01). Further analysis
revealed that phenacetin or diltiazem were the two adulterants to cause the
increased likelihood of cardiac effects (see Table 3,
2
=7.7, P<0.01;
2
=9.3, P<0.01, respectively). Also, hallucinations (often accompanied by
mental disorientation) were reported more often when phenacetin,
hydroxyzine or diltiazem were present as an adulterant in cocaine
compared to cocaine without adulterants (see Table 3,
2
=12.0, P=0.02;
2
=4.8, P=0.04;
2
=14.0, P<0.01, respectively).
Discussion
These data suggest that in a majority of instances powder sold as cocaine
in The Netherlands does indeed contain cocaine as major component.
There was a statistically significant upward trend in the occurrence of
adulterated cocaine powders between 1999 and 2007. Cocaine samples
adulterated with phenacetin, caffeine, diltiazem and levamisole increased
in frequency over this period. A possible explanation for this worrying
phenomenon might be that the demand for cocaine has risen in Europe.
This is reflected by the increasing amount of cocaine seized by law
enforcement agencies during 2000 to 2005 (UNODC; 2007). Furthermore,
consumption of cocaine in this period has also increased (UNODC; 2007;
96
EMCDDA; 2007). We hypothesize that adulterants are added to meet the
increased demand and that they are used as cheaper alternatives to
cocaine to increase the profits by diluting the final product. Whereas a
number of previous studies have reported all of the main adulterants in
cocaine that we detected in this report (McKinney, Postiglione & Herold;
1992; Fucci & De Giovanni; 1998; Kenyon, Ramsey, Lee, Johnston & Holt;
2005; Staack, Paul, Schmid, Roider & Rolf; 2007; Behrman; 2008), to our
knowledge, this is the first report of trends over time.
Based on self-report, the analysis in this study suggests that adulterated
cocaine is more frequently associated with reported adverse effects than
unadulterated cocaine. Phenacetin, hydroxyzine and diltiazem appeared to
be three adulterants contributing to these reported adverse effects. Further
evaluation of these adulterants requires some reference to their
mechanism of action and possible interactions with cocaine. In terms of
drug interactions with cocaine very little is known from literature and in
most cases evidence is confined to speculation. It is important to note that
many of these adulterants are prescribed for oral ingestion in
circumstances of medical treatment. In the case of adulterated cocaine
they are ingested through other routes, such as intranasally or by
inhalation. This may affect pharmacokinetic parameters, such as rate of
absorption or bioavailability.
Diltiazem is a calcium channel blocker, and its main mechanism of action
and clinical use as an anti-arrhythmic and anti-ischemic has already led it
to be investigated in relation with the cardiotoxic properties of cocaine
(Schindler, Tella, Erzouki & Goldberg; 1995; Apostolakos; & Varon; 1996).
It is possible that the distributors of street cocaine may have actually tried
to alter the hazard profile of the drug by trying to attenuate some of the
negative cardiac responses to cocaine by adding diltiazem. However, from
these studies no consistent protective effect or interaction of diltiazem on
cocaine-induced cardiac toxicity is apparent. The data we present actually
suggest the contrary, since many of the adverse effects of diltiazem were
cardiovascular. Interaction between cocaine and diltiazem is probably
complex (Rowbotham, Hooker, Mendelson & Jones; 1987; Ansah, Wade &
Shockleu; 1993). The hallucinatory effects experienced by some users may
97
be due to secondary events of the cardiac effects (faintness, fatigue). Only
limited evidence is available that describes psychoactive phenomena after
use of (high doses) diltiazem (Punukollu, Gowda, Khan & Dogan; 2003). It
remains to be investigated whether nasal insufflation with diltiazem
adulterated cocaine may result in similar systemic doses.
Both the cardiac effects and hallucinations reported in association with
phenacetin are difficult to interpret. The carcinogenic risk associated with
chronic exposure to high doses of phenacetin has been assessed as at
least 0.5 gram of phenacetin a day (Ames, Magaw & Gold; 1987). To reach
these doses however, a user would need to consume cocaine well in
excess of this amount, at which point direct adverse effects of cocaine
would be more likely. No studies have described acute toxicity of
phenacetin. Intranasal administration of phenacetin has not been studied
however, and there might be some evidence to suggest that this route of
administration could play a role in increased toxicity (Ding & Kaminsky;
2003; Peters, Morishima, WArd, Coakley, Kimura & Gonzalez; 1999).
Toxicity may be the result of certain toxic metabolites that are formed by
enzymes present in the intranasal mucosa (Gu, Cui, Behr, Zhang, Zhang,
Yang et al., 2005; Brittebo; 1987; Hinson; 1983). There may also be a
possibility of direct interaction of cocaine or one of its metabolites with
phenacetin or one of its metabolites, but this is clearly a topic for further
research. Although it has been banned from sale in some countries, there
is evidence to support that phenacetin is still widely available (McTavish;
2004). Nevertheless, there is uncertainty as to why this substance is used
as an adulterant in the illicit drug distribution market.
Hydroxyzine is used both as anxiolytic and antihistamine (Sweetman;
2006). It is a competitive histamine H1-receptor antagonist and causes
relief from histaminergic reactions, such as bronchoconstriction. The
anxiolytic properties of hydroxyzine are not completely understood (Llorca,
Spadone, Sol, Danniau, Bougerol, Corruble et al.; 2002). The
hallucinations that were reported in our study are most likely explained by
the adverse side-effects of hydroxyzine, such as dizziness and drowsiness
(Sweetman; 2006). Nothing is known about intranasal administration of
hydroxyzine. Possibly, unpredictable effects of intranasal application could
98
play a role in occurring adverse effects. No interactions between
hydroxyzine and cocaine are described. However, both are inhibitors of the
same cytochrome P450 isoform CYP2D6 (Rendic; 2002). This may result
in possible adverse reactions due to decreased detoxification (Miksys &
Tyndale; 2004). It is not known why hydroxyzine is used as adulterant,
other than to simply cut cocaine and increase profit (Behrman; 2008).
Another substance that was added to cocaine was atropine. In certain
aspects atropine may exert similar effects on the CNS as cocaine does, but
its mechanism of action is different. It inhibits the parasympathic nervous
system by antagonizing the muscarinergic acetylcholine receptor system
(Geyermek; 1998). Atropine causes symptoms such as increased heart
rate, hallucinations, blurred vision, delirium and eventually coma. Cocaine
enhances the toxicity of atropine by inhibiting the same receptor
mechanism (Sharkey, Ritz, Schenden, Hanson & Kuhar; 1988).
Additionally, the sympathicomimetic effects of cocaine are no longer
counterbalanced by the parasympathic nervous system and heart rate is
disproportionately increased. One might hypothesize that small amounts of
atropine are added to “boost” or “mimic” cocaine‟s effects, while actually
making a cheaper product.
In interpreting these findings and speculating on possible mechanisms we
have to mention some limitations that are a result of the way our data were
assembled. First of all, the drug users did not report anything about the
dosage of cocaine that was used after experiencing adverse effects or
about the circumstances or combinations with medicines, drugs or alcohol
at the time they used cocaine. This does not question the fact that there is
an obvious difference between unadulterated cocaine and adulterated
cocaine, but it does raise questions concerning the exact cause of adverse
effects in these instances. Furthermore, most adulterants were not
quantified by the laboratory, so it is unknown how much of an adulterant
was actually ingested after experiencing certain adverse effects. Another
limitation of this study with regard to the trends in cocaine is the fact that
these samples may not be entirely representative of the cocaine on the
street. A possible bias may occur due to the possibility that testing drug
users often have their drugs tested because of specific concern to their
99
health (Korf, Benschop & Brunt; 2003). The DIMS might have actually
received proportionally more suspicious (diluted) samples as there are
circulating on the street.
Despite these possible shortcomings, the present data provide a unique
insight into the drug market with regard to individual and public health.
Especially for cocaine powders that do not display any recognizable
characteristics, it is important to keep track on what is added to them and
what the consequences for health might be. Clearly, the increase in
adulterated cocaine causes additional concern to the health of (potential)
drug consumers. Further risk assessments of adulterated street drugs
could serve to keep public and government informed and can be used for
drug prevention activities. This information may be vital, as was the case
with atropine where mass media warning campaigns were carried out to
alert the public. It is this exchange of information where the DIMS system
serves as a monitor in order to prevent potentially serious health hazards
from escalating.
100
Chapter 5
Impact of a transient instability of the
ecstasy market on health concerns
and drug use patterns in The
Netherlands
Tibor M. Brunt, Raymond J.M. Niesink and Wim van den
Brink
Based on:
International Journal of Drug Policy (2011),
doi:10.1016/j.drugpo.2011.05.016
Abstract
Background: Recently, a profound decline in MDMA-like substances in
ecstasy tablets has been reported for a number of countries within the
European Union. This study aims to describe this instability of the ecstasy
market in The Netherlands during 2008 and 2009 and investigates whether
this had any impact on health concerns and drug use patterns of drug
users. Methods:
The effect of the ecstasy market instability on the
health concerns of drug users handing in drug samples at drug testing
facilities was measured using intervention time-series analysis. In addition,
ecstasy users handing in tablets were asked about changes in their drug
use pattern. Results: Nationwide, the instable situation on the ecstasy
market showed an impact on the number of users handing in ecstasy
tablets for the reason of health concerns. This impact was substance
specific, since there was no impact the number of users handing in cocaine
or gamma hydroxybutyrate (GHB). Despite increased health concerns,
respondents reported no major changes in their drug use due to the
shortage of MDMA-like substances. Conclusions: These findings provide
further insight in drug policy based on both harm reduction and use
reduction. In the event of reduced ecstasy quality, ecstasy users in The
Netherlands increasingly utilized drug testing as a potential harm reduction
tool, but there was no change in their drug use pattern. This might indicate
that a transient reduction of drug quality does not serve as a good drug use
reduction strategy for ecstasy users.
Introduction
One of the foremost clandestine manufactured synthetic drugs that has
gained worldwide popularity in the party scene is ecstasy (3,4methylenedioxymethamphetamine or MDMA) (EMCDDA, 2010; UNODC,
2010). The ecstasy market in The Netherlands during the last decade has
been described to be relatively stable in terms of MDMA content (Vogels et
al., 2009). The percentage of tablets containing an MDMA-like substance
(MDMA and its structural analogues 3,4-methylene-dioxyamphetamine
103
(MDA), 3,4-methylene-dioxyethylamphetamine (MDEA) and N-methyl-a(1,3-benzodixol-5-yl)-2-butamine (MBDB)) varied between 80% to more
than 95% from 1999 to 2008. However, during 2008, the percentage of
ecstasy tablets containing MDMA-like substances (MLS) declined rapidly,
resulting in a situation in the first six months of 2009 with only 40% of the
tablets containing MLS (Brunt et al., 2010). A decline in MLS has also been
described for other countries within the European Union (EU) during the
same time period (EMCDDA, 2010; UNODC, 2010).
Various reasons have been suggested underlying the decline of MLS in the
EU: redirected export and import, law enforcement measures to curtail
manufacture, and increased efforts to prevent diversion of precursors to
manufacture MLS, such as piperonyl methyl ketone (PMK) (UNODC,
2010). Whatever the background, this shortage of MLS in The Netherlands
provided a unique natural experiment to study the impact of declining
ecstasy quality on the behaviour of drug users. Shortages on the drug or
alcohol consumer market have been conceptualized before as natural
experiments to provide insights into environmental, sociological or physical
phenomena (Smithson et al., 2004; Cunningham & Liu, 2003, 2005;
Gilmour et al., 2006; Asbridge & Weerasinghe, 2008; Callaghan et al.,
2009). However, these studies were restricted to drugs with a high
addictive potential (e.g. heroin, methamphetamine) and very little research
has been devoted to relatively less addictive drugs of abuse, such as
ecstasy.
The aim of this study is to establish the impact of the shortage of MLS on
health-related behaviour of ecstasy users. More specifically, a convenience
sample of drug users that submit ecstasy tablets to the drug testing
facilities of the Drug Information and Monitoring System (DIMS) in The
Netherlands is investigated. Drug users can hand in their drug samples at
the DIMS and provide additional information, such as their main reason for
having drugs analyzed. After toxico-chemical analysis, they receive
information about the content of the tablets or powders they handed in
(Spruit, 2001; Vogels et al., 2009). It has been established in previous
research that one of the main reasons why drug users utilized the drug
testing system was health concerns (Benschop et al., 2002). In the current
104
study, data of the collected drug samples at the DIMS are analysed
prospectively, i.e. comparing the number of users handing in drug samples
preceding, during and after the event of shortage of MLS by intervention
time-series analysis. This analysis method has been frequently used by
others to study the impact of a natural event on regularly collected
surveillance data on different health outcomes of interest (Cunningham &
Liu, 2003, 2005; Gilmour et al., 2006; Koski et al., 2007; Asbridge &
Weerasinghe, 2008; Callaghan et al., 2009; Herttua et al., 2009).
Shortage of MLS might also have led to a change in drug use, since many
ecstasy users are in fact polydrug users (Gouzoulis-Mayfrank & Daumann,
2006; Medina & Shear, 2007; Wu et al., 2009). Previous studies describing
reductions in drug availability also addressed the issue of drug consumers
switching to other, better available, drugs or quitting drugs altogether (Topp
et al., 2003; Weatherburn et al., 2003). Alternatively, drug users might
compensate lower quality by increasing the number of ecstasy tablets they
ingest to obtain the desired effect (Tanner-Smith, 2006). Therefore, the
current study examines whether the decline of MLS led to subsequent
changes in drug use patterns among a convenience sample of ecstasy
users.
This is the first study investigating the impact of a real world reduction in
the quality of ecstasy on the drug users‟ behaviour. The outcomes will be
discussed in the context of drug policy and drug-related use or harm
reduction strategies.
Methods
Drug data
All drug samples were collected at the DIMS according to the methods
described previously by Vogels et al. (2009). The DIMS covers all
provinces and major cities in The Netherlands. Briefly, drug users handed
in their drugs voluntarily and free of charge at a DIMS testing facility, in
order to find out the chemical contents of the specific drugs they purchased
and whether there were unexpected health risks associated with those
purchases. The prevention professionals at the testing facilities
105
communicated the analysis outcomes to the users. The drugs were
analysed by gas spectrometry coupled to mass spectrometry. For this
study, all tablets containing at least a trace of any of the MLS were
specified as percentage tablets containing MLS.
Within the DIMS, drug samples are tested on a weekly basis. This allows
for a very detailed monitoring of the situation on the street drug market and
DIMS data can be considered as the best possible up-to-date indicator of
the illicit drug market in The Netherlands. DIMS data are used annually by
the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA),
which in turn supplies information to the United Nations Office on Drugs
and Crime (UNODC) (EMCDDA, 2010; UNODC, 2010). Comparison of the
DIMS data with those of 'seized samples' by the police from various cafés,
clubs and dance venues in The Netherlands has shown that DIMS data are
representative for the Dutch drug market (Vogels et al., 2009).
Measuring impact on drug users
One of the routine questions asked at the drug testing facilities is why the
drug user wants to have a particular drug tested; one the foremost reasons
given for testing drugs was “health concerns” (Benschop et al., 2002). The
possible impact of the shortage of MLS on the number of users utilizing
drug testing facilities for various reasons, and especially “health concerns”,
was investigated with monthly time series of users handing in ecstasy
tablets. Control series of users handing in other drugs at DIMS for the
reason of health concerns were included in the analysis to check for further
specificity of the impact of the intervention (i.e. MLS shortage) and to
exclude possible confounders affecting supply of drug samples to the
DIMS system. Possible confounders include increased popularity or
accessibility of the testing facilities in general or some other underlying
cause. Similar shifts in the use of the test services for cocaine and GHB as
for ecstasy would be suggestive of another explanation than the specific
shortage of MLS. Cocaine and GHB were used because these drug
markets were reported to be stable in terms of purity throughout the
studied period (Van Laar et al., 2010). In addition, these drugs are often
106
reported to be used by the same groups in the club circuit that also use
ecstasy (Grov et al, 2009; Van Laar et al., 2010).
Time series analysis
Because the exact time of onset of shortage of MLS (the intervention
event) was not reported by the available official sources, it was inferred in
an exploratory fashion, as previously described by others (Smithson et al.,
2005; Gilmour et al., 2006; Wood et al., 2006). It was possible to infer the
time of onset using the chemo-analytical monitoring data on ecstasy tablets
as an objective and reliable source for timing the event of the shortage of
MLS. To obtain a more rigorous set of validity criteria, two different
parameters of MLS shortage were used simultaneously and findings were
cross-referenced: percentage of tablets containing MLS and average dose
of MDMA per tablet (in mg), on the assumption that these two measures
are defining parameters of a shortage of MLS. Both timelines were
analyzed using a change-point analysis method (for more details, see
Taylor, 2000). Change points with probabilities of >99% were identified and
the cross-referencing of both timelines revealed common change points.
Average dose of MDMA was taken as an indicator of the ecstasy quality,
because the presence of other MLS on the Dutch market was very low
during the entire studied period, and because other MLS are not dosageequivalent.
Autoregressive Integrated Moving Average (ARIMA) intervention timeseries analysis was used to investigate the impact of the shortage of MLS
on the number of users handing in drugs at the drug testing facilities. For
all time series, the model fitting and noise component was estimated using
pre-intervention time series (Box & Jenkins, 1975; Box & Tiao, 1976).
Except for the intervention, the ARIMA model was fitted directly to the
series, the intervention was then modelled and the nature of the time series
after the intervention was estimated by applying transfer functions. In order
to describe the relationship between the intervention and its effect, the best
candidate model was determined according to the following criteria:
smallest Akaike Information Criterion (AIC), autocorrelation function (ACF)
and partial autocorrelation function (PACF). ARIMA models were fitted to
107
the time series, adjusting for outliers, serial dependence, autocorrelation
and adjusting for seasonal effects. SPSS version 15.0 was used for all
ARIMA statistics.
Drug use patterns
Possible changes in drug use patterns during the MLS shortage were
investigated by self-reports of ecstasy users at the DIMS testing facilities.
Participants were asked whether they were frequent users (i.e. at least
monthly use of ecstasy) and whether they were aware of the shortage of
MLS (the main inclusion criteria). 914 users handing in tablets sold as
ecstasy completed questionnaires and 761 were eventually included. The
others were excluded, because post hoc inclusion criteria revealed no
frequent ecstasy use or no ecstasy use altogether. In compliance with
basic DIMS guidelines, the participants were treated anonymously.
Therefore, no additional information was asked. Questionnaires were
collected from May 1st 2009 until October 1st 2009.
Results
Shortage of MLS
Three change points were identified (> 99% confidence) on the timeline of
percentage of tablets containing MLS, and five change-points (> 99%
confidence) on the timeline of average dose MDMA/tablet (Figure 1). Of
these, two common change-points were identified (November 2008 and
December 2009), whereas the other change points showed no overlap.
The first change point (November 2008) was taken as time of onset of MLS
shortage, the second as time of offset. The period in between was
considered the intervention interval.
108
Percentage of tablets containing MLS
100
90
80
70
60
50
40
30
20
10
0
2004
2005
2006
Months
2007
2008
2009
2010
2004
2005
2006
Months
2007
2008
2009
2010
100
Average content MDMA/ tablet (mg)
90
80
70
60
50
40
30
20
10
0
Figure 1. Graphical display of the timelines of percentage of tablets
containing MLS and average content of MDMA per tablet in mg with arrows
denoting change points detected by change point analysis; black arrows,
change points not showing overlap between timelines; white arrows,
change points showing overlap between timelines.
109
Drugs handed in at DIMS
A total of 22,280 users handed in ecstasy tablets during the period January
2004 - September 2010 motivated by various reasons. 13,445 users
specifically indicated “health concerns” as reason for having their ecstasy
tablet analyzed. A seasonal effect seemed to be present, with relatively
more users handing in tablets during summertime (Fig. 2). The number of
users indicating “health concerns” in the pre-intervention period (until
November 2008) ranged from 90 to 169 per month. A sharp increase in the
slope of the time series was visible in the beginning of 2009, indicating that
many more users were handing in tablets because of health concern by
this time. The increase resulted in a maximum of 395 users in July 2009,
then steeply declined during the second half of 2009 and towards the
beginning of 2010 and then stabilized at a level that was still relatively high
compared to the period before 2008. No shifts of this magnitude in the
patterns of any of the control time series (ecstasy other reasons, cocaine
health concerns, GHB health concerns) were detectable upon visual
inspection (Fig. 2).
110
111
111
Figure 2. Number of drug users handing in ecstasy tablets, cocaine samples and GHB samples from January 2004
- September 2010, intervention interval indicated by dotted lines.
Intervention analysis
Based on the pre-intervention time series the best fitting ARIMA models
were determined and shown in Table 1. The study of the ACF and PACF
suggested a (1,0,0)(0,1,1)12 model for the time series of users handing in
ecstasy because of health concern, with differencing required for removing
the seasonal trend. Then, the nature of the transfer function was tested on
the time series of health concern and the hypothesis of a gradual,
temporary intervention effect was rejected (according to McCleary & Hay,
1980). Subsequently, the intervention effect was modelled as a step
function. ARIMA intervention analysis was done, with time points coding 1
for the intervention interval and 0 for the remaining time points as the
intervention dummy variable. Box-Ljung Q statistics revealed that residuals
of all analyses were consistent with white noise for the first 24 lags (Table
1, last row). The impact of the intervention interval (i.e. shortage of MLS)
on the number of users handing in drugs was expressed by the estimated
coefficient for the intervention dummy variable. The estimated number of
users handing in tablets because of “health concern” increased after the
intervention with 62 users per month (Table 1). Intervention analysis
revealed no significant impact of the shortage of MLS for each of the
control series.
Changes in drug use pattern
Out of 761 ecstasy users that completed the questionnaires, 555 (72.9%)
indicated that they had not changed their drug use pattern after they knew
about the shortage of MLS (Fig. 3). The others reported that they had
decreased their ecstasy use (8.2%), increased their ecstasy use (4.8%),
switched to other substances (12.7%) or stopped using drugs altogether
(1.4%). The 12.7% ecstasy users that reported a switch mainly indicated
using cocaine instead of ecstasy, often in combination with alcohol (Fig. 4).
Of the 72.9% users reporting no change in their drug use, about 25%
indicated in the free space for comments to be more cautious about the
112
source of their ecstasy and more alert on testing before using future
ecstasy purchases.
Figure 3. Drug use patterns of ecstasy users, following the shortage of MLS.
Figure 4. Frequencies of the different drugs used by ecstasy users that switched
to other drugs than ecstasy.
113
114
9.98
3.11
3.17
Q = 16.55 (p = 0.42)
0.05
0.18
19.46
t
0.03
1.36
11.48
SE
0.60
-28.30
-0.71
t
Q = 21.77 (p = 0.15)
-0.95**
-0.96
6.92
Estimate
Ecstasy
other reasons
(0,0,1)(0,0,1)12
0.08
-
6.31
SE
8.83
-
0.71
t
Q = 10.26 (p = 0.89)
0.73**
-
4.50
Estimate
Cocaine
(0,1,1)
114
0.26
-
8.42
SE
1.00
-
-1.10
t
Q = 19.01 (p = 0.33)
0.26
-
-4.88
Estimate
GHB
(1,0,1)
AR: autoregressive term; MA: moving-average term; SMA: seasonal moving-average term; *P <0.01; **P <0.001.
Box-Ljung
test (24
lags)
0.90**
0.60*
61.70**
Intervention
AR(1)
MA(1)
SMA(1)
Estimate
ARIMAintervention
parameters
SE
Ecstasy
health concern
(1,0,0)(0,1,1)12
Dependent
variables
Table 1. Impact of shortage of mdma-like subtances on the number of users handing in drug samples; ARIMA model parameter
estimates.
Discussion
The present results suggest that the recent shortage of MLS was
accompanied by an increase in health concern among Dutch ecstasy users
who visited drug testing facilities. Apparent efforts made by more users to
visit these testing facilities for health concerns largely reflected the need for
reassurance. The increase in the number of ecstasy users with
approximately 62 per month after the shortage of MLS might also indicate
a rapid increase in awareness about the situation of the ecstasy market
among users throughout The Netherlands. This was confirmed by personal
communication with the testing facilities, which revealed many first time
visitors during 2009 and more awareness than usual through their own
experiences, friends or internet about the shortage of MLS. Alternative
hypotheses for the increase in ecstasy testing, such as increased
population prevalence of ecstasy use, were not supported by any national
figures (Van Laar et al., 2010).
It is important to note that, in general, there were no immediate reasons for
major health concern during the period of shortage of MLS from a public
health perspective: e.g. no new substances were found in tablets sold as
ecstasy that were known to cause acute toxicity. Nevertheless, there might
have been grounds for concern among ecstasy users. A host of alternative
substances were sold as ecstasy during the shortage of MLS to meet the
market demand: 2C-B, amphetamine, methamphetamine, 4-fluoroamphetamine, ketamine, n-formylamphetamine, 1-(4-fluorophenyl)piperazine and most notably mCPP (in >30% of the ecstasy tablets) and
mephedrone (in approximately 10% of the ecstasy tablets) (Brunt et al.,
2010). Some of these substances may have been introduced by producers
in an attempt to market them through an already successful vehicle product
like ecstasy tablets (Parrott, 2004). None of these substances mimic the
effects of MDMA very closely and some actually exert distinct unpleasant
effects, especially if one is expecting an MDMA-like experience (Bossong
et al., 2010; Brunt et al., 2010). Additionally, scientific facts or even
commonplace knowledge about the effects of many of these substances is
115
lacking. This may well explain the increased health concerns and the level
of uncertainty expressed by many ecstasy users.
There have been a number of reasons proposed that might be the cause of
the transient shortage of MLS in the EU: increased demand in other parts
of the world for PMK intended for MDMA manufacture, effective law
enforcement to curtail manufacture and prevention of illegal imports or
diversions of precursor chemicals from countries of origin (UNODC, 2010).
The rapid resurgence in 2010 of ecstasy tablets containing MLS again
seen in this study could suggest retooling ecstasy manufacture in Europe.
It has been suggested that other countries have taken over the role of
China as supplier of PMK and also that other precursors are now being
used to synthesize MLS (Milhazes et al., 2007; UNODC, 2010). This latter
hypothesis could be tested by tracing the origin of the MDMA present in
tablets using synthetic drug profiling (Europol, 2007; Milliet et al., 2009).
Because many ecstasy users are polydrug users, they might have changed
their drug use, following the unavailability of good quality ecstasy (Parrott
et al., 2001; Parrott, 2004). Some studies have predicted hypothetical
lower consumption of ecstasy by drug consumers if ecstasy quality was
considered to be poor (Sumnall et al., 2004; Goudie et al., 2007; Cole et
al., 2008). However, this was never investigated in a real world market
situation. The present findings suggest that the majority of ecstasy users,
despite awareness of the market situation, did not change their ecstasy
use during the peak of the shortage of MLS. Apparently, ecstasy use is
less elastic in response to quality fluctuations than would be predicted
beforehand (given the relatively low addiction potential; van Amsterdam et
al., 2010; Nutt et al., 2007, 2010).
The finding that most ecstasy users did not change their ecstasy use is
confusing, but might be explained by one or more of the following reasons:
(1) confidence about their own networks of ecstasy supply, (2) peer
pressure or drug dependence preventing a change in drug use, (3) users
being oblivious to the risks involved in using drugs sold as ecstasy or (4)
test results and communication about these test results not being alarming
enough. Reasons 3 and 4 are less likely to play an important role since the
current study seems to indicate increased health concerns during the
116
shortage period and because the DIMS emphasized the unknown risks
when ingesting new substances with unknown psychopharmacological
effects and in fact stated that users were experimenting on themselves.
Actually, it has been described previously that ecstasy users were
depending on their network of peers to eventually obtain safe good quality
tablets (Korf et al., 2003).
There are some studies on real world examples of illicit drug shortages that
reported switching to other, better available, drugs or drug users leaving
the drug market altogether (Topp et al., 2003; Weatherburn et al., 2003;
Roxburgh et al., 2004; Cunningham et al., 2008). For example, the heroin
shortage in Australia between 2000 and 2001 was associated with heroin
users temporarily switching to cocaine and methamphetamine. However,
these examples of drug substitution involved highly addictive drugs
associated with a marginalized and problematic group of users, in contrast
to the generally well-integrated ecstasy users who tend to use in a
recreational, not depended, fashion (Van Laar et al., 2010). Dependent
users may be more driven to look for substitutes when their preferred drug
is no longer available.
Whereas this study tries to describe drug user‟s behaviour in response to a
changing drug market, it has to be stressed that a convenience sample
was used, i.e. drug users that had access to ecstasy tablets and had the
opportunity to test them. Therefore, generalization of results to the whole
population of potential ecstasy users is hampered. Notwithstanding this
limitation, the situation on the ecstasy market seemed to have drawn more
ecstasy users than usual to the testing facilities. With regard to the timeseries analysis, there are also some limitations of this study that have to be
mentioned. ARIMA intervention time-series analysis is one of the most
powerful methods to infer causality in time-dependent phenomena
(Edwards, 2001; Shadish et al., 2002), but other influences can not entirely
be excluded. With a time-series analysis design with only one intervention
event there is a slight possibility of another event that co-occurred and
influenced the effect. Secondly, the time points of the intervention event
(shortage of MLS) in this study were not known a priori, as is the case with
well documented dates like law or policy regulations (Koski et al., 2007;
117
Herttua et al., 2008; Callaghan et al., 2009). However, some studies have
successfully coped with poorly identified time points of the intervention, like
the heroin shortage in Australia (Smithson et al., 2005; Gilmour et al.,
2006). In the present study, there is confidence about the timing of the
MLS shortage intervention event in the current study, because of the exact
nature of the month-by-month chemo-analytical monitoring data of a large
and representative number of Dutch ecstasy tablets from the streets, which
might even be considered a more precise measurement of the shortage of
MLS, without using the presumption that law or policy regulations actually
resonated to the level of the street drug market.
Shortages of MLS do not occur frequently and there has been only one
previous period reported in The Netherlands in the mid-nineties (Spruit,
2001; Vogels et al., 2009). However, the DIMS did not cover the whole
country in those days and the database was not as informative as it is
today. Therefore, the present data provided an unprecedented challenge to
measure the impact of a shortage of MLS on drug user behaviour and this
may be a valuable contribution to previous insights gained from other drug
markets (Weatherburn et al., 2003; Wood et al., 2004; Callaghan et al.,
2009). Secondly, it may provide further insight into drug policy based on
both harm reduction and use reduction (Caulkins & Reuter, 1997;
Weatherburn, 2009). When alerted about a drastic change on the ecstasy
market, more ecstasy users in The Netherlands utilized the DIMS as a
potential harm reduction tool for their own safety and probably for
reassurance. As a behavioural intervention however, the shortage of MLS
did not prove to be effective in reducing ecstasy use in this specific
population. The unavailability of good quality ecstasy did not lead ecstasy
users to suddenly reduce or change their use, in contrast to what has
described with more dependent drug users. Their behaviour could be of a
rather pragmatic nature: awaiting the endurance of the shortage of MLS
and having their drugs tested in the meantime for health reassurance. The
increased motivation to have their drugs tested in this study showed that
many users were at least unwilling to take too many health risks.
118
Chapter 6
Instability of the ecstasy market and a
new kid on the block: mephedrone
Tibor M. Brunt, Anneke Poortman, Raymond J.M. Niesink
and Wim van den Brink
Based on:
Journal of Psychopharmacology (2011), 25(11): 15431547. Epub: September 2010
Abstract
Recently, several reports have indicated instability of the ecstasy market in
The Netherlands and other EU countries. In the current study, we
demonstrate this instability in The Netherlands, showing a decrease of
ecstasy tablets containing MDMA (3,4-methylenedioxymetamphetamine)
by more than 50% in 2009. In addition, we describe a partial replacement
of MDMA in tablets sold as ecstasy by a previously unseen substance,
mephedrone (or 4-methylmethcathinone). Mephedrone was quantified and
ecstasy tablets contained between 96 and 155 milligrams of this new
compound. So far, no studies about mephedrone's effects have been
published. For this study, we gathered information on the acute subjective
effects of mephedrone from 70 regular ecstasy users. Overall, the majority
of users considered the effects enjoyable. Mephedrone seemed to evoke
effects similar to other amphetamine-type psychostimulants, including
MDMA. In contrast to MDMA, however, mephedrone induced strong
feelings of craving in most users. If the unstable ecstasy market situation
persists, the potential of mephedrone to substitute for MDMA might be
substantial. Mephedrone, sold as ecstasy, is therefore likely to be a valid
cause for health concern.
Introduction
The market of illicit drugs can be considered just as dynamic as markets
for legal products. For a variety of reasons, new synthetic drugs, surnamed
designer drugs, are continuously appearing on the illicit drug market; if a
new drug shows interesting marketing potential, if it's not yet under a
controlled substance act and/or if an established drug has become scarcer
as a result of increased drug enforcement activities (Jerrard, 1990; Wodak,
2008). Over the past two years there have been reports on a shortage of
MDMA in the ecstasy market in The Netherlands and other EU countries,
probably resulting from increasingly successful efforts to prevent the
diversion
of
precursors
to
manufacture
MDMA,
such
as
piperonylmethylketone (PMK) (EMCDDA, 2009). At the same time,
previously unseen substances on the illicit drug market were reported by
121
the European Early Warning System (EWS), such as substituted
piperazines, N-methylated cathinones and halogenated amphetamine
derivates among other chemical classes. Some of these substances were
categorized as designer drugs, intended to replace MDMA in ecstasy
tablets.
New designer drugs usually display characteristics similar to already
popular and established illicit drugs. Often they are just chemically modified
at a single position of the original molecule. For instance, MDA, MDMA and
MDEA (commonly sold as ecstasy) are commonly referred to as designer
drugs of the amphetamine-type (Maurer, et al., 2004), also called
phenylethylamines. But a whole range of new designer drugs is emerging.
For instance, methcathinone was launched into the recreational drug
market after the increased criminalization of ecstasy (Sparago, et al.,1996;
Dal Cason, et al., 1997; Hegadoren, et al., 1999). Methylone (3,4-methylenedioxy-N-methylcathinone) and mCPP (meta-chlorophenyl-piperazine)
were previously described as serotonergic substitutes for ecstasy
(Bossong, et al., 2005). Whether these designer drugs are suitable
alternatives from the consumer's health perspective, in terms of effects or
even toxicology often remains to be investigated however.
The Drug Information and Monitoring System (DIMS) in The Netherlands is
a toxicoepidemiologic monitor of illegal drug markets and one of its
objectives is to identify trends and new substances circulating on the drug
market from the perspective of health care (Bossong, et al., 2009). In this
article, we aim to describe the recent instability of the ecstasy market and
investigate whether this has led to the introduction of new designer drugs
to the market and their possible health risks.
Methods
Drug samples
All DIMS drug samples were collected according to the methods described
by Vogels et al. (2009). In the current study, 12,331 ecstasy tablets were
122
analysed over the period 2008-2009 from individual consumers using the
DIMS system. We used data on tablets sold as ecstasy (MDMA) to
describe the instability of the ecstasy market. Secondly, we describe the
rise of the main identified new substance on the Dutch synthetic drug
market: mephedrone (4-methylmethcathinone, shortly 4-MMC, ‟meow
meow‟ or MMCAT). Data from The Netherlands Forensic Institute (NFI)
were used to confirm the rise of this substance. The NFI illicit drug samples
were obtained by police seizures. All samples were received at The
Netherlands Forensic Institute during the year 2009.
Laboratory analysis
Identification of mephedrone was done by The Netherlands Forensic
Institute (NFI). For identification electron impact (EI) mass spectra were
obtained using an Agilent 6890 gas chromatograph equipped with an
Agilent 5973 Mass Selective Detector (MSD) and an Agilent G2614
autosampler. Helium was used as the carrier gas at a constant flow rate of
1.0 mL/min. An Agilent Ultra-1 12 m x 0.20 mm x 0.33 µm column was
used with an oven temperature program from 110°C (1 min hold) with
40°C/min to 300°C (2.75 min hold); the injector temperature was 275°C
and the MSD interface was set at 280°C. The standard split/ splitless liner
was used in split injection mode (1:50).
Quantitative analysis of mephedrone was performed using an Agilent 6890
gas chromatograph equipped with Flame Inisation detector (FID) and an
Agilent G2614 autosampler. Nitrogen was used as the carrier gas at a
constant flow rate of 1.6 ml/min. An Agilent Ultra-1 25 m x 0.32 mm x 0.52
µm column was used with an oven temperature program from 175°C (5
min hold) with 10°C/min to 280°C (0 min hold); the injector and detector
temperatures were 275°C and 300°C, respectively. The standard split/
splitless liner was used in split injection mode (1:25). From ground and
homogenised tablet mass an alkaline extract was made using hexane with
C20 as internal standard. Certified reference mephedrone was obtained by
the NFI from the National Measurement Institute (Pymble NSW, Australia).
123
Acute subjective effects
We obtained descriptions of the acute subjective effects of mephedrone
from regular ecstasy users through the DIMS network and through the
peer-led intervention network Unity. An information request was put to all
members of the DIMS network, asking users specifically about their
previous experiences with the drug sample they handed in. It takes about
one week before the person who has his sample tested gets the result from
the laboratory, which means that these drug users were not aware of the
chemical contents of their drug samples when they provided information on
their experience with the drug they handed in for analysis. In addition, we
obtained descriptions of the acute subjective effects of mephedrone from
users through the Unity-network: a peer led intervention that is part of a
national Dutch 'safer dancing' policy, a prevention mix of education,
support facilities and juridical measures. Unity attends over 40 festivals and
dance events per year. We collected acute subjective effects from June
2009 until December 2009.
Results
Instability of the ecstasy market and mephedrone
Starting from July 2008 the ecstasy market changed quite drastically. From
being a fairly stable market for years with more than 90% of the ecstasy
tablets containing mainly MDMA (for an overview of the Dutch ecstasy
market, see Vogels, et al., 2009), the market became diluted from the
second half of 2008 on, leading to less than 50% of ecstasy tablets
containing MDMA in the first half of 2009 (Figure 1). The lack of MDMA in
ecstasy tablets was mainly compensated for by mCPP (ranging between
23% and 54% in all ecstasy tablets from 2008 to 2009). Other previously
described substances were: amphetamine (50 tablets), methamphetamine
(40 tablets), caffeine (in more than 500 tablets) and 2C-B (34 tablets).
Besides these typically encountered substances on the Dutch ecstasy
market some previously unseen pharmacologically active components
started to emerge during 2008 and 2009: 4-fluoroamphetamine (25
124
tablets), ketamine (10 tablets), N-formylamphetamine (16 tablets), 1-(4Fluorophenyl)piperazine or pFPP (6 tablets), metoclopramide (15 tablets)
and domperidone (46 tablets). The latter two are medicines and suspected
to be added to tablets containing mCPP to suppress the nausea often
experienced with that substance.
By far, the most prevalent new compound we found during this period was
mephedrone. Mephedrone, misleadingly sold by the dealer as ecstasy,
was increasingly detected during 2009 (Figure 1). At the DIMS system, 995
tablets were handed in, representing 11.5% of the total amount ecstasy
tablets in 2009. These tablets exclusively contained mephedrone as
pharmacologically active substance. DIMS findings were confirmed by
police seizures during the same period (more than 100 seizures reported).
Based on 21 tablets analysed from different seizures, the quantity of
mephedrone base ranged between 96 and 155 milligrams per tablet.
Mephedrone was the first and, so far, only cathinone derivative found in
tablets sold as ecstasy in The Netherlands.
80
mephedrone
no MDMA
70
60
50
%
40
30
20
10
0
1
2
3
4
5
6
7
8
9 10 11 12 1
2008
2
3
4
5
6
7
8
9 10 11 12
2009
Figure 1. Dilution of the ecstasy market throughout 2008 and 2009, expressed as
percentage of tablets not containing MDMA measured per month (total shaded
area), the percentage of mephedrone tablets therein is darkly shaded.
125
Acute subjective effects of mephedrone
In order to gain some information concerning the effects of mephedrone,
we collected information on the acute subjective effects of mephedrone
from 70 recreational drug consumers. Most of these users were regular
ecstasy users (n=63). The others (n=7) were experimental users,
deliberately searching for mephedrone as a novel substance. The reported
effects are summarized in Table 1. The contents of tablets of 43 users
could be traced back from the quantitative laboratory results and contained
between 111 and 120 mg of mephedrone base per tablet. Most effects
were reported after ingestion of a single tablet. Information reported by the
remaining 27 users broadly indicated similar dosages, but confirmation of
this was lacking. The most frequently reported emotional effects were
euphoria, talkativeness, improved mood and craving (often reported as the
compulsive urge to redose). The most frequently described somatic effects
were increased energy and accelerated heartbeat. Most users experienced
the overall mephedrone effects as enjoyable and were considering using
the substance if the opportunity were to occur again.
Discussion
What we describe here is the emergence of a new synthetic drug of the
amphetamine-type in the context of an unstable synthetic drug market.
Whereas new designer drugs keep emerging regularly, we want to
emphasize that in the present report we might have revealed a more
causative relation between the situation on the ecstasy market and the rise
of novel compounds. Recently others have also hinted at this possibility
(Measham, et al., 2010). Producers of illicit drugs may consider a switch to
these novel compounds, if the situation with regard to MDMA does not
change. A worrying phenomenon is that some new designer drugs, like
methcathinone, have been reported to be synthesized in the home
environment, made from readily available pharmaceuticals like ephedrine
or pseudoephedrine (Belhadj-Tahar and Sadeg, 2005). The unprofessional
nature of this manner of drug synthesis could be associated with additional
health risks (Stephens, et al., 2008).
126
Table 1. Most frequently reported acute subjective effects by 70 drug consumers
that have tried mephedrone tablets.
Emotional (n)
Somatic (n)
Increased alertness, more focused (28)
Increased energy, hyperactivity (56)
Euphoria, excitement, improved mood (63)
Urge to talk, openness in communication
Dizziness (17)
Distorted vision, restless eye movements
(51)
(33)
Craving for the drug (61)
Depressed, feeling down or sad (11)
Hyperthermia, warm all over (24)
Nausea, feeling sick (20)
Anxiety, panicky or nervous (19)
Accelerated heart/heartbeat, tachycardia
(44)
Loss of appetite (29)
Bruxism, jaw clenching (26)
Disturbed sleep-pattern (33)
Low energy, exhaustion, lethargy (23)
Overall experience: pleasant, enjoyable
58
Overall
experience:
undesirable
12
unpleasant,
Figure 2. Chemical structure of: mephedrone (a), methcathinone (b),
methamphetamine (c) and 3,4-methylenedioxymetamphetamine (MDMA)
(d).
127
The Psychonaut Research Project, an EU organisation that searches the
internet for information regarding new drugs, first identified mephedrone in
2008 (for the Psychonaut Project, see Schifano et al., 2003). The drug first
became available in Europe in 2007. The drug was sold as Neodove pills,
by the legal high company Neorganics (based in Israel), but this was
discontinued in 2008 after Israel made mephedrone illegal (BBC news,
2009). Mephedrone has thus far been reported as having been sold as
ecstasy in Australia, Europe and the United States (EMCDDA, 2008).
An advantage for producers of mephedrone is that it is not yet under the
scheduled substances act in the Netherlands. Furthermore, mephedrone is
available by simply clicking on the internet (BBC news, 2009). Mephedrone
supply seems to be dominated worldwide by laboratories situated in China
and most EU webshops indicate to order their stocks there. It seems to be
sold as a plant fertilizer through various websites. Currently, the EMCDDA
and Europol are working on a joint report on mephedrone, which may lead
to a formal risk assessment procedure on the substance (EMCDDA, 2010).
A similar trajectory has recently been followed for benzylpiperazine (BZP),
also sold as „ecstasy‟ in tablets, and resulting in legal control measures for
this substance in 17 EU Member States (EMCDDA, 2009). Although this is
certainly a strong collective effort for prevention, it seems that drug
producers are already trying to circumvent the law by offering other „legal‟
substituted piperazines through various online webshops. This underlines
the difficulties in targeting this relatively new and rapidly shifting designer
drug market.
Concerning the subjective effects of mephedrone, the are some
exploratory sources from the United Kingdom. They reflect many similar,
but not all, acute subjective effects we have found in the current study. For
instance, the Lifeline Project has described side-effects, like nose bleeds,
nose burns, hallucinations, blood circulation problems, rashes, anxiety,
paranoia, fits and delusions (Newcombe, 2009; Measham, et al., 2010).
The results of an online poll carried out by the National Addiction Centre
among 2,222 readers of a clubbing magazine showed further indications of
negative side-effects of mephedrone: headaches (51%), heart palpitations
(43%), nausea (27%) and cold or blue fingers (15%) (Dick and Torrance,
128
2010). One of the possible explanations for some of the differences in
effects between these studies and our study could lie in the fact that
mephedrone was exclusively taken orally in tablet form by the Dutch drug
users, whereas in the United Kingdom, also the intranasal route of
administration has been frequently reported.
Mephedrone is structurally closely related to cathinone and methcathinone
(for molecular structures, see Figure 2), which are structural analogues of
amphetamine and methamphetamine respectively (Sparago, et al., 1996;
Gygi, et al., 1996; Dal Cason, et al., 1997). As of yet, very little about
mephedrone has been described in scientific literature. Based on our
study, it is a psychostimulant with similar properties to MDMA (for MDMA,
see the meta-review on acute subjective effects by Baylen and Rosenberg,
2006). But it also differs in some aspects, with perhaps as most striking
difference the craving experienced by the drug users with mephedrone,
whereas this has rarely been described for MDMA (Huxster, et al., 2006;
Baylen and Rosenberg, 2006). This interesting difference might point
towards mephedrone inducing a more potent dopaminergic- (DA) relative
to serotonergic (5-HT) response in the CNS: it has been postulated that the
addictive potential of a drug is lowered if the 5-HT releasing potency
relative to DA is higher (Rothman, et al., 2008). For its analogue,
methcathinone, chronic use has been described to result in drug
dependence (Goldstone, 1993; Calkins, et al., 1995). An alternative
explanation for the induced craving by mephedrone could be the relatively
short biological half-life of the conpound.
Regarding (neuro-)toxicity, we can only refer to compounds with a high
structural similarity such as methcathinone. A number of studies have
reported acute toxicity of methcathinone (Sparago, et al., 1996; McCann, et
al., 1998; Cozzi and Foley, 2003) showing CNS neurotoxicity to 5-HT and
DA neurons; persistent reductions in dopamine transporter (DAT) density
were found in abstinent methcathinone users, indicative of a loss of DAT or
DA terminals (McCann, et al., 1998). Its toxic effects on the DA system
have repeatedly been linked to Parkinsonism observed in methcathinone
abusers, although this was ascribed to manganese, formed in the
synthesis of methcathinone (Sikk, et al., 2007; Stephens, et al., 2008;
129
Varlibas, et al., 2009). Anyway, extreme caution is needed when inferring
similar toxicology to mephedrone. Clearly, experimental research into this
subject is needed.
In conclusion, the acute subjective effects we described in this study
provide some insight into the mechanism of action of mephedrone and its
potential as a substitute for ecstasy. Notwithstanding the neurotoxic effects
of MDMA, sold as ecstasy, mephedrone is a valid cause for health
concern. It appears a more addictive substance and may otherwise
resemble dangerous analogues, such as methcathinone or
methamphetamine. It remains unclear whether the situation on the ecstasy
market is temporary or more sustained (EMCDDA, 2009). If the unstable
synthetic market situation persists, the potential of mephedrone to replace
MDMA in ecstasy tablets might be substantial. The present rise of this new
designer drug could therefore prove to be more hazardous than in previous
instances, when the MDMA market could otherwise be considered to be
stable.
130
Chapter 7
Linking the pharmacological content
of ecstasy tablets to the subjective
experiences of drug users
Tibor M. Brunt, Maarten W. Koeter, Raymond J.M. Niesink
and Wim van den Brink
Based on:
Psychopharmacology (2011), doi: 10.1007/s00213-0112529-4
Abstract
Rationale: Most studies on the subjective effects of ecstasy are based on
the assumption that the substance that was taken is 3,4methylenedioxymethamphetamine (MDMA). However, many tablets sold
as ecstasy contain other substances and MDMA in varying doses. So far,
few attempts have been made to take this into account while assessing
subjective effects. Objectives: This study aims to link the pharmacological
content of tablets sold as ecstasy to the subjective experiences reported by
ecstasy users. Methods: Self-reported effects on ecstasy tablets were
available from 5,786 drug users who handed in their tablets for chemical
analysis at the Drug Information and Monitoring System (DIMS) in The
Netherlands. Logistic regression was employed to link the pharmacological
content of ecstasy tablets to the self-reported subjective effects and
compare effects with MDMA to other substances present. Results: MDMA
showed a strong association with desirable subjective effects, unparalleled
by any other psychoactive substance. However, the association of MDMA
was dose-dependent, with higher doses (> 120mg/tablet) likely to evoke
more adverse effects. The novel psychostimulants mephedrone and pfluoroamphetamine were considered relatively desirable, whereas metachlorophenylpiperazine (mCPP) and para-methoxymethamphetamine
(PMMA) were strongly associated with adverse subjective effects. Also,
3,4-methylene-dioxyamphetamine (MDA) and benzylpiperazine (BZP) were
not appreciated as replacement for MDMA. Conclusion: Linking the
pharmacological content of ecstasy sold on the street to subjective
experiences contributes to a better understanding of the wide range of
subjective effects ascribed to ecstasy and provides a strong rationale for
the prolonged endurance of MDMA as the key ingredient of the ecstasy
market.
133
Introduction
There has been an accumulation of data on the (acute) subjective effects
of ecstasy (Verheyden et al. 2002; Huxster et al. 2006; Baylen and
Rosenberg 2006; Sumnall et al. 2006) ranging from desirable to adverse
experiences (Peroutka et al. 1988; Liechti et al. 2001; Baylen and
Rosenberg 2006; Sumnall et al. 2006). Predictors for acute subjective
effects of ecstasy include setting, precautions that were taken, pattern of
use and dose (Parrott et al. 2002; Thomasius et al. 2003; Parrott 2006;
Parrott et al. 2006; Kolbrich et al. 2008). In addition, gender may influence
the subjective effects of ecstasy with more profound hallucinogen-like
effects in women (Liechti et al. 2001). Finally, changes over time were
reported in long-term ecstasy users with a general decline of positive
subjective effects and rather stable levels of negative experiences (Murphy
et al. 2006). In contrast to these psychobiological and environmental
predictors of the subjective effects of ecstasy, very little is known about the
relationship between the pharmacological composition of ecstasy tablets
and subjective effects.
The term ecstasy generally refers to 3,4-methylenedioxymethamphetamine
(MDMA) and its structural analogues 3,4-methylenedioxyethylamphetamine (MDEA), 3,4-methylenedioxyamphetamine (MDA) and 2-methylamino-1-(3,4-methylenedioxyphenyl)butane (MBDB) (Schifano et al. 2006).
These analogue substances mostly seem to exert similar subjective effects
as MDMA (Hegadoren et al. 1999). Whereas MDMA is the main
component, other psychoactive substances were also frequently encountered in tablets sold as ecstasy (Cole et al. 2002; Simonsen et al. 2003;
Cammilleri and Caldicott 2005; Kenyon et al. 2005; Tanner-Smith 2006;
Vogels et al. 2009). Mostly, these substances are similar to MDMA in
structure or effect, but entirely other classes of pharmacological
compounds were also marketed through ecstasy tablets (Boyer et al. 2001;
Cammilleri and Caldicott 2005; Bossong et al. 2010; Brunt et al. 2010).
Also, the dose of MDMA may vary considerably between different batches
of tablets (Vogels et al. 2009).
134
Whereas the ecstasy market in the EU has been relatively stable during
the first decade of the 21st century with ecstasy tablets mainly containing
MDMA and/or MDMA-like substances (Simonsen et al. 2003; Parrott 2004;
Giraudon and Bello 2007; Vogels et al. 2009), a sharp drop in MDMA and
MDMA-like substances has been noted in recent years all across the EU
(Brunt et al. 2010; EMCDDA 2010; Schifano et al. 2011); a situation known
outside the EU already for a much longer period (UNODC 2010). Secondly,
novel compounds, referred to as designer drugs, were introduced via the
ecstasy market throughout the years, e.g. piperazine derivates acting on
the serotonin system in an effort to mimic MDMA actions (de Boer et al.
2001; Staack and Maurer 2003; Staack 2007; Bossong et al. 2010).
The pharmacological composition of ecstasy tablets is obviously of crucial
importance for the perceived subjective effects by drug users. The
discrepancy between tablets sold as “ecstasy” and the actual content has
been addressed before emphasizing the importance of a better insight into
the market of illicit drugs when discussing subjective effects reported by
drug users (Parrott 2004; Tanner-Smith 2006). Conclusions about
subjective effects could be misleading if ecstasy tablets turn out to be of
varying purity or contain unsuspected pharmacological compounds. For
instance, piperazine derivates have been on the ecstasy market for more
than ten years now and the different piperazines are chemically
heterogeneous, which is reflected in different pharmacokinetics and
subjective effects. Some studies have reported similar subjective effects of
various piperazine derivatives and MDMA (Tancer and Johanson 2003; Lin
et al. 2011), whereas other studies have indicated substantial differences
in the subjective effects of these designer compounds and MDMA
(Bossong et al. 2009; Jan et al. 2010). Similar differences in subjective
effects were found for other pharmacological classes of compounds
commonly found in ecstasy tablets (Aerts et al. 2000; Brunt et al. 2010).
Overall, relatively little is known about the link between the
pharmacological composition of ecstasy tablets, sold on the street, and the
effects experienced by drug users. This study aims to describe the
relationship between the psychoactive content in ecstasy tablets and selfreported effects of its users. To this aim, subjective effects linked to
135
chemically analyzed ecstasy tablets were collected in retrospect from the
database of the Drug Information and Monitoring System (DIMS) in The
Netherlands and the relationship of the pharmacological content with these
effects was studied.
Materials and methods
Participants
Participants were drug users that utilized the drug testing facilities of the
Drug Information and Monitoring System (DIMS). The DIMS covers all
provinces and major cities in The Netherlands. Drug users handed in their
drugs voluntarily and anonymously at a testing facility to have the
pharmacological composition of their ecstasy tablets chemically analysed
in order to know the possible health risks associated with their purchases.
Tablets were tested by the laboratory and within one week prevention
workers communicated the results to the individual drug users. For this
study, only requests about tablets that were sold as ecstasy were included.
Between 2000 and 2010, a total of 27,492 subjects asked for a chemical
analysis of their ecstasy tablets. Of these, 5,786 (21%) also reported on
previous subjective effects with the ecstasy tablet they handed in for
analysis. In compliance with the DIMS guidelines, participants were treated
anonymously and, therefore, no additional individual information was
available.
Subjective effects
The testing facilities of the DIMS have direct personal contact with the drug
users at the moment they hand in their drugs for laboratory analysis. If they
had purchased several tablets from one batch and had already taken one,
they were invited to report on their previous subjective experiences with
this tablet. Results of the chemical analyses were only available one week
later and, therefore, the reported effects could not be biased by the
analytical results. The section for reporting effects provided an open space
to specify the details of the effects, like the specific psychological and
136
physical effects. Regardless of the nature of the reported effects (physical
or psychological), all effects were treated as subjective, as they were not
measured otherwise. These items were not preselected by DIMS, and drug
users were free in the choice of their own vocabulary in describing
subjective effects. To facilitate further analysis, researchers of the DIMS
(blind to the pharmacological composition of the tablet that was handed in
and subsequently analysed) interpreted and recoded these reported effects
into discrete terms used in scientific literature, because of the drug user‟s
unfamiliarity with these (scientific) terms. In a final step, these discrete
terms were classified into three main categories: (1) desirable effects, (2)
adverse effects, and (3) lack of effects (see Table 1). For statistical
purposes, it was decided to discriminate between desirable and adverse
effects for further analyses, by comparing category 1 (desirable) to the
combination of categories 2 and 3 (adverse and lack of effect) and similarly
comparing category 2 (adverse) to the combination of categories 1 and 3
(desirable and lack of effect).
Pharmacological categorization
Categories of pharmacological contents were constructed, starting with the
most potent psychoactive ingredients present in tablets in a substantial
amount. Traces of pharmacological substances or additives with no
pharmacological properties were disregarded for the categorization.
Caffeine was not subcategorized, unless it was the only psychoactive
compound present. Since a number of tablets consisted of more than one
psychoactive component, a sub-categorization was made of the
combinations of the different psychoactive substances in the ecstasy
tablets. All 5,786 tablets were categorized this way resulting in 22 mutually
exclusive categories (see Table 2).
Drug analysis
Qualitative and quantitative chemical analyses of the drugs samples were
performed using a set of analytical methods to identify known and unknown
components. In principle, three different analytical procedures were used.
137
As a first step, thin layer chromatography (TLC, Toxilab®A) was performed
for identification. The analytes were identified by relating their position (RF)
and color to standards through four stages of detection: a coloring stage I
(Marquis reagent), a washing stage II, an UV fluorescence stage III, and
finally a coloring stage IV with Dragendorff‟s reagents. An extensive library
enabled to locate known spots and the possible crude identification of new
substances. As a second step, the quantification of the common
components (e.g. amphetamine, methamphetamine, MDMA, MDA, MDEA,
caffeine, cocaine, 2,5-dimethoxy-4-bromophenethylamine (2C-B), metachlorophenylpiperazine (mCPP) and heroin) was performed with gas
chromatography - nitrogen-phosphorous detection (GC-NPD) using an
internal standard (Chirald, Sigma-Aldrich, Zwijndrecht, The Netherlands).
Finally, gas chromatography - mass spectrometry (GC-MS) was used as a
decisive instrument in cases where TLC and GC-NPD results were not in
agreement with each other. This was necessary in approximately 10% of
the samples. Also, GC-MS was used for the identification of unknown
compounds or the quantification of uncommon compounds. All analyses
were done in a Good Laboratory Practice (GLP) compliant laboratory. The
combination of various analytical methods has led to a comprehensive list
of identified components in ecstasy tablets over the years.
Statistical analysis
Summary statistics (e.g. percentages) were used to describe the
prevalence of subjective effects and pharmacological categories in the
ecstasy tablets. Associations of pharmacological categories other than
MDMA with subjective effects were obtained by multiple logistic regression.
Pharmacological category, a categorical predictor with k categories was
entered as k-1 dummy variables with MDMA as the reference category.
This means that the regression coefficient bj of the j-th dummy variable
reflects the effect of substance j relative to MDMA. Dose effects could not
be taken into account for these analyses, because most of these other
substances are not dosage-equivalent with MDMA. In all statistical
analyses, effect estimates are presented as odds ratio‟s (OR) relative to
138
MDMA and the probabilities of the occurrence of an effect, given the value
of the dummy variable xj is estimated by:
P(effect | subst
j) 1/(1 e
(b0 b j )
)
With P(effect | substance=j) denoting the probability of the effect for
substance j and b0 and bj are estimates from the multiple logistic
regression analysis.
For the dose-effect analysis of MDMA, dose was categorized in classes of
20 mg because the effect of dose on outcome was not linear in the logit
(Hosmer and Lemeshow 2000). In the analyses of combinations of MDMA
with other psychoactive substances, interactions between all combinations
were found by logistic regression, so the dose effect of MDMA was left out
of these analyses. All analyses were conducted separately for desirable
effect vs undesirable effect and adverse effect vs desirable/ no effect as
dependent variable. For all analyses SPSS (version 17.0) software was
used. Results were considered significant if p<0.05.
Results
Description of subjective effects
The various subjective effects that were described by the drug users were
clustered as adjectives under three main subjective effect categories (see
Table 1). Of the 5,786 drug users that reported a previous experience with
an analysed ecstasy tablet, 59.5% reported desirable subjective effects,
and 40.5% experienced undesirable effects, being either adverse (16.0%)
or a lack of effect (24.5%). The subjective adverse effects category was
richest in adjectives, ranging from agitation to palpitations. A total of 53
drug users (0.9%) reported emergency care treatment or even
hospitalization due to the reported adverse effects, mostly nausea or
hyperthermic seizures.
139
Table 1 The various subjective effects after ecstasy use as reported by the
drug users at the drug testing facilities of the DIMS
Desirable Effect
N=3,440 (59.5%)
Liking, general
Euphoric
Relaxed
Arousal
Sociable/entactogenic
Effect Categories
Undesirable Effect
N= 2,346 (40.5%)
Adverse Effect
No effect
N=924 (16.0%)
N=1,422
(24.5%)
1,582
752
688
789
529
Nausea*
453
Headache
120
Hallucinations
110
Agitation
74
Palpitations*
65
Abdominal
40
cramps
26
Hyperthermic
96
seizure*
44
Dizziness
Allergic reactions
Sometimes more than one subjective effect was mentioned
* Emergency treatments or hospitalizations were mentioned with these
adverse effects
Description of pharmacological categories
Subdividing the content into categories led to 22 distinct pharmacological
categories of ecstasy tablets (Table 2). MDMA alone was by far the most
prevalent category (69.9%), followed by mCPP alone (10.6%) and all the
other categories were pretty much spread out over the rest of the tablets.
Caffeine was not included in the categories, unless tablets contained this
substance exclusively (0.7%). Average dose per tablet for each of the
pharmacological categories was calculated, except for pharmacological
substances that were not quantified by the laboratory. In the case of a
combination of MDMA with another psychoactive substance, only the
average dose of MDMA (in mg/ tablet) is given.
140
Table 2 Pharmacological categories in ecstasy tablets
Prevalence
Average dose (±
SD)
Pharmacological
N
%
mg/ tablet
categories
Total
5786
100
One psychoactive
substance only
5343
92.3
MDMA
mCPP
mCPP+metoa
MDA
BZPa
amphetamine
Mephedronea
2C-B
Caffeine
pFluoroamphetaminea
MDEA
4044
614
126
107
95
88
85
74
42
35
Min-max.
mg/ tablet
-
-
69.9
10.6
2.2
1.8
1.6
1.5
1.5
1.3
0.7
0.6
82.5 (35.2)
26.6 (13.8)
33.1 (12.9)
44.2 (18.0)
8.8 (7.7)
7.2 (3.2)
66.5 (55.0)
-
2.0-218.0
1.0-88.0
2.0-55.0
3.0-104.0
1.0-41.0
1.0-16.0
10.0-234.0
-
33
0.6
60.9 (21.6)
5.0-124.0
Combinations of
psychoactive
substances
443
7.7
MDMA+MDEA
MDMA+mCPP
MDMA+PMMAa
MDMA+amphetamine
MDMA+MDA
MDMA+2C-B
MDA+amphetamine
MDA+MDEA
BZPa+amphetamine
BZPa+mCPP
MDMA+MDA+MDEA
146
114
70
65
39
2
2
2
1
1
1
2.5
2.0
1.2
1.1
0.7
< 0.1
< 0.1
< 0.1
< 0.1
< 0.1
< 0.1
66.8 (26.9)
50.1 (21.3)
43.9 (31.1)
67.3 (33.6)
56.8 (23.7)
43.8 (6.5)
-
6.0-174.0
2.5-95.3
5.0-128.0
6.0-166.0
12.0-106.0
39.2-48.4
-
Average dose MDMA is given in case of a combination with MDMA,
average of mCPP is given in case of its combination with metoclopramide
(meto) a Dichotomous variables, not quantified by gas chromatography
141
Distribution subjective effects
The vast majority (900/924 or 97.4%) of adverse subjective effects
occurred in nine of the 22 pharmacological categories covering 15.6% of all
the tablets, these categories were: mCPP, MDMA, MDMA+mCPP, MDA,
MDMA+PMMA, amphetamine, BZP, mCPP+metoclopramide and 2C-B
(Figure 1). To give an impression of the adverse subjective effects that
were associated with which specific (combinations of) pharmacologic
substances, the numbers and relative occurrences within the adverse
effects category mentioned are presented for these nine pharmacological
categories (Figure 1). The remaining adverse effects were distributed in
low occurrences amongst 11 other pharmacological categories: pfluoroamphetamine (6), mephedrone (4), caffeine (4), MDMA+amphetamine (4), MDMA+MDA (2), MDA+amphetamine (1), mCPP+BZP (1),
BZP+amphetamine (1), MDMA+MDEA+MDA (1), MDMA+2C-B (1), and
MDEA (1). With two of the pharmacological categories no adverse effects
were reported (MDMA+MDEA and MDA+MDEA). MCPP alone (N=614)
and its combination with MDMA (N=114) accounted for most cases with
nausea (287/453 or 63.3%), whereas agitation and palpitations occurred
more frequent with amphetamine and with MDA. The combination MDMA
and PMMA (N=70) led to several reported cases of hyperthermic seizure in
drug users.
Desirable effects, on the other hand, were mostly a-specific, such as
general liking of the effect or relaxed feelings. The majority of desirable
effects (3,102/3,440 or 90.2%) were reported across 2 pharmacological
categories: MDMA (N=3,000) and MDMA+MDEA (N=102). General liking
(38%), euphoria (21%) and sociability/ entactogenic feelings (16%) were
the most prevalent effects with MDMA alone. MDA (N=26), MDMA+MDA
(N=26) and MDMA+mCPP (N=29) relatively caused more arousal and less
sociability/ entactogenic feelings (on average less than 12% of desirable
effects) than MDMA or MDMA+MDEA, whereas MDMA+amphetamine
(N=32) and MDEA (N=21) relatively caused more euphoria (both more
than 40% of desirable effects). Increased sociability and entactogenic
feelings, typically subscribed to ecstasy, was also reported with
142
mephedrone (N=54) and p-fluoroamphetamine (N=17) (both more than
30% of desirable effects).
143
144
MDMA
317
34.3%
MDMA+mCPP
53
5.7%
MDMA+PMMA
39
4.2%
Dizziness
Palpitations
Headache
MDA
42
4.5%
AMPH
24
2.6%
mCPP+meto
21
2.3%
144
is given and percentage of total within the adverse effects category, AMPH amphetamine, meto metoclopramide
2C-B
16
1.7%
Hyperthermic seizure
Agitation
Nausea
BZP
24
2.6%
Fig. 1 Distribution of majority of adverse effects among nine different pharmacological categories. Amount of tablets
Allergic reactions
Abdominal cramps
Hallucinations
mCPP
Category
364
N (tablets)
%(adverse events) 39.4%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
145
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0-20
(3.1)
0.18
0.05
21-40
(6.2)
0.29
0.05
*
41-60
(16.7)
0.66
0.04
*
61-80
(28.8)
0.83
0.05
*
81-100
(19.0)
0.88
0.06
*
*
*
*
*
*
*
101-120 121-140 141-160 161-180
(10.7)
(8.9)
(3.9)
(2.1)
0.81
0.75
0.62
0.36
0.08
0.15
0.21
0.55
*
*
>180
(0.5)
0.01
0.86
*
145
Fig. 2 Dose-effect relationship of MDMA with adverse and desirable effects. P(effect) probability of the effect.
*Odd ratio‟s significantly different from 1 in logistic regression (p<0.05, two-tailed)
0
dose range (mg)
% of MDMA alone
desirable
adverse
P(effect)
Linking pharmacological contents to subjective effects: statistical analysis
Dose-effect relationship of MDMA
The category MDMA alone consisted out of 4,044 tablets of varying doses.
Logistic regression showed an interesting biphasic relationship between
MDMA dose with subjective effects: MDMA dose was both positively
related to desirable effects (OR, 1.012; 95% CI, 1.009-1.014; p<0.001) and
adverse effects (OR, 1.024; 95% CI, 1.020-1.027; p<0.001). A more
detailed analysis of the dose-effect relationship showed that these
relationships were not linear in the logit. Entering dose as categorical
variable, after categorising dosage into 20 mg categories, resulted in a
more valid description of the dose response relationship as presented in
Figure 2. The curve for desirable effects shows that the probability of
experiencing desirable effects increases until 81-100 mg MDMA, then it
slowly decreases with high doses of MDMA showing increasingly lower
probabilities of experiencing desirable effects. In contrast, the probability of
experiencing adverse effects increases rapidly with MDMA doses
exceeding 120 mg.
Other pharmacological contents and subjective effects
Differences in subjective effects between different ecstasy tablets
containing only one psychoactive substance were analysed by multiple
logistic regression, with MDMA alone as reference category (Table 3).
Firstly, there is no single psychoactive substance that paralleled the
desirable effects of MDMA. The probabilities were all lower than with
MDMA alone (0.74) and in seven of ten categories, other than MDMA, the
OR‟s were significantly lower than 1. Only MDEA, mephedrone and pfluoroamphetamine were comparable to MDMA. Moreover, seven out of
ten categories, other than MDMA, showed a higher probability of adverse
effects compared to MDMA (Table 3). This was confirmed by the OR‟s for
these categories, with especially mCPP and MDA showing robust
increased likelihoods of experiencing adverse affects. Also BZP,
146
amphetamine and 2C-B were associated with more unpleasantness.
Interestingly, if mCPP was combined with the psycho-inactive anti-emetic
compound metoclopramide, the likelihood of adverse subjective effects of
mCPP almost disappeared. It should be noted, however, that this
combination still had a relatively low probability of desirable effects.
If combinations of MDMA with one additional psychoactive substance were
compared to MDMA alone, none of these combinations paralleled the
probability of desirable effects of MDMA alone (Table 4). Together with the
odds for desirable effects, the combinations of MDMA and its structural
analogues (MDEA or MDA) were most comparable to MDMA alone. All
other combinations had OR‟s considerably lower than 1. If adverse effects
were taken into account, the contrast between MDMA and these
combinations became even more pronounced, with MDMA in combination
with PMMA or mCPP showing a very high likelihood of experiencing
adverse affects (Table 4). On the other hand, the probability of adverse
effects with the combination of MDMA with MDEA was significantly lower
than MDMA alone.
147
148
148
Table 3 Linking subjective effects to ecstasy tablets containing only one psychoactive substance
Probability
OR (95% CI)
N desirable adverse
desirable effect
adverse effect
effect
effect
MDMA1
4044
0.74
0.08
MDA
107
0.24
0.39
0.11 (0.07 – 0.18)
7.60 (5.07 – 11.39)
MDEA
33
0.64
0.03
0.61 (0.30 – 1.24)
0.37 (0.05 – 2.70)
amphetamine
88
0.09
0.27
0.04 (0.02 – 0.07)
4.41 (2.72 – 7.15)
mCPP
614
0.09
0.59
0.03 (0.02 – 0.04)
17.12 (14.05 – 20.90)
mCPP+
126
0.23
0.17
0.10 (0.07 – 0.16)
2.35 (1.45 – 3.80)
metoclopramide
caffeine
42
0.26
0.07
0.12 (0.06 – 0.25)
0.90 ( 0.28 – 2.94)
2C-B
74
0.23
0.22
0.10 (0.06 – 0.18)
3.24 ( 1.84 – 5.71)
mephedrone
85
0.64
0.06
0.61 (0.39 – 0.95)
0.74 ( 0.30 – 1.83)
p-fluoroamphetamine
35
0.59
0.14
0.53 (0.27 – 0.70)
1.96 ( 0.76 – 5.09)
BZP
95
0.05
0.25
0.02 (0.01 – 0.05)
3.97 ( 2.47 – 6.40)
Odds ratios significantly different from 1.00 (p<0.05 two-tailed) are shown in bold
1
) reference category in the logistic regression is MDMA
149
149
Table 4 Linking subjective effects to ecstasy tablets containing combinations of psychoactive substances
Probability
OR (95% CI)
N desirable
adverse
desirable effect
adverse effect
effect
effect
MDMA1
4044
0.74
0.08
MDMA+PMMA
70
0.11
0.56 0.05 (0.02 – 0.09)
14.79 (9.10 – 24.03)
MDMA+mCPP
114
0.24
0.47 0.11 (0.07 – 0.17)
10.22 (6.95 – 15.02)
MDMA+MDEA
146
0.70
0.01 0.81 (0.56 – 1.16)
0.16 (0.04 – 0.66)
MDMA+amphetamine
65
0.50
0.08 0.34 (0.21 – 0.55)
0.98 (0.39 – 2.46)
MDMA+MDA
39
0.67
0.03 0.70 (0.36 – 1.36)
0.31 (0.04 – 2.26)
Odds ratios significantly different from 1.00 (p<0.05 two-tailed) are shown in bold
1
) reference category in the logistic regression is MDMA
Discussion
This study demonstrates the large variation in the pharmacological content
of tablets that were sold as ecstasy (MDMA) in The Netherlands between
2000 and 2010 and the related subjective effects experienced with these
different tablets. However, it must be noted that the prevalence of the
different pharmacological categories also varied greatly and that some of
the categories only occurred in small batches of marketed ecstasy tablets.
It is also noteworthy that desirable subjective effects (60%) were more
prevalent than undesirable (adverse and lack of effects), suggesting that
participants in this study did not necessarily hand in their drugs for analysis
for reasons of discontent or health concern based on previous negative or
worrisome experiences.
Overall, the results in this study show why MDMA has been such a
successfully marketed recreational party drug over such a long period of
time: MDMA has the highest probability of a desirable effect and a low
probability of adverse effect, and no other substance or combination of
substances matched MDMA‟s profile in terms of these subjective effects.
Furthermore, all subjective effects of ecstasy that were reported by the
participants in this study have been reported before by others, such as
nausea, hallucinations, headache, palpitations, dizziness but also
euphoria, relaxation and arousal (Peroutka et al. 1988; Liechti et al. 2001;
Baylen and Rosenberg 2006; Sumnall et al. 2006; Kolbrich et al. 2008). In
those studies the incidence of serious adverse effects or reactions has
been reported to be relatively low and this was confirmed by the small
proportion of such effects reported in this study (0.9%). And, despite the
lack of validated questionnaires in this study, the results on subjective
effects in this study are in good agreement with previous studies using
measures like the Visual Analogue Scales (VAS) or Profile of Mood States
(POMS) (Dumont and Verkes 2006). Similar to the current study, in
laboratory controlled studies, desirable effects were most prevalent with
the typical recreational doses, whereas adverse reactions tended to rise
with high doses of MDMA (Tancer and Johansen 2001, 2003; Baylen and
150
Rosenberg 2006; Dumont and Verkes 2006). High dose MDMA tablets
have been known to be dangerous for both unsuspecting and first time
users, possibly leading to acute serotonin syndrome reactions like extreme
hyperthermia (Parrott et al. 2002). In addition, these studies have shown
that cardiovascular effects started to occur with MDMA doses between 1.02.1 mg/kg (Dumont and Verkes 2006); doses that correspond very well to
the high doses where adverse effects started to emerge in this study (>
120 mg/tablet).
With regard to the MDMA-like substances, tablets containing MDEA and
combinations of MDMA with MDEA showed similar effects to MDMA alone,
which is in line with previous research on this substance (Hermle et al.
1993; Gouzoulis-Mayfrank et al. 1999; Hegadoren et al. 1999).
Interestingly, in the present study, MDA alone showed a decreased
likelihood of desirable effects and an higher likelihood of adverse effects. A
possible explanation could be that MDA has greater potency and a longer
duration of effect compared to MDMA or MDEA (Kalasinsky et al. 2004;
Morefield et al. 2011). By contrast, the combination of MDMA with MDA
showed a desirable profile with few adverse effects. This might be related
to some interaction between these two analogues or an additive effect of
MDA to MDMA; the MDMA dose was quite low in these tablets (56.8 mg)
compared to the tablets with MDMA alone (82.5 mg) and any resulting lack
in stimulatory effects might have been compensated for by the addition of
low amounts of MDA.
Psychoactive substances that were increasingly reported in tablets sold as
ecstasy or in “party pills” are piperazine derivatives, mainly BZP and mCPP
(Maurer et al. 2004; Tanner-Smith 2006; Antia et al. 2009; Bossong et al.
2005, 2010; Cohen and Butler 2010; EMCDDA 2010; Lin et al. 2011).
Adverse effects after ingestion of mCPP were already described by others
(Tancer and Johanson 2001, 2003; Feuchtl et al. 2004; Gijsman et al.
2004; Bossong et al. 2010). In the present study mCPP proved to be a very
poor substitute for MDMA with a very high probability of adverse effects
(59%). Confirming previous findings, nausea was the most frequent
adverse effect associated with mCPP or its combination with MDMA.
Interestingly, the likelihood of adverse subjective effects of mCPP almost
151
disappeared when metoclopramide was added to tablets containing mCPP.
Metoclopramide is a mixed dopamine D2 and serotonin 5-HT3 antagonist
and is clinically applied as an anti-emetic drug in the treatment of nausea
caused by various conditions (Cunningham 1997; Hyiama et al. 2009;
Matok et al. 2009). Metoclopramide has also been proven effective against
drug-induced nausea, but these studies did not include psychoactive drugs
like mCPP (Bytzer and Hallas 2000). Interestingly, mCPP is a potent 5-HT3
activator and the results presented here strongly suggest nausea being
induced through the 5-HT3 receptor, with subsequent antagonism by
concurrent metoclopramide ingestion (Glennon et al. 1989; Higgins and
Kilpatrick 1999). Although the producers were effective in reducing the
adverse subjective effects of mCPP through the addition of
metoclopramide, this new combination failed to produce significant
desirable properties.
Adverse events of BZP in drug users have been described previously by
others (Butler and Sheridan 2007; Johnstone et al. 2007; Thompson et al.
2010). On the other hand, similarity between subjective effects of BZP and
MDMA was suggested in studies done with healthy volunteers (Lin et al.
2009, 2011). The results of the present study indicate that BZP‟s subjective
effects are not similar to MDMA, and BZP was mainly associated with a
decreased likelihood of desirable effects and an increased likelihood of
adverse subjective effects in ecstasy users. However, most studies on
subjective effects of BZP were done in healthy, drug-naive volunteers and
doses were not determined in the present study, important factors which
might contribute to the differences in effects found and make comparisons
difficult.
The adverse subjective effects reported in this study after ingestion of
tablets containing MDMA with PMMA largely support the existing
toxicological findings by others of casualties and fatalities after
consumption of PMMA or its metabolite PMA (Caldicott et al. 2003;
Johansen et al. 2003; Becker et al. 2003; Lin et al. 2007). Extreme
hyperthermia was described as one of the symptoms of PMMA
intoxication, especially in crowded environments (Rohanova and Balikova
2009; Palenicek et al. 2011). PMMA showed a more gradual peak
152
concentration in the brain compared to MDMA, leading to a delayed pattern
of activation and prolonged endurance of effects of the drug, with
increased toxicity as consequence (Palenicek et al. 2011). Also, PMMA
may inhibit serotonin reuptake in the brain more efficiently than MDMA,
leading to extracellular serotonin accumulation (Callaghan et al. 2005).
Moreover, a mixture of PMMA with MDMA, as described in this study, has
been suggested to lead to increased and unpredictable toxicity as
compared to either compound alone (Lora-Tamayo et al. 2004).
Mephedrone (4-MMC, “Meow Meow”) is a relative newcomer on the Dutch
ecstasy market (Brunt et al. 2010). In the current study, mephedrone had a
desirable profile with a high probability of subjective desirable effects and a
low probability of adverse subjective effects. Desirable subjective effects in
drug users have been reported by a number of other studies in this field,
but also by anecdotal reports on the internet (Brunt et al. 2010; Erowid
2010; Carhart-Harris et al. 2011; McElrath et al. 2011; Winstock et al.
2011). Mephedrone is a substituted phenylethylamine, which action
probably resembles that of amphetamine and methamphetamine (Brunt et
al. 2010; Winstock et al. 2011). Its subjective effects are often described to
be similar to ecstasy and cocaine, with stimulation and alertness, euphoria,
intensity of senses and also empathy or sociability and talkativeness
(Schifano et al. 2011). Adverse subjective effects were also described and
largely resembled those of amphetamine or cocaine. However, in contrast
to the current study, most studies reported effects in users that snorted the
substance.
The recreational drug p-fluoroamphetamine (PFA, “Flux”) has
pharmacological properties distinct from amphetamine (Marona-Lewicka et
al. 1995). In rats and in vitro, p-fluoroamphetamine resembles MDMA in its
higher potency to release serotonin (5-HT) and lower potency to release
dopamine (DA) compared to amphetamine (Marona-Lewicka et al. 1995;
Wee et al. 2005; Nagai et al. 2007). In line with its 5-HT actions, users
describe it as a mild MDMA (Erowid 2006). In the current study, pfluoroamphetamine was associated with a relatively high probability of
desirable subjective effects without a significant probability of experiencing
adverse effects. By contrast, amphetamine itself did not show a desirable
153
profile of subjective effects in the participants of this study. In the light of
this, it is important to emphasize that participants were expecting an
MDMA-like experience in all cases, which may well have impacted the
subjective experience they reported on a different tablet, with amphetamine
not resembling the (expected) effects of MDMA very closely.
Inherent to the design of this study, some limitations have to be mentioned.
First of all, the DIMS is a system that is purposely anonymous because
drug users would be deterred from using the testing facilities if personal
details were an integral part of the testing session. Therefore, potential
confounders could not be included in the logistic regression models (e.g.
gender, age, psychosomatic history, education). Also, important
information about the setting or polydrug use was lacking, which could
have had an impact on the reported drug experiences. The findings are
therefore within the boundaries of a strictly pharmaco-centric approach to
drug-induced effects and need to be seen in the background of the
complexity of the ecstasy market and all its various pharmacological
appearances. Second, the study relies on the accuracy of participant‟s selfreport and there was no way of confirming the actual use of the tablets they
reported on. However, considering the sample size together with the
consistency of the dose-response relationship of MDMA in this study
suggests that most users had probably used the same tablets as they
reported on. Furthermore, the frequency of desirable and undesirable
subjective effects suggested that no selective bias for reporting sensational
or worrying effects occurred. Finally, the quality of the reported information
by drug users would be greatly improved by expanding the standard DIMS
data with at least one standardized and validated questionnaire measuring
subjective effects (Tancer and Johanson, 2001,2003).
In general, the results from this study provide strong evidence for the
prolonged endurance of MDMA as the key ingredient of the ecstasy
market, unrivalled by any other psychoactive substance addition or
substitution. It thereby suggests that all attempts to create a better product,
at least for the target population of ecstasy users in terms of its subjective
effects, have failed thus far, and leaves MDMA to be the gold standard.
This is an interesting finding in light of an ever growing attention towards
154
emerging novel designer drugs and psychoactive substances (EuropolEMCDDA 2011). In light of this it is comprehensible that many potential
substitutes for MDMA already left the market a long time ago (e.g. MBDB,
MDEA, MDA, 4-MTA) (EMCDDA 2003-2011). Furthermore, the findings
from this study may help to understand differences in subjective effects of
ecstasy found between studies from different countries and timeframes,
when ecstasy tablets were of varying purity and/ or composition.
Considering the substantial differences in effects associated with the
different pharmacological content in ecstasy tablets, it remains important to
continue monitoring the markets of illicit drugs.
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Chapter 8
General discussion
General discussion
This chapter contains a summary, a general discussion, some general
limitations of the methods that were used, and finally a general conclusion
and ideas for future research.
Summary of results
Chapter 2. The Drug Information and Monitoring System (DIMS) in The
Netherlands: implementation, results and international comparison.
In this chapter, a comprehensive overview of the DIMS was given in terms
of history, organization, methodology, laboratory analysis and some of the
main results of monitoring psychostimulants throughout the years. The
ecstasy-, cocaine- and amphetamine markets proved to be very dynamic
and often declines in purity of these substances coincided with the rise of
novel pharmacological substances. In the case of amphetamine, declines
in purity were quite simply counterbalanced with increases of caffeine
content. For ecstasy and cocaine this was more complex with mCPP,
mephedrone, 4-fluoroamphetamine or BZP emerging in street ecstasy over
the years and procaine, lidocaine, phenacetin and levamisole appearing in
street cocaine. However, the rationale behind these added substances
probably differed in some instances. Whereas the novel substances in
ecstasy tablets were very likely added to mimic the effects of MDMA,
adulterants in cocaine may have simply been added to increase profit by
selling a more diluted product. A rough international comparison with other
drug monitoring systems was made to provide some insight into the
different drug markets globally. Interestingly, the cocaine markets
appeared similar over a wide geographical dispersion, whereas synthetic
stimulant markets sometimes differed considerably between countries in
close vicinity to each other. These differences are probably best explained
in terms of export and local manufacturing of illicit drugs. Cocaine is
exported from a similar source (Latin America) to all other countries,
whereas synthetic stimulants can be locally produced. Finally, this chapter
argued for combining illicit street drug data from different sources, such as
159
a consumer derived drug monitoring system like DIMS and forensic drug
data. In conclusion, having accurate street drug data facilitates monitoring
of the continuously changing markets and aids in making risk assessments
for prevention and (international) drug policy.
Chapter 3. The relationship of quality and price of the psychostimulants
cocaine and amphetamine with health care outcomes.
This chapter approached drug monitoring from a socioeconomic
perspective of the drug market by relating the DIMS data on cocaine and
amphetamine price and quality to regularly collected data on two different
health outcomes of interest: addiction treatment and hospital admissions.
There was a strong relationship throughout time (1992-2008) for purity,
price and adulteration of cocaine in relation to both these health outcomes,
whereby purity and price were inversely correlated and adulteration was
positively correlated. In contrast, amphetamine purity, price and
adulteration hardly showed any relationship, only price showed a moderate
positive correlation with addiction treatment. This showed that illicit cocaine
market variables probably influenced the consumption patterns and
subsequently explain the increases in health care outcomes, along similar
lines as regular market dynamics influence consumption and, thereby,
health. Mechanisms other than pure market dynamics might underlie the
difference that was found between cocaine and amphetamine, such as a
higher desirability of cocaine and a greater population of problematic users
in The Netherlands (Van Laar et al., 2010). This might have caused users
to be more responsive to price decrements of cocaine for instance.
Chapter 4. An analysis of cocaine powder in The Netherlands: content and
health hazards due to adulterants.
This chapter described aspects of the cocaine market in The Netherlands,
such as purity and adulteration between 1999 and 2007. The data showed
that cocaine was increasingly adulterated. The group of adulterants
consisted of other psychostimulants, such as caffeine, local anaesthetics,
such as lidocaine or procaine and various prescription medicines with
160
various applications, such as diltiazem or levamisole. Adulterated cocaine
was associated with more adverse effects than unadulterated cocaine and
might pose additional health hazards. Diltiazem, hydroxyzine and
phenacetin were the main adulterants contributing to these adverse effects.
Diltiazem was primarily associated with adverse cardiovascular effects,
although it was probably added to counteract cocaine‟s cardiotoxicity
(Rowbotham et al., 1987; Ansah et al., 1993). Hydroxyzine was associated
with hallucinations, in line with its described side-effects (Sweetman,
2006). Phenacetin also showed an increased association with adverse
effects, but this could not be attributed to a clear mechanism of action.
Chapter 5. Impact of a transient instability of the ecstasy market on health
concerns and drug use patterns in The Netherlands.
This study described the transient shortage of MDMA on the ecstasy
market in The Netherlands in 2008 and 2009 and its impact on health
concerns and drug use patterns of ecstasy users. As it turned out, the
shortage had a considerable impact on the number of users handing in
ecstasy tablets at the DIMS for the reason of health concerns, whereas
respondents, recruited at the testing facilities, reported no major changes
in their ecstasy use. The finding that users did not adjust their use in the
event of a shortage of their drug of choice was in contrast with other
studies (Topp et al., 2003; Weatherburn et al., 2003; Roxburgh et al., 2004;
Cunningham et al., 2008). However, these studies all involved highly
addictive drugs and a marginalized and problematic group of users. This is
the first study to demonstrate that well-integrated recreational ecstasy
users show a different behavior: apparently, the reduction of available
MDMA did not cause a major shift in drug use. Possible explanations could
be confidence about their own networks of ecstasy supply or peer pressure
or drug dependence preventing a change in drug use, for example.
Actually, it has been described previously that ecstasy users were
depending on their network of peers to obtain safe, good quality tablets,
supporting the first reason (Korf, Benschop, & Brunt, 2003). As a drug use
reduction intervention, the shortage of MDMA did not affect ecstasy use
amongst this subset of users. However, drug users were more concerned
161
about their health and more often decided to use of a system for harm
reduction (DIMS) to reduce possible health risks. This is an example of the
typical balance between the policies of use reduction and harm reduction
(Caulkins & Reuter, 1997; Weatherburn, 2009).
Chapter 6. Instability of the ecstasy market and a new kid on the block:
mephedrone.
The transient shortage of MDMA on the ecstasy market during 2008 and
2009 coincided with a worrisome phenomenon that has drawn
considerable attention over the years: the introduction or rise of new
substances on the synthetic drug market. The data strongly suggested that
mephedrone was used as a substitute for MDMA in ecstasy tablets during
the shortage. In the UK, mephedrone was perceived an important cause
for health concerns and it was quickly banned under Misuse of Drugs Act
1971 (de Paoli et al., 2011; McElrath & O‟Neill, 2011). In our study there
was some support for this health concern with mephedrone proving a
strong psychostimulant with properties similar to ecstasy, but also cocaine
or methamphetamine. In comparison with MDMA, mephedrone appeared
more addictive with many users reporting craving for the substance.
Chapter 7. Linking the pharmacological content of ecstasy tablets to the
subjective effects of drug users.
This chapter aimed to address the discrepancy between tablets sold as
ecstasy and the actual content with respect to subjective effects reported
by drug users (Parrott, 2004). The DIMS database was utilized to link the
chemical composition of the tablets to the effects that were reported
beforehand by the users that handed in these tablets. A wide variety in the
chemical content was present in these tablets and it was possible to
discriminate between the effects with tablets containing MDMA alone and
tablets containing other substances. MDMA alone showed the strongest
association with desirable subjective effects, unparalleled by any other
psychoactive substance present in ecstasy tablets. This association was
dose-dependent, with higher doses of MDMA showing an increased
162
likelihood of desired effects, but very high doses to evoke adverse
subjective effects. The piperazine derivates benzylpiperazine (BZP) and
meta-chlorophenylpiperazine (mCPP) showed a high association with
adverse
subjective
effects,
whereas
mephedrone
and
pfluoroamphetamine showed relatively high associations with desirable
subjective effects. This unique way of using the DIMS data showed that
there is a strong rationale for the prolonged presence of MDMA as the key
ingredient of the ecstasy market from the perspective of the users and,
subsequently, the producers. It may further help to understand differences
in subjective effects found between studies from different countries and/or
different timeframes, when ecstasy tablets were of varying purity and/ or
composition.
General discussion
Results of this thesis will be discussed according to the main aims that
were stated in the introduction.
1. The DIMS can be used for identifying risky substances in illicit street
drugs.
Many studies in this thesis have touched upon this, either directly or
indirectly. The function of DIMS as a surveillance tool to detect hazardous
situations or substances has been discussed in chapter 2, illustrated by
examples of many new substances that were detected over the years of
monitoring and finally by warning campaigns that were orchestrated by the
DIMS in the case of dangerous substances, including atropine in cocaine
or PMA in ecstasy tablets (EMCDDA, 2007; Braida et al., 2008 and Felgate
et al., 1998; Kraner et al., 2001; Dams et al., 2003). The study results in
chapter 4 clearly demonstrate drug monitoring data as a means to identify
potentially risky and hazardous adulterants in cocaine. By describing the
increase of adulterated cocaine on the streets throughout the monitoring
period and comparing the adverse subjective effects with those of
unadulterated cocaine it was already clear that adulteration causes more
adverse effects. By further describing the nature of the adulteration and the
163
specific relationships of the different adulterants with adverse effects, it
appeared that certain adulterants were responsible for health problems in
specific. In part, these adverse events could be explained by the wellknown side-effects of these adulterants, such as atropine (Gyermek, 1998).
But many adverse effects could probably be attributed to the interaction
with cocaine itself or to the route of administration of cocaine.
Likewise, the results of chapter 6 were an effort to identify a new substance
in the ecstasy street market with possible risks. Since no scientific
information was available at the time for mephedrone, it was a preliminary
effort in describing its effects and placing those in a context of possible
harm indication. Mephedrone is a substituted cathinone and is part of a
new wave of very diverse chemicals tentatively referred to as “legal highs”
or “research chemicals” (EMCDDA, 2010; Brandt et al., 2010; Nichols,
2011). The term “legal high” is derived from the fact that most of these
substances do not have a legally controlled status yet, which is of course
an advantage from point of view of global commercial trade. However, in
2011 mephedrone was banned in the UK. These new chemicals are
manufactured in laboratories worldwide, sometimes on demand by
experimenters and users alike. But usually, the chemicals are shipped and
meant for sale through commercial internet suppliers, often sold under
false pretences with names that do not arouse suspension with the
authorities, such as insect repellent or plant fertilizer (Evans-Brown et al.,
2011). As the results showed, mephedrone could indeed pose an unknown
health threat, because it seemed to be more addictive and was ingested by
naive ecstasy users. The nature of this threat only starts to be unravelled in
very recent pharmacology and toxicology journals (Motbey et al., 2011;
Hadlock et al., 2011; Kelly, 2011).
2. The DIMS can be used to resolve some basic health issues that are very
difficult or impossible with more traditional techniques used in
pharmacological science.
An important aim of this thesis was to show that drug monitoring can be
more than a mere toxico-chemical data collection tool over time. For
example, the information on the street market for psychostimulants could
164
be coupled to other information sources to shed light on larger dynamic
processes, as was done in chapter 3 where DIMS data were coupled with
health outcomes. This provided a useful way of handling drug monitoring
data and results seemed consistent with similar efforts by others (Hyatt, Jr.
and Rhodes, 1995; Caulkins, 2001, 2007; Smithson et al., 2004; Dave,
2006). Moreover, frequent sampling allows for a more reliable and accurate
prediction and the relationship between relevant time-dependent
phenomena can only be studied with a detailed monitoring system
(Brownstein & Taylor, 2007).
Combining the toxico-chemical data of the DIMS with the information
provided by drug users that handed in their drug samples made it possible
to investigate the pharmacodynamics and health consequences of
(combinations of) illicit street drugs. For example, in chapter 4 this strategy
provided information on the health effects of many different
pharmacological adulterants in cocaine powder; something that would have
been impossible with the use of regular psychopharmacological research
methods, such as questionnaires or experimental laboratory settings. This
strategy was also used in chapter 7 to study the pharmacodynamic profile
of pure MDMA compared to its substitutes or its combination with different
additives. This would have been virtually impossible with conventional
ways of measuring subjective effects in the interview setting, when there is
no way of confirming actual intake of a substance, let alone the nature of
the substance (Liechti et al., 2001; Verheyden et al., 2002; Huxster et al.,
2006; Baylen and Rosenberg, 2006; Sumnall et al., 2006). In the
experimental laboratory setting it would be very difficult, because all
substances and mixtures would have to be prepared and tested on the
participants separately, which would have been dismissed on ethical
grounds alone (Tancer and Johanson, 2003; Jan et al., 2010; Lin et al.,
2011). This way of adapting the DIMS data provided a unique way of
understanding the rationale for the prolonged presence of MDMA as a key
ingredient of ecstasy in the dynamic illicit drug market. It also provided
unique information on the relationship between the chemical composition
of ecstasy tablets and desirable or adverse effects and their possible
relevance to health risks.
165
3. The value of drug monitoring for harm reduction and prevention.
How could the DIMS aid in harm reduction or prevention? Classical
prevention involves the government investing in encouraging young people
not to take drugs, by mass media campaigns or school programs for
example (Derzon & Lipsey, 2002; Cuijpers et al., 2002). However,
evidence for the effectiveness of this kind of approach is limited. The
recognition that drug use is unavoidable, harm reduction is a much more
active approach of offering prevention care to drug users, as exemplified
by the famous syringe-exchange program with injecting drug users
(Hartgers et al., 1989). In chapter 2, two arguments were given in favour of
a drug analysis and testing system as a worthwhile prevention tool. First,
individual harm-reduction advice might serve the needs of existing users
better than promoting full abstention (Gamma et al., 2005). The DIMS
provides this individual approach. Secondly, regulatory efforts by the
government, either by law enforcement or prevention scaring tactics are
often considered as tendentious and untrustworthy and conflicts with the
individual‟s idea of self-regulation (Ritter, 2010). Drug users might be better
persuaded by personal contacts with well-informed peers or professionals
of the DIMS (Allott et al., 1999; Falck et al., 2004; Toumbourou et al.,
2007). Moreover, drug testing has been suggested as a useful tool to
change drug use during a situation where drugs contain chemical
compounds that are unwanted or unknown (Johnston et al., 2006).
The results presented in chapter 5 show that the shortage of MDMA on the
ecstasy market increasingly led many more Dutch ecstasy users to have
their drugs tested at the DIMS, mainly for reasons of health concern. This
led to a rapid increase in awareness about the situation on the ecstasy
market, which in turn led to a greater knowledge about the possibility of
drug testing possibly through friends or internet (Benschop et al., 2002;
Boyer et al., 2005; Gordon et al., 2006). Also, many drug testing facilities of
the DIMS made their activities known through internet and certain test
results may be have been circulated by means of internet as well. Taken
together, this study showed that DIMS had an effective reach as a harm
reduction tool, even though the information of shortage of MDMA provided
166
by the DIMS did no appaear to change drug use or drug use patterns of
ecstasy users frequenting the testing facilities. At least, this showed that
Dutch ecstasy users were responsive to harm reduction strategies and
unwilling to take too many risks with their health. On the other hand, it
could be argued that a system like the DIMS might also contribute to a
mistaken feeling of safety about the drugs these users were taking. The
absence of acute toxicological substances is in no way a guarantee that
drugs are safe to be used. In fact, every form of drug use is potentially
hazardous. However, a system like DIMS acknowledges this and tries to
transfer prevention based on scientific information and gives education
about general drug risks. Moreover, another criticism might be that the
existence of a drug testing system might even encourage young people to
start using drugs and in fact lead to an increased drug use. This argument
can be simply invalidated by comparing the prevalence figures of stimulant
drug use in The Netherlands to countries that do not have an elaborate
system for drug testing. Prevalence of psychostimulant drug use for the
last decade in The Netherlands has rather been on the low end of the scale
if compared to countries with no means of public drug testing (UNODC,
2011; EMCDDA, 2010). The same basically applies to the other countries
that have a drug testing system for some time. This suggests that the
existence of a drug testing system does not contribute to a higher
prevalence of drug use.
Another interesting way of harm reduction is through the surveillance
function of the DIMS using warning campaigns such as described in
chapter 2. Substances that were identified as hazardous in those warning
campaigns were always quickly removed from the market (Spruit, 2001).
Also, in other countries with drug testing and monitoring systems, the
chemical composition of illicit drugs seems to correspond more closely to
what is expected than in countries without such systems, suggesting at
least some influence of the drug testing systems on the illegal market
(Kriener et al., 2001; Parrott, 2004).
4. The added value of drug monitoring as a tool to aid national and
international drug health policy.
167
Despite some skepticism and criticism, illicit drug market monitoring is
recognized more and more as a valuable tool for public health (Winstock et
al., 2001; Katz et al., 2010; Ritter, 2010). Drug monitors keep track of
(more) hazardous substances in illicit street drugs and this may result in
national or international politics to take action. In collaboration with the
Netherlands Health Care Inspectorate (IGZ) and under the authority of the
Dutch Ministry of Health, Welfare and Sport (VWS), a national warning
campaign (also referred to as a “Red Alert”) can be orchestrated, often
through the media, in the case of dangerous adulterants or other risk
situations related to the illicit drug market. In chapter 2 the different warning
and prevention activities in The Netherlands were described. Furthermore,
risk assessments were sometimes deemed necessary on the basis of
DIMS results, that are made by the Coordination Centre for the
Assessment and Monitoring of new drugs (CAM) (Van Amsterdam et al.,
2004). A risk assessment is an official scientific evaluation of a certain
substance and is presented to the government in order to determine
whether further decisive steps should be undertaken legally to remove this
substance from society. This may result in a re-evaluation of the national
drug policy and registration of substances under the Dutch Opium Act,
making trade and possession illegal offences.
On an international level, DIMS data are essential in alerting the European
Union. The European Early Warning System (EWS), an European Union
collaborative system, regularly updates information with DIMS data, and
can call for an official risk assessment to be made when widespread use of
new and hazardous chemicals is suspected. As was described in chapter
2, the reporting of BZP, 4-MTA, PMA and MBDB in ecstasy tablets to the
EWS was followed by risk assessments and consecutive bans of these
substances (EMCDDA, 2010). The DIMS was amongst the first drug
monitors to report these substances (Spruit, 1999). More recently, there
were DIMS reports of the partial replacement of MDMA in tablets sold as
ecstasy by the previously unseen substance mephedrone (chapter 6). In
the UK, there was widespread use of mephedrone reported among youth,
which was partly due to the deteriorated ecstasy- and cocaine markets in
the UK (Winstock et al., 2011; Measham et al., 2010; Brandt et al., 2010a).
168
Reports of incidents and fatalities with the substance and the general
unfamiliarity with it caused it to be banned in the UK in 2010 (Morris, 2010).
Based on the DIMS data and EWS reports from other states, a risk
assessment has been conducted by the EMCDDA, which will possibly lead
to a ban in all remaining EU member states (EMCDDA, 2011). The
EMCDDA has a special interest in the continuing rise of these new
psychoactive substances and adulterants, and this will undoubtedly keep
monitoring systems like the DIMS at the heart of international policy
making.
Limitations
Although the data presented in this thesis have some valuable applications
and can provide some unique insights, there are also limitations that need
to be discussed. First, there is the representativeness of the monitoring
data to consider. For instance, in chapters 3 and 5, DIMS data were
treated as predictive drug time series to represent the situation on the drug
market. However, by definition, the DIMS is not an exact representation of
the Dutch drug market situation, but it rather functions as an
approximation. It is mainly focused on the national diversity of illicit drugs
rather than the precise number of drugs and the precise frequency of
events. Moreover, it is limited to a fraction of all drug users. Most drug
users will probably never enter a testing facility of the DIMS. In its form, it is
probably the best possible way to describe the diversity of the drug
markets. But this still means that representative information about the
market is missed and purity or adulteration figures are best possible
estimates of the actual situation. However, there is an indication that the
DIMS data are a good approximation of the illicit drug market since the
DIMS drug market data were in good agreement with police seizures over
two years (Vogels et al., 2009). Another limitation in inferring causality of
the DIMS derived time series to other time dependent phenomena was the
fact that only annual time series were available from health care monitoring
systems in The Netherlands. With this long sampling lag period (one year)
it is only possible to detect broad patterns in fluctuation, whereas important
details about short-term effects are missed. In that respect, it would be
169
profitable to have more frequent reports from the other monitoring
agencies, so more could be inferred about exact causes and effects.
Another recurring limitation of the DIMS methodology in this thesis is the
possible sample bias. For instance, in chapter 5 it was stressed that a
convenience sample was used, i.e. drug users that had access to ecstasy
tablets and had the opportunity to test them. There was no way of knowing
whether the increased health concerns or changed drug use behaviour
were also applicable to the total population of ecstasy users. Likewise, in
the other chapters, possible bias in submitted drugs at the DIMS may have
occurred because of specific concerns or discontent with the effects of the
drugs in question. However, some results implied that this was not the
case, such as the results in chapter 7, were many more ecstasy tablets
were submitted that were associated with desirable effects than tablets
which weren‟t. Nevertheless, some caution has to be warranted as the
DIMS might have received proportionally more suspicious (diluted)
samples than were actually circulating on the streets. It is also important to
bear in mind that many of the effects reported in this thesis (e.g. chapters
4, 6 and 7) were experienced under the assumption that substances
contained something else or were of higher purity.
Finally, it has to be stressed the DIMS is a purposely anonymous system
because drug users would otherwise refrain from using the testing facilities
for reasons of personal privacy and possible fear of prosecution. It
therefore lacks interesting variables (e.g. gender, age, psychosomatic
history, education) that would enrich some studies and give better answers
in terms of causative factors for effects or outcomes. Additionally,
information about the settings of use, routes of administration, dose or
polydrug use was lacking in much of the individual cases. Therefore,
findings are often very basic and only allow the study of a pharmacocentric route of drug-induced effects. The lack of potentially confounding
factors often makes it difficult or even impossible to reach causal
inferences and interpretations. On the other hand, this is the strength of the
system, because pharmaco-centric data are often missing in most
psychopharmacological studies.
170
Future developments and future research
As is shown in this thesis, drug monitoring is a dynamic process that can
be adjusted and evolved over the course of time. For all its strengths, there
may be additions or further developments that await continuously, for
example, the expansion and improvement of the DIMS website to generate
more valididated and accurate data about the illicit drug markets. But other
systems of monitoring might also be considered. To sum up some
possibilities:
sewage epidemiology (broad scale for monitoring existing drugs,
but also small scale for detection of new drugs)
adding information to the current DIMS databank to allow a better
control for potential confounders
designing a specific website to collect user data on illicit drugs in
order to monitor the nature of effects, separate from the DIMS data
collection
general internetsurveys to collect a vast amount of data concerning
drugs
linking DIMS with other databases
Conclusion
The findings in this thesis show that drug monitoring can be used to
resolve some health issues and that it can also be applied to gain insights
for the development of drug policy. Through all layers of drug politics,
nationally or internationally, the DIMS is consulted for information updates.
The data in this thesis show that the illicit psychostimulant markets in The
Netherlands are very dynamic and continuously changing. When the purity
of certain psychostimulants dropped, the probability of new psychoactive
substances or new adulterants appearing on the market increased. Also,
the market dynamics of illicit drugs showed remarkable similarities with that
of regular consumer products. With regard to prevention activities, timely
monitoring by DIMS has repeatedly resulted in timely mass media
171
warnings and through the DIMS network the communication was
specifically directed at the groups at risk and maintained at a level of
professionalism appreciated by these specific groups. The results in this
thesis support the awareness of drug users about the drugs they consume
and show the increasing awareness about the option of drug testing.
Coupling the chemical data of the DIMS to the information that was
communicated by the drug consumers yielded many new insights into the
different effects of the expected, but mainly unexpected, psychostimulants
and other substances in the drug samples. These examples can be seen
as a basis for more refined research.
Finally, with some notes on future directions, promising new avenues for
assembling drug data are underway, like drug monitoring through the
analysis of public wastewater for example. Especially, combining different
sources of drug data and more frequent reports would hold promise for
optimal data for interpretation and creating timely drug policies.
Furthermore, while warranting anonymity, enriching the DIMS database in
the future with new items, like dose, route of administration, age, gender
etc., would greatly increase the scientific value of the DIMS data, leaving
less room for speculation or misinterpretation of effects.
172
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Nederlandse samenvatting en discussie (Dutch summary &
discussion)
Samenvatting
In het hoofdstuk 2 wordt een gedetailleerd overzicht geboden van het
DIMS, de geschiedenis, organisatie, methodologie en belangrijkste
resultaten. .In dit hoofdstuk worden de resultaten van het monitoren van de
belangrijkste illegale psychostimulantia markten weergegeven, namelijk de
ecstasy-, cocaïne- en amfetamine markt. Nadruk wordt gelegd op de
trends in zuiverheid van de betreffende drugs en toevoegingen die
opduiken. Daarnaast worden enkele internationale intiatieven beschreven
om de markt voor illegale drugs te monitoren en de resultaten daarvan in
vergelijking met elkaar en het DIMS. Het hoofdstuk probeert het nut te
laten zien van het monitoren van de illegale drugsmarkt voor de inschatting
van de risico‟s waarop vervolgens preventie en beleid kunnen worden
gebaseerd.
Hoofdstuk 3 laat de fluctuaties in de tijd zien van de prijzen en zuiverheid
van cocaïne en amfetamine en legt het verband met aan deze drugs
verbonden ziekenhuisopnames en verslavingszorg. Met behulp van
specifieke tijdreeks regressie is aangetoond dat zowel zuiverheid als prijs
van cocaïne sterk samenhangen met deze twee uitkomstmaten voor
gezondheid. Dit in tegenstelling tot amfetamine. Dit laat zien dat de
marktvariabelen voor een illegale drug als cocaïne van invloed zijn op de
consumptie en daarmee de gezondheid. Dit gaat niet op voor amfetamine,
ondanks sterke psychoactieve gelijkenis van dit middel met cocaïne.
Vermoedelijk zijn er andere factoren in het spel, zoals hogere incidentie
van problematisch gebruik van cocaïne en daarmee een grotere vraag.
Hoofdstuk 4 beschrijft de cocaïnemarkt in Nederland in detail en richt zich
op de zuiverheid en versnijdingen van dit poeder. Cocaïne blijkt door de
jaren heen steeds meer te worden versneden met allerlei andere
pharmacologisch actieve stoffen, met name andere psychostimulantia,
lokale anaesthetica en medicijnen met allerlei toepassingen. Over het
algemeen bleek cocaïne, versneden met deze stoffen, meer negatieve
206
bijwerkingen te geven als onversneden cocaïne. Het zou dus kunnen dat
veel van deze toevoegingen extra gezondheidsrisico‟s met zich
meenemen.
Hoofdstuk 5 beschrijft een tijdelijk tekort aan MDMA, het psychoactieve
hoofdbestanddeel van ecstasy, op de pillenmarkt in Nederland tussen
2008 en 2009. Er word teen verband gelegd tussen dit tekort en het
druggebruik en de zorgen over de gezondheid bij ecstasygebruikers.
Gedurende dit tijdelijke tekort werden veel meer pillen ingeleverd bij het
DIMS als normaal en de voornaamste reden daarvan was bezorgdheid om
de gezondheid. Daarnaast bleek dat ecstasygebruikers die gebruik
maakten van het DIMS niet massaal hun druggebruik veranderden als
gevolg van de vermindering aan MDMA in ecstasypillen. Dit is eigenlijk in
tegenspraak met wat verwacht werd. Kennelijk passen ecstasygebruikers
niet zonder meer hun gebruik aan aan een verandering in de markt,
waarschijnlijk vanwege het feit dat de drang om ecstasy te gebruiken niet
zo groot is als bij meer verslavende middelen en omdat ecstasygebruikers
in Nederland doorgaans vertrouwen op de kwaliteit van hun bronnen om
ecstasy te verkrijgen. De vermindering van MDMA op de markt heeft dus
niet meteen effect op het gebruik, wel op de zorg over de gezondheid
vanwege allerlei mogelijke toevoegingen aan de pillen. Vandaar de
toename aan pillen bij het DIMS gedurende die periode.
Hoofdstuk 6 gaat verder in op het tekort aan MDMA op de ecstasymarkt en
beschrijft welke andere middelen zijn toegevoegd aan de pillen om het
tekort op te vangen of mee te compenseren. In 2009 kreeg het DIMS
opeens erg veel pillen aangeleverd waarin de onbekende stof mefedrone
zat. Het lijkt erg veel op dat mefedrone is gebruikt om het tekort aan
MDMA mee op te vangen. Mefedrone had elders in Europa al tot
zorgwekkende berichten geleid en in dit hoofdstuk worden enkele van de
belangrijkste subjectieve effecten van mefedrone weergegeven, zoals
beschreven door de gebruikers. Mefedrone blijkt met name een stof met
sterkere verslavende effecten als MDMA, waarmee de zorg voor
gezondheidsproblemen niet geheel onterecht bleek.
In hoofdstuk 7 wordt meer uitvoerig gekeken naar de subjectieve effecten
die gebruikers van ecstasy meldden aan het DIMS en de daadwerkelijke
207
inhoud van de pillen. Hierbij werden de effecten van het hoofdbestanddeel
MDMA afgezet tegen de belangrijkste andere bestanddelen die werden
gevonden bij chemische analyse. Het bleek dat eigenlijk MDMA een erg
hoge associatie had met gewenste effecten en een lage associatie met
ongewenste effecten. Dit profiel was ongeëvenaard in vergelijking met alle
andere psychoactieve bestanddelen of combinaties daarvan. Wel was de
associatie dosis gerelateerd, hogere doses MDMA zorgden voor relatief
meer ongwenste effecten. Dit hoofdstuk toont de hoge populariteit van
MDMA op de ecstasymarkt aan en waarom het al zo lang repertoire houdt,
tevens waarom allerlei potentiële vervangers na verloop van tijd weer van
de markt zijn verdwenen.
Discussie
Ten eerste laat dit proefschrift zien dat het DIMS kan gebruikt worden om
riskante stoffen te detecteren op de markten van illegale drugs. Dit wordt
duidelijk
aangetoond
in
hoofdstuk
2,
waarin
ook
de
waarschuwingscampagnes voor deze stoffen over de jaren worden
besproken. In hoofdstuk 4 worden potentieel gevaarlijke toevoegingen aan
cocaïnepoeder beschreven door de tijd heen en is het duidelijk dat het
toevoegen van allerlei andere stoffen een extra gevaar vormt voor de
gezondheid van de gebruikers. Hoofdstuk 6 beschrijft het opduiken van
een nieuwe stof op de ecstasymarkt en de potentiële risico‟s die daarmee
gepaard gaan, alhoewel er nog moet blijken uit verder onderzoek hoe
gevaarlijk mefedrone echt is. En hoofdstuk 7 geeft ook tal van stoffen weer
op de ecstasymarkt die in elk geval gepaard gaan met vervelende
bijwerkingen bij gebruikers.
Dit proefschrift toont tevens aan dat het DIMS gebruikt kan worden om
gezondheidsgerelateerde zaken te onderzoeken die met andere
pharmacologische onderzoeksmethodes heel moeilijk zouden zijn. Zoals
de monitoring data uit hoofdstuk 3 die inzicht geven over de invloed van de
drugsmarkt op uitkomstmaten voor gezondheid. Hierin is duidelijk te zien
dat gezondheidsuitkomsten sterk van de markt afhankelijk kunnen zijn, in
het geval van cocaïne. Ook is het mogelijk om in detail te kijken naar
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bijwerkingen van verschillende toevoegingen aan cocaïne, iets dat vrijwel
onmogelijk zou zijn in een experimentele klinische setting of met
vragenlijsten. Hetzelfde geldt voor de resultaten in hoofdstuk 7, waar de
farmacologische samenstelling van ecstasy over de hele breedte van de
markt is bekeken en gerelateerd aan subjectieve effecten bij de gebruikers.
Deze farmacologische samenstellingen zouden via vragenlijsten nooit
kunnen worden uitgezocht, en in klinische studies zou de enorme variëteit
aan doses en verschillende farmacologische substituten of toevoegingen
stuiten op ernstige praktische en ethische problemen.
Het proefschrift probeert ook de bijdrage van DIMS aan “harm reduction”
en preventie te onderschrijven. Het is al jaren bekend dat generieke
preventie van bovenaf (beleid) niet erg effectief is (Derzon & Lipsey, 2002;
Cuijpers et al., 2002). “Harm reduction” is een meer pragmatische
benadering, namelijk de onderkenning van het feit dat drugs bestaan en
waarschijnlijk altijd gebruikt zullen worden. Het DIMS en haar netwerk
heeft een wetenschappelijke en informatieve benadering hierin, door de
één-op-één contacten met de preventiezorg kunnen gebruikers goed
bereikt worden en voorgelicht over risico‟s van stoffen en druggebruik.
Daarnaast beschouwen veel druggebruikers de waarschuwingsboodschappen door de regering over druggebruik vaak als overdreven
tendentieus en bemoeizuchtig. Het DIMS en haar netwerk is een
geloofwaardiger bron met goed onderbouwde informatie en feiten over
drugs en druggebruik. De resultaten van hoofdstuk 5 tonen aan dat weinig
ecstasygebruikers meteen reageren in druggebruik naar aanleiding van
een tekort aan MDMA, maar dat wel veel meer gebruikers opeens geneigd
zijn zich te laten voorlichten en hun drugs te laten testen via het DIMS. Ze
zijn dus zeker niet bereid om alle gezondheidsrisico‟s zomaar voor lief te
nemen. Dit laat zien dat Nederlandse gebruikers zeker responsief zijn op
“harm reduction” benaderingen. Argumenten dat het DIMS zorgt voor een
vals gevoel van veiligheid bij de gebruiker worden niet ondersteund door
de aanhoudende vraag naar informatie en het snel rondverspreiden van
waarschuwingssignalen via drugsfora en vriendenkringen. Verder leert de
vergelijking met landen zonder drug monitoring systemen dat het DIMS
ook niet meteen het gebruik in de hand werkt. Eerder omgekeerd.
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Het belang van het DIMS voor het nationale en internationale drugsbeleid
wordt ook onderstreept in dit proefschrift. Steeds meer wordt het monitoren
van de illegale drugsmarkt als een belangrijk instrument gezien voor de
volksgezondheid (Winstock et al., 2001; Katz et al., 2010; Ritter, 2010).
Nationale waarschuwingscampagnes kunnen worden opgezet als er zich
iets extra gevaarlijks afspeelt op de drugsmarkt. Daarnaast kunnen
risicoschattingen worden gedaan op basis van de gegevens die het DIMS
aanlevert. Dit zijn veelal wetenschappelijke beleidsdocumenten die een
regering ertoe kunnen besluiten een bepaalde stof op de Opiumwet te
zetten of de opsporing te intesiveren. Maar de DIMS gegevens zijn ook
essentieel voor internationale systemen als het Early Warning System
(EWS) van de Europese Unie (EU) om risicoanalyses te doen en beleid te
voeren op Europese schaal. Vele stoffen zijn zo al op lijsten van verboden
middelen gekomen in de gehele EU, vaak op basis van gegevens van
onder meer het DIMS, het recenste voorbeeld hiervan is het in hoofdstuk 6
beschreven mefedrone. Dit soort Pan-Europese activiteiten zal
vermeodelijk alleen maar toenemen, en het DIMS vormt een belangrijke
spil in dit proces.
Er zijn ook vele beperkingen van het soort onderzoek dat in dit proefschrift
beschreven wordt en onzekere factoren. De meesten hebben te maken
met de opzet van het DIMS en de manier van gegevensverzameling.
Daarom worden er enkele verbeteringen van de opzet van
gegevensverzameling en mogelijke toekomstige alternatieven om de
drugsmarketen te monitoren gegeven, zoals daar zijn: de huidige DIMS
databank uitbreiden met meer items die een betere kwaliteit van de
gegevens opleveren; het meten van illegale drugs in afvalwater ten
behoeve van een veel breder en completer plaatje ten aanzien van de
drugssituatie in Nederland; betere samenwerking en verbinding van DIMS
met andere bronnen voor gegevensverzameling.
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Dankwoord (words of praise)
Terwijl de hevigheid van het beschreven onderwerp nog tot u doordringt,
kunt u even ontspannen tijdens het meest begrijpelijke en informele deel
van het proefschrift, namelijk het dankwoord. En dat zal zeker niet een
kwestie zijn van last and least! Want hoewel ik iedere letter in dit
proefschrift eigenhandig heb opgeschreven, zijn er best wat mensen te
noemen die een belangrijke contributie hebben geleverd aan dit werk.
Lastige is alleen, met wie begin je, met wie eindig je en vergeet je niet een
paar namen? Ik kies ervoor om te beginnen bij de professionele kring en af
te sluiten met de persoonlijke kring om me heen die me hebben
gestimuleerd, geholpen of anderzijds van nut zijn geweest.
Allereerst wil ik beginnen met Wim, mijn promotor en belangrijkste
sparringspartner voor dit proefschrift. Wim, toen ik je benaderde een paar
jaar terug om je te vragen of je mijn promotor wilde zijn vond ik je al aardig,
maar kon niet vermoeden wat een uitstekende en prettige begeleider je
was! Met name de combinatie van begrip, snel overzicht en prima ter zake
doende suggesties en opmerkingen maakt dat ik me op ieder overleg met
jou verheug en een nieuwe stimulans opdoe voor mijn verdere plannen.
Vooral de enthousiaste lichtjes in de ogen die beginnen te branden zodra
je een leuk fris idee voor verder onderzoek ontwaart. Ik voel ook meteen
een soort van rust en vertrouwen bij je zodra ik in je kamer plaatsneem,
ondanks het voortdurende en hardnekkige gezoem van drukte en chaos
dat jou overal lijkt te vergezellen. Daarom vind ik het extra
bewonderingswaardig dat je na ieder stuk dat ik je opstuur en iedere vraag
die ik voor je heb altijd vrijwel direct antwoord geeft via de mail. Je
voornemens om het eens een tijdje wat rustiger aan te doen lijken dan ook
voorlopig nog even in de koelkast te moeten worden gestald. Ik hoop toch
dat je hier binnenkort wat meer tijd voor kunt vrijmaken, alhoewel ik het
gevoel heb dat die drukte je ook wel prima ligt, net zoals die mij wel ligt.
Daarnaast wil ik mijn directe collega‟s van het DIMS team natuurlijk
bedanken. Ten eerste Raymond, die mij altijd alle vertrouwen en vrijheid
heeft gegund om te doen waar ik goed in ben. Wij hebben een bijzonder
ontspannen basis van samenwerken gevonden waarbij je je allang geen
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zorgen meer maakt over mijn instelling of kundigheid. Daarnaast ben je
een markante persoonlijkheid met een bijzonder goed gevoel voor humor,
iets waar ik iedere dag wel lol van heb. Die humor kan evengoed naar
voren komen in gesprekken over Jiskefet als over de wetenschappelijke
kringen waarin we hebben vertoefd. Peter, jij bent ons gezicht naar de
media. Dat doe je buitengewoon goed en vakkundig, met behoud van je
eigen persoonlijkheid en nuances. Ik ben het vrijwel altijd met je eens in
gesprekken daarover en kan meestal hardop lachen om je rake
bespiegelingen over het “drugswereldje” waarin iedere keer weer dezelfde
discussies, mythes en stereotypes opduiken. Van jou heb ik ook de
gouden uitdrukking “organoleptisch”, iets waarvan ik erg in verleiding kwam
om dat een keer onopvallend te gebruiken bij de beschrijving van onze
testmethodes. Sander, altijd monter en vrolijk en altijd in voor een
opmerking met een (al dan niet cynische) knipoog. Ook wij matchen goed,
ik kan regelmatig bulderen om je rake observaties en ironische
opmerkingen. Ondanks dat je altijd een notoire afkeer van de wetenschap
veinst, geloof ik dat je het stiekem wel leuk vindt, zoals de appel die nog
niet zover van de boom is gevallen. Neeltje, als een geduldig bloempje zit
je het gebral en gekift uit van weer een bewogen discussie over
testuitslagen en correspondentie naar de DIMS deelnemers of de pers.
Zoals je weet gaan de meeste van die discussies vaak nergens over en
komt het uiteindelijk altijd wel goed. Een bijzondere vermelding voor
Matthijs, alhoewel je nu alweer 4 jaar actief bent bij Nick Ramsey op het
veld van neuroimaging en MRI‟s, heb je me destijds aangestoken met je
pure enthousiasme om mijn wetenschappelijke carrière niet te laten
versloffen. Daarnaast heb ik tijdens alle borrels ook veel aan je gehad, ik
ben erbij op je promotie!
Het Drug Monitoring team heeft ons als onderdeel heel soepel opgenomen
en de onderlinge samenwerking en contacten lopen prima. Vooral is dit te
danken aan Margriet. Net zoals Raymond heb ik veel aan jou te danken,
het feit dat je me min of meer een beetje op het spoor hebt gezet wat tot dit
proefschrift heeft geleid. Daarnaast je aanmoediging en het feit dat je me
volledige vrijheid en extra tijd hebt gegund om te kunnen blijven schrijven.
Je liet meteen blijken dat je het belangrijk vond dat ik zou promoveren en
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dat het de deskundigheid en professionaliteit van het team ten goede zou
komen. Ik zal er alles aan doen om dat ook waar te maken in de toekomst,
je kunt me altijd ergens voor inzetten, zoals je weet. En je bent een prettige
en zeer stimulerende gesprekspartner als het over onze onderzoeken gaat.
Verder stel ik het erg op prijs dat je me regelmatig even naar mijn
dochtertjes vraagt. Toine, Guus, Gerda, Esther en Ellen bedankt voor de
leuke gesprekken en de ondersteuning. Peggy, jij bent erg prettig als
sparringspartner en als mede-promovendus van Wim, zo heb je me al een
paar keer wegwijs gemaakt in de wondere wereld die AMC Graduate
School heet en de papieren die je daarvoor allemaal in orde moet hebben.
Ook wordt het erg op prijs gesteld dat jij de borrel levend houdt. En
tenslotte Franz, don‟t waste your water!
Verder wil ik uitdrukkelijk de DIMS deelnemers bedanken. Dat zijn er
echter zoveel en het netwerk zo breed en divers dat ik daarvoor geen
namen ga opnoemen. In plaats daarvan zal ik de instellingen nog even
allemaal bij naam noemen en wil benadrukken, net zoals ik in mijn
artikelen heb gedaan, dat zonder hun tomeloze, enthousiaste en vaak
onbaatzuchtige inzet er géén DIMS bestond! Stichting Adviesburo Drugs,
Stichting Jellinek, Tactus Verslavingszorg, Novadic-Kentron, Stichting
Mondriaan, Stichting GGZ-NML, Stichting Traject, Stichting Mainline,
Centrum Maliebaan, Stichting Iriszorg, Verslavingszorg Noord Nederland,
Parnassia Bavo Groep, Brijder Verslavingszorg, Bouman GGZ, Stichting
Emergis. Met vrijwel iedereen van jullie heb ik een uitstekend contact en ik
hoop jullie nog veel te spreken, tijdens overleggen of telefonisch. Ook wil ik
de andere partijen die belangrijk zijn voor het voortbestaan van het DIMS
nog even bedanken, VWS, de begeleidingscommissie, het EMCDDA, EWS
en het focal point.
De staf van het AMC wil ik ook nog even bedanken, met name Bep, de
gezellige babbelkont en bewaker van Wim‟s overvolle agenda. Ook voor
jou hoop ik dat je genoeg rust kunt meepakken in de toekomst, zodat je
niet helemaal afgedraaid bij je kleinkinderen aankomt. Maarten, een betere
mentor op het gebied van statistiek ben ik tot dusver nog niet
tegengekomen. Cleo, Vlaams vogeltje van me! Ik hoop ook snel op jouw
promotie aanwezig te zijn en we moeten nog eens een mooie review
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schrijven over cocaïne. Ik hoop dat je het ook wat rustiger aan doet, want
je bent nu verantwoordelijk voor twee.
Dan de persoonlijke kring, te beginnen met al mijn (gepromoveerde)
vrienden. Ik zal ze niet allemaal opsommen, maar een greep doen uit het
aanbod. Ronny, je hebt het me nog zo gezegd, “Tibor, doe het niet..”,
maargoed, ik ben eigenwijs en hier ligt het bewijs. Joris, onze vriend op
aanzienlijke afstand, ik hoop dat je snel een kans vind om over te komen,
want zoals iedere keer weer blijkt: u bent de ontbrekende schakel! Jan, als
Ronny de stenen zijn, Joris het cement, ben jij toch zeker de fundering. Dat
laat mij over als de man die er in het steegje tegenaan staat te plassen,
maar soit. Remko, laat je deadlines voor wat ze zijn en kom er eens vaker
uit. Debje, mijn diehard studiekameraadje en socializer, ik hoop je ook wat
vaker te zien. Paul, inmiddels bijna vader van drie, zullen we eens met de
meisjes door de stad gaan fietsen? Sande, artistiek genie, spreek je snel.
Bas, mijn langste vriend en concertbuddy, was je nou sumo of cum?
Evelientje, ik kom snel je nieuwe huis bewonderen.
Dan mijn familie, te beginnen bij mama. Emma, je bent voor mij van
onschatbare waarde. Als een ware inspirator en klankbord ben je er altijd
om iedere stemming van me op te vangen en daar uitvoerig over te
analyseren. Ook tijdens het schrijven van mijn proefschrift hebben we
menigmaal languit over allerlei zaken zitten bellen. Ik hoop dat je toen is
opgevallen dat ik vaak heb onderstreept hoeveel ik op je gesteld ben en
het respect dat ik inmiddels voor de schrijverskunde heb (“het was nacht”)!
Papa Lo, ik weet nog dat je heel erg blij en trots was toen ik je vertelde dat
ik ging promoveren. “Wordt het toch nog wat met die jongen”, moet je
gedacht hebben. Daarnaast heb je ontzettend lief al mijn artikelen
geprezen die ik je heb opgestuurd en Imani opgehaald als ik weer eens
een huisartsencursus moest geven. Oompie, ik ben ontzettend blij dat ik
jou als broer heb. Al zien we elkaar vanwege drukte en kinderen niet meer
zo vaak als vroeger blijf je voor mij mijn grote broer en voorbeeld. Volgens
mij zijn we allebei superpapa‟s geworden en gaan die kleintjes ons ook nog
voor grote verrassingen zetten. Zodra ze het huis uit zijn gaan we weer
samen zuipen, toch?
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Fabiënne, mijn allerliefste grote meisje, aan jou heb ik natuurlijk het meest
gehad buiten de professionele kring om. Jouw ervaring met reviewers,
jaloerse concurrenten van buitenaf en andere zeurpieten maakte dat ik
heel veel kon verdragen over mijn eigen ellende. Maar daarnaast ben je er
altijd voor mij en onze twee kleintjes, heb je er altijd het volste vertrouwen
in gehad dat ik kon wat ik kan en heb je me over heel wat dalen en
afgronden heen getrokken in de loop van de tijd. Ik weet dat dat lang niet
altijd een pretje was, maar je onverstoorbaarheid heeft ons altijd weer met
de voeten op de grond teruggebracht. Daarnaast ben je natuurlijk mijn
ultieme muze en klankbord, waarbij ik alles kwijt kan en altijd tot leuke
relativerende inzichten kom. Je hebt een onverwoestbaar stralend humeur
en een heerlijk aanstekelijk gevoel voor humor en ook tijdens de vieste
luiers ooit of belachelijkste foutieve aanmaningen in de post blijven we wat
aflachen met zijn tweeën. Imani, ik weet dat je dit allemaal nog niet kan
lezen, maar ik twijfel er niet aan dat er een dag komt waarop je dit hele
boekje begrijpt. Sterker, dat je feilloos papa‟s zwakke punten eruit weet te
halen en het meteen beter zou kunnen. Ik weet dat je nu ernstig twijfelt of
je later nou hulpfee of elvenvlinder wilt worden, maar je bent eigenlijk al
beide voor mij. Het spijt me dat je vader slechts een eenvoudige
academicus is geworden, had ik mijn elvenschool nou maar afgemaakt! Ik
hou nu al meer van je dan goed voor me is schatje, iedere dag met jou is
een parel op mijn denkbeeldige elvenkroontje. Olivia, je bent er pas twee
maanden en nu al ben ik smoorverliefd op je. Gek hoe dat blijkbaar gaat bij
vaders en dochtertjes. Ik hoop dat je dit ooit ook nog eens zult lezen en
hopelijk iets meekrijgt van wat die ouwe van je allemaal op zijn werk aan
het bekokstoven was tijdens jouw verwekking en geboorte. Hoe blij ik ook
ben met dit boekje, dat valt volstrekt in het niet bij jouw komst op 24
augustus!
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Curriculum Vitae
Tibor Markus Brunt was born in Amsterdam on the 19th of July 1970. He
finished secondary school education in 1991. Thereafter, he followed
higher vocational education for one year from 1992 to 1993 and completed
his propaedeutics. From 1993 he studied medical biology at the University
of Amsterdam and completed his master‟s degree in 1998, with the
speciality subject neurobiology. He followed two internships during his
study; one at the department of Human Genetics at the University of
Utrecht under supervision of prof. dr. C. Wijmenga, and the other at TNO
prevention and health in Leiden under supervision of dr. L. Nagelkerken.
Following his master‟s degree he worked for the National Institute for
Public Health and Environment from 2000 until 2001 on the research
project of tobacco additives and nicotine addiction under supervision of dr.
J. van Amsterdam. From 2001 until 2003 he took on a research project
within the Department of Criminology of the University of Amsterdam under
supervision of prof. dr. D.J. Korf. This project investigated possible better
alternatives for pill testing in The Netherlands and the role of the Drug
Information and Monitoring System (DIMS) project of the Trimbos institute.
After finishing this project, he worked at the faculty biology of the University
of Amsterdam for two consecutive years as assistant lecturer during
various practical courses. In 2005 he was employed at the Trimbos
institute as research associate within the DIMS project. He initially worked
at coordination of the DIMS network, drug testing and maintenance of the
protocols safeguarding the Good Testing Practice. Later on, he became
more specialized at coordination of research, reporting and publications. In
2009 he agreed on a PhD course under supervision of prof. dr. W. Van den
Brink of the Psychiatry department at the Academic Medical Centre of the
University of Amsterdam. Currently, he is still active at the Trimbos Institute
and is involved in various research projects investigating dependence
potential and associated harm of illicit psychoactive substances.
Tibor Markus Brunt is geboren in Amsterdam op 19 juli 1970. Hij heeft zijn
V.W.O. diploma behaald in 1991. Daarna heeft hij zijn propedeuse diploma
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lerarenopleiding biologie gehaald in 1993 aan de Hogeschool Holland te
Diemen. Vanaf 1993 is hij medische biologie gaan studeren aan de
Universiteit van Amsterdam en heeft zijn doctoraal afgerond in 1998 met
als specialisatie onderwerp neurobiologie. Hij heeft twee stages gevolgd
gedurende zijn opleiding: één op de afdeling Humane Genetica aan de
Universiteit Utrecht onder begeleiding van prof. dr. C. Wijmenga en de
andere bij TNO preventive en gezondheid in Leiden onder begeleiding van
dr. L. Nagelkerken. Na zijn doctoraal heeft hij tussen 2000 en 2001
gewerkt voor het Rijksinstituut voor Volksgezondheid en Milieu op het
onderzoeksproject van toevoegingen aan tabaksproducten en nicotine
verslaving onder leiding van onder meer dr. J. van Amsterdam. Daarna
heeft hij tot 2003 aan een onderzoeksproject gewerkt bij de afdeling
Criminologie aan de faculteit Rechten van de Universiteit van Amsterdam
onder leiding van prof. dr. D.J. Korf. In het kader van dit project werden
alternatieven onderzocht voor het testen van pillen en de rol van het Drugs
en Informatie Monitoring Systeem (DIMS) van het Trimbos-instituut hierin.
Na het afronden van dit project heeft hij nog twee jaar geassisteerd als
docent bij het universitair onderwijs bij de faculteit Biologie aan de
Universiteit van Amsterdam. In 2005 werd hij aangenomen op het Trimbosinstituut als wetenschappelijk medewerker binnen het DIMS project. Daar
is hij begonnen met de organisatie en coördinatie van het DIMS netwerk,
het testen van drugs en het onderhouden en waarborgen van de
protocollen voor Good Testing Practice. Hij is zich daarna steeds meer
gaan toeleggen op het doen van onderzoek, coördineren hiervan en
rapporteren en publiceren. In 2009 heeft hij een promotietraject ingezet
onder leiding van prof. dr. W. van den Brink van de afdeling psychiatrie aan
het Academisch Medisch Centrum in Amsterdam. Momenteel is hij nog
actief als wetenschappelijk medewerker aan het Trimbos-instituut en is
betrokken bij tal van onderzoeksprojecten die betrekking hebben op
verslaving en gezondheidsschade van illegale drugs.
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220
List of publications
Chapters of this thesis
Brunt, T.M., Rigter, S., Hoek, J., Vogels, N., van, D.P., Niesink, R.J.
(2009). An analysis of cocaine powder in the Netherlands: content
and health hazards due to adulterants. Addiction 104, 798-805
Brunt T.M., van Laar M., Niesink R.J.M., van den Brink W. (2010). The
relationship of quality and price of the psychostimulants cocaine and
amphetamine with health care outcomes. Drug and Alcohol
Dependence 111(1-2), 21-29
Brunt T.M., Poortman A, Niesink R.J., van den Brink W. (2011). Instability
of the ecstasy market and a new kid on the block: mephedrone.
Journal of Psychopharmacology 25(11), 1543-1547
Brunt T.M., Niesink R.J. (2011). The Drug Information and Monitoring
System (DIMS) in the Netherlands: Implementation, results, and
international comparison. Drug Testing and Analysis 3(9), 621-634
Brunt T.M., Niesink R.J., van den Brink W. (2011). Impact of a transient
instability of the ecstasy market on health concerns and drug use
patterns in The Netherlands. International Journal of Drug Policy
doi:10.1016/j.drugpo.2011.05.016
Brunt T.M., Koeter M.W., Niesink R.J., van den Brink W. (2011). Linking
the pharmacological content of ecstasy tablets to the subjective
experiences of drug users. Psychopharmacology (Berl) doi:
10.1007/s00213-011-2529-4
References in this thesis
Korf, D.J., Benschop, A., Brunt, T.M. (2003). Pill testing in The
Netherlands. Rozenberg, Amsterdam, The Netherlands
Bossong, M., Brunt, T.M., Van Dijk, J.P., Rigter, S., Hoek, J., Goldschmidt
,H., & Niesink, R.J. (2010). mCPP: an undesired addition to the
ecstasy market. Journal of Psychopharmacology 24(9), 1395-1401
221
Vogels, N., Brunt, T.M., Rigter, S., Van Dijk, P., Vervaeke, H., Niesink,
R.J.M. (2009). Content of ecstasy in the Netherlands: 1993-2008.
Addiction 104, 2057-2066
van Laar, M.W., Cruts, A.A.N., van Ooyen-Houben, M.M.J., Meijer, R.F.,
Brunt T.M. (2010). The Netherlands National Drug Monitor: Annual
Report 2009. Trimbos Institute, Utrecht, The Netherlands.
van Laar, M.W., Cruts, A.A.N., van Ooyen-Houben, M.M.J., Meijer, R.F.,
Brunt T.M. (2011). The Netherlands National Drug Monitor: Annual
Report 2010. Trimbos Institute, Utrecht, The Netherlands.
Other publications
Visser J., van Boxel-Dezaire A., Methorst D., Brunt T., de Kloet E.R.,
Nagelkerken L. (1998). Differential regulation of interleukin-10 (IL-10)
and IL-12 by glucocorticoids in vitro. Blood 91(11), 4255-4264
Giltay JC, Brunt T.M., Beemer F.A., Wit J.M., van Amstel H.K., Pearson
P.L., Wijmenga C. (1998). Polymorphic detection of a
parthenogenetic maternal and double paternal contribution to a
46,XX/46,XY hermaphrodite. American Journal of Human Genetics
62(4), 937-940
Wijmenga C., Muller T., Murli I.S., Brunt T.M., Feichtinger H., Schonitzer
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