Clinical Toxicology
ISSN: 1556-3650 (Print) 1556-9519 (Online) Journal homepage: http://www.tandfonline.com/loi/ictx20
Phencyclidine analog use in Sweden—intoxication
cases involving 3-MeO-PCP and 4-MeO-PCP from
the STRIDA project
Matilda Bäckberg, Olof Beck & Anders Helander
To cite this article: Matilda Bäckberg, Olof Beck & Anders Helander (2015) Phencyclidine
analog use in Sweden—intoxication cases involving 3-MeO-PCP and 4-MeO-PCP from the
STRIDA project, Clinical Toxicology, 53:9, 856-864, DOI: 10.3109/15563650.2015.1079325
To link to this article: http://dx.doi.org/10.3109/15563650.2015.1079325
Published online: 21 Aug 2015.
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Date: 06 January 2017, At: 19:55
Clinical Toxicology (2015), 53, 856–864
Copyright © 2015 Informa Healthcare USA, Inc.
ISSN: 1556-3650 print / 1556-9519 online
DOI: 10.3109/15563650.2015.1079325
CRITICAL CARE
Phencyclidine analog use in Sweden–intoxication
cases involving 3-MeO-PCP and 4-MeO-PCP from the
STRIDA project
MATILDA BÄCKBERG,1 OLOF BECK,2,3 and ANDERS HELANDER2,3
1Swedish
Poisons Information Centre, Stockholm, Sweden
Institutet, Department of Laboratory Medicine, Stockholm, Sweden
3Karolinska University Laboratory, Clinical Pharmacology, Stockholm, Sweden
2Karolinska
Background. 3-Methoxy-phencyclidine (3-MeO-PCP) and 4-methoxy-phencyclidine (4-MeO-PCP) are analogs of and drug substitutes for
the dissociative substance PCP (“Angel dust”), a recreational drug that was most popular in the 1970s. In Sweden, use of methoxylated
PCP analogs was noted starting in mid-2013, according to statistics from the Poisons Information Centre. The objective of this case
series was to present clinical and bioanalytical data from analytically confirmed non-fatal intoxications associated with 3-MeO-PCP
and/or 4-MeO-PCP within the STRIDA project. Study design. Observational case series of consecutive patients with self-reported or
suspected exposure to new psychoactive substances (NPS) and who require hospital care. Patients and methods. Blood and urine samples
were collected from intoxicated patients presenting at emergency departments (ED) or intensive care units (ICU) all over Sweden. NPS
analysis was performed by multicomponent liquid chromatographic–tandem mass spectrometric (LC–MS/MS) and LC–high-resolution
MS (LC–HRMS) methods. Data on clinical features were collected during Poisons Information Centre consultations and retrieved from
medical records. Results. The Poisons Information Centre registered its first call related to methoxylated PCP analogs in July 2013, while
analytically confirmed cases first appeared in October 2013. From July 2013 to March 2015, 1243 cases of suspected NPS intoxication
originating from ED or ICU were enrolled in the STRIDA project. During the 21-month period, 56 (4.5%) patients tested positive for
3-MeO-PCP and 11 (0.9%) for 4-MeO-PCP; 8 of these cases involved both substances. The 59 patients were aged 14–55 (median: 26)
years and 51 (86%) were men. Co-exposure to other NPSs and/or classical drugs of abuse was common with only 7 cases (12%) indicated
to be 3-MeO-PCP single-substance intoxications; prominent clinical signs seen in the latter cases were hypertension (systolic blood
pressure ⱖ 140 mmHg; 7 cases), tachycardia (ⱖ 100/min; 5 cases), and altered mental status (4 cases) including confusion, disorientation,
dissociation, and/or hallucinations. Mixed-drug users displayed not only the same clinical features, but also more sympathomimetic effects
including agitation (38%) and dilated pupils (33%). Patients testing positive for 3-/4-MeO-PCP were typically under medical care for 1–2
days (85%), and 37% of all cases were graded as severe intoxications (Poisoning Severity Score 3). Besides standard supportive therapy,
49% of the patients were treated with benzodiazepines and/or propofol. Conclusion. Laboratory analysis constitutes an important basis for
the assessment of NPS hazard and availability. The adverse effects noted in cases of acute intoxications involving 3- and/or 4-MeO-PCP
resembled those of other dissociatives such as PCP, ketamine, and methoxetamine. However, similar to intoxications involving other NPS,
poly-substance use was found to be common.
Keywords Arylcyclohexylamines; Designer drugs; Dissociative drugs; Drug intoxication; Internet drugs; Legal highs; Mass spectrometry
methods; 3-MeO-PCP; 4-MeO-PCP; New psychoactive substances; NMDA receptor antagonist; Phencyclidine; Research chemicals;
STRIDA project.
Background
The number of new psychoactive substances (NPS) introduced on the recreational drugs market shows a steadily
increasing trend, with an average of two new substances per
week reported for the first time in Europe in 2014.1 This may
largely result from the web-based open NPS trade, which is
Received 11 June 2015; accepted 29 July 2015.
Address corresponding to Dr. Matilda Bäckberg, Swedish Poisons
Information Centre, SE-171 76 Stockholm, Sweden.
Tel: ⫹ 46–8-6100500. E-mail: [email protected]
made possible by a delayed legislative control of many new
substances. In Sweden, the control action taken for NPS is
to regulate each new compound separately, which is a timeconsuming procedure.2 For that reason, before a new and
potentially hazardous substance is finally under legal control,
a number of emergency department (ED) visits related to
severe intoxications have often occurred. In fact, this kind
of information is used to support the need for regulation
of NPS.
Previously, NPS were commonly synthetic variants
of phenethylamines (i.e., amphetamine-type stimulants),
cathinones, and cannabinoids but, currently, there is also a
856
3-MeO-PCP and 4-MeO-PCP intoxications 857
growing occurrence of other substance classes, including
designer opioids, benzodiazepines, and dissociatives.1 With
the increasing diversity of drugs of abuse that are often used
in combination,3,4 expected and undesired clinical symptoms
and harmful effects become even more difficult to predict.
Arylcyclohexylamines is a miscellaneous group of dissociative anesthetic-type substances, acting by antagonism
on N-methyl-D-aspartate (NMDA) receptors.5,6 In this
group, pharmaceuticals such as ketamine, dextromethorphan (DXM), and phencyclidine (PCP; also known as
“Angel dust”) are included. PCP (Fig. 1) is a well-known
narcotic substance that was most popular in the 1970s.7
Substituted analogs to these substances providing similar
mind-altering effects include methoxetamine (MXE),
3-methoxy-PCP (3-MeO-PCP), 4-MeO-PCP (also known as
“methoxydine”), diphenidine, and methoxphenidine (MXP,
2-MeO-diphenidine) (Fig. 1), all of which have emerged on
the NPS market as legal alternatives to the classical banned
dissociatives.5,6,8–10
The methoxylated PCP analogs 3- and 4-MeO-PCP were
among the first designed dissociatives introduced on the
NPS market.10,11 For these and other novel drugs of abuse,
it is important to study the acute and chronic clinical features and adverse effects, and determine the best treatment
options in case of intoxication. This report aimed to present
laboratory results and clinical characteristics in analytically
confirmed non-fatal acute intoxications involving 3- and/or
4-MeO-PCP from the Swedish STRIDA project.
Methods
Patients and samples
STRIDA (an acronym of the project name in Swedish) is a
collaborative project between the Swedish Poisons Information Centre (a nation-wide 24/7 phone service to clinicians
and the public), the Karolinska University Laboratory, and
the Karolinska Institutet that monitors acute intoxications
PCP
Ketamine
3-MeO-PCP
Methoxethamine
4-MeO-PCP
Diphenidine
Fig. 1. Chemical structures of the dissociative psychoactive substances
PCP, its methoxylated analogs 3- and 4-MeO-PCP, ketamine,
methoxetamine, and diphenidine (1-(1,2-diphenylethyl)piperidine).
The structural similarity between the substances is marked in red.
Copyright © Informa Healthcare USA, Inc. 2015
related to NPS. Intoxicated patients with self-reported or
suspected intake of NPS, or of unknown drugs of abuse,
presenting at EDs or intensive care units (ICU) all over
Sweden are invited to take part in the STRIDA project. The
results of blood and urine drug testing and documented clinical features and treatments carried out from NPS-exposed
patients are compiled.4,12 Only cases where the Poisons
Information Centre is consulted are enrolled, because, at the
consultation, a unique case code number is provided which
anonymizes the patient and entitles free laboratory analysis.
The STRIDA project is conducted in accordance with
the Helsinki Declaration and has been approved by the
regional ethical review board (Nr. 2013/116–31/2).
Collection of clinical data and samples
The clinical information related to the intoxication cases
was collected in a standardized way by Poisons Information
Centre staff, during the telephone consultations and later
also from medical records. The severity of poisoning was
graded using the standardized Poisoning Severity Score
(PSS); there are five PSS grades ranging from PSS 0
(no symptoms) to PSS 4 (fatal outcome).13
Blood and urine samples were collected as soon as
possible after admission to the ED/ICU and forwarded to the
Karolinska University Laboratory for analysis of NPS and
classical drugs of abuse, as detailed elsewhere.4,12
Laboratory analysis of NPS
Identification and quantification of 3- and 4-MeO-PCP,
and of many other NPS, in samples of urine and serum
were performed by flexible multicomponent liquid
chromatographic–tandem mass spectrometric (LC–MS/
MS) and LC–high-resolution MS (LC–HRMS) methods
that are updated with new drug substances as they appear
and reference material becomes available.14,15 Reference
material of 3-MeO-PCP was obtained from Cerilliant
(Round Rock, TX, USA) and of 4-MeO-PCP from LGC
Standards (Teddington, UK).
For both compounds, the detection limit (S/N ratio ⬎ 3)
was ⬍ 0.2 ng/mL and the routine measuring range 1–
500 ng/mL in serum and 1–10000 ng/mL in urine. Urine
samples exceeding the upper limit of the measuring range
were reanalyzed following dilution with water. To achieve
chromatographic separation of 3- and 4-MeO-PCP, a
longer analytical column and a more flat gradient compared
with the original method had to be used (manuscript in
preparation).
Cross-reactivity of PCP analogs in a PCP immunoassay
Experiments to study the possible cross-reactivity of
methoxylated PCP analogs in the CEDIA PCP screening
assay (Thermo Scientific, Fremont, USA) was performed on
an Olympus 680 instrument, using the applications recommended by the manufacturer. Calibration was performed
with calibrators from Thermo Scientific. The cross-reactivity
was determined for standard solutions of 3- and 4-MeO-PCP
858 M. Bäckberg et al.
prepared in blank urine at 6–1000 ng/mL. The substance
concentration producing a test result nearby the 25 ng/mL
PCP cutoff was used to calculate the cross-reactivity.
The response in the PCP immunoassay was then determined for all clinical urine samples (n ⫽ 53) that were
obtained from the 3- and/or 4-MeO-PCP-positive cases.
Results
Poisons Information Centre statistics on NPS
intoxications
From the start of the STRIDA project in January 2010 until
June 2013, only 5 consultations related to “PCP” intoxication were registered at the Poisons Information Centre.
However, none of these cases were included in the project
and the actual substance involved was thus never analytically
identified.
The first inquiry related to 4-MeO-PCP occurred on
July 31, 2013 (blood or urine samples were not available
for analysis), and the first one related to 3-MeO-PCP on
November 21, 2013. However, because the actual PCP
analog involved was often not specified, these inquiries were
registered as “PCP” intoxications.
From July 2013 to March 2015 (21 months), 2687
consultations regarding suspected intoxications by NPS
were registered at the Poisons Information Centre. During
this observation period, 80 cases (3.0%) were registered as
3-MeO-PCP, 4-MeO-PCP, or “PCP” intoxications (Fig. 2).
In 30 (38%) of these cases, blood and/or urine samples were
available for analysis within the STRIDA project, and all but
3 of those (90%) were analytically confirmed to involve 3and/or 4-MeO-PCP exposure, whereas none involved PCP.
Intoxication cases enrolled in the STRIDA project
During the 21-month period from July 2013 to March 2015,
1243 cases of suspected NPS intoxication originating from
all over the country were enrolled in the STRIDA project
Swedish PIC consultations
9
Analytically confirmed cases
(i.e., both biological samples and clinical data were available), corresponding to 46% of all suspected NPS-related
consultations registered at the Poisons Information Centre.
Of the 1243 cases, 59 (4.7%) tested positive for 3-MeO-PCP
and/or 4-MeO-PCP. 3-MeO-PCP was detected in 56 (4.5%;
found throughout the study period) and 4-MeO-PCP in 11
(0.9%; found from February to October 2014) serum and/or
urine samples; in 8 (0.6%) of these cases both isomers were
present. Altogether, less than half (46%) of the analytically
confirmed intoxications involving 3- and/or 4-MeO-PCP
in the STRIDA project had been indicated as such, or as
“PCP,” during the consultation with the Poisons Information
Centre.
The patients testing positive for 3- and/or 4-MeO-PCP
were aged 14–55 (mean: 27.7, median: 26) years and 51
(86%) were men. The route of drug administration was
reported (oral, nasal, nasal or intravenous, and rectal) in
14 cases of self-reported 3-/4-MeO-PCP/”PCP” exposure
with oral intake (64%) being most common. Only few patients
shared information on drug doses and the preparations used;
7 reported use of 3-/4-MeO-PCP or “PCP” powder, and
4 of tablets. One patient declared rectal administration of
100 mg powder dissolved in water, and 3 admitted ingestion of 2 tablets, 3–4 tablets, and 10 “blade tips” of powder,
respectively, but information on the content of active substance in the tablets and powder was missing.
The concentration of 3-MeO-PCP in serum samples
ranged between 1 and 242 (mean: 29, median: 16) ng/mL
and in urine between 2 and 52759 (mean: 4281, median:
879) ng/mL. When the urinary concentration was normalized to the creatinine concentration, to compensate for
variations in urine dilution, the 3-MeO-PCP/creatinine
ratio ranged between 0.2 and 4325 (mean: 411, median:
120) μg/mmol. The corresponding results for 4-MeO-PCP
were 17–705 (mean: 178, median: 131) ng/mL in serum,
61–71673 (mean: 14979, median: 6506) ng/mL in urine, and
the urinary 4-MeO-PCP/creatinine ratio ranged between 6.0
and 5389 (mean: 1147, median: 639) μg/mmol creatinine.
Legislative
control
8
No. of cases
7
6
5
4
3
2
1
0
4 4 4
3 3
4 4
5 5 5
4 4 4
3 3
3
4
3
4
4
4
-1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1
ly ug ep ct ov ec an eb ar pr ay ne uly ug ep ct ov ec an eb ar
u
J F M
J F M A M Ju J
S O N D
S O N D
J A
A
Fig. 2. Statistics of phone inquiries to the Swedish Poisons Information Centre (PIC) from hospital caregivers and the public regarding suspected
intoxications by PCP or methoxylated PCP analogs (n ⫽ 80), and analytically confirmed hospital cases of 3-MeO-PCP and/or 4-MeO-PCP
exposure within the Swedish STRIDA project (n ⫽ 59), from July 2013 to March 2015. 3-MeO-PCP and 4-MeO-PCP were classified in Sweden
on January 16, 2015.
Clinical toxicology vol. 53 no. 9 2015
3-MeO-PCP and 4-MeO-PCP intoxications 859
In 50 cases (85%), the time of blood and/or urine sampling after admission to the ED/ICU was reported, and
typically (62%) occurred within 2 h of admission. However,
in one case that was not sampled until 16 h after admission,
3-MeO-PCP was still detectable in urine (a blood sample
was not collected). Examples of chromatograms from the
LC–HRMS analysis of 3- and 4-MeO-PCP in serum and
urine samples are shown in Fig. 3.
Co-exposure to other NPS and/or classical drugs of abuse
was very common with other substances detected in the
urine and/or serum samples from 52 of the 59 cases (88%).
All 7 single-substance cases involved 3-MeO-PCP. Besides
classical benzodiazepines that were, however, commonly
administered during hospital care treatment (i.e., diazepam, and its metabolites: oxazepam, desmethyldiazepam,
and midazolam), the most frequent other psychoactive
substances detected were cannabis (i.e., THC-COOH) and
ethanol (parent substance and/or the conjugated metabolites
ethyl glucuronide and ethyl sulfate). Overall, in addition
to 3-MeO-PCP and 4-MeO-PCP, another 55 psychoactive
substances (parent compounds and/or metabolites) were
identified (Table 1), the most common other NPS being
5-MeO-N-methyl-N-isopropyltryptamine (5-MeO-MiPT; 17%)
and 4-fluoro-α-pyrrolidinopentiophenone (4F-PVP; 15%).
Analysis of NPS products
In 10 of the 59 (17%) cases testing positive for 3- and/or
4-MeO-PCP, NPS products were brought to hospital along
with the patients (1 item each in 9 cases, and 10 items in
2.79E7
100
26.60
(a)
80
Serum sample
60
40
26.00
20
0
24.5
25.0
25.5
26.0
26.5
27.0
27.5
25.5
26.0
26.5
27.0
27.5
25.5
26.0
26.5
27.0
27.5
26.0
26.5
27.0
27.5
7.78E8
100
(b)
80
Urine sample
Relative abundance (%)
60
40
20
0
24.5
25.0
6.05E8
100
(c)
80
3-MeO-PCP standard
60
40
20
0
24.5
25.0
5.44E7
100
(d)
80
60
4-MeO-PCP standard
40
20
0
24.5
25.0
25.5
Time (min)
Fig. 3. Chromatograms from the LC–HRMS analysis of a non-fatal case of NPS intoxication in the STRIDA project testing positive for 3-MeOPCP 4-MeO-PCP in serum (a; 24 and 137 ng/mL, respectively) and urine (b; 5180 and 13780 ng/mL, respectively). Shown are also the results for
standard solutions of 3-MeO-PCP (c) and 4-MeO-PCP (d). The theoretical exact mass for the 3-/4-MeO-PCP monoisotopic ion is 273.2093.
Copyright © Informa Healthcare USA, Inc. 2015
860 M. Bäckberg et al.
Table 1. Frequency of analytically confirmed psychoactive substances
detected along with 3-MeO-PCP and/or 4-MeO-PCP in 52 non-fatal
cases of acute intoxication enrolled in the STRIDA project.
Ntotal ⫽ 52
%
Analytically confirmed psychoactive
substance1
25
18
17
9
8
8
7
6
6
5
5
5
4
4
4
4
4
3
3
3
3
3
3
3
2
2
2
2
2
2
2
2
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
48
35
33
17
15
15
13
12
12
10
10
10
8
8
8
8
8
6
6
6
6
6
6
6
4
4
4
4
4
4
4
4
4
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Diazepam/Oxazepam/Midazolam
Cannabis
Ethanol/Ethanol metabolites
5-MeO-MiPT
4F-PVP
Pregabalin
Clonazepam
Alprazolam
α-PBP
5-MeO-NiPT
Amphetamine
Flubromazolam
4-MEC
Diphenidine
Flubromazepam
Lorazepam (Diclazepam metabolite)
α-PVP
5-APB/6-APB
Buprenorphine
Butylone
Butyr-fentanyl
Fentanyl
MT-45
Tramadol/O-desmethyl-tramadol
2-APB
5-MeO-EiPT
MDMA, MDA
Meclonazepam
Methiopropamine
Morphine
N-Ethylbuphedrone
Nitrazepam
α-PPP
25C-NBOMe
3C-P
4-HO-MET
25B-NBOMe
25H-NBOMe
25N-NBOMe
2C-P
2-FA
2-FMA
2-MMC
3,4-CTMP
4-BMC
4F-α-PV8
5-MAPB
Cocaine
Clonazolam
DPT
Ethylone
MDPBP
Mephedrone
Methadone
Methylphenidate/Ritalinic acid
Methoxetamine
MXP
Pentobarbital
Thiopental
1Some
substances are likely treatment-related (i.e., benzodiazepines, fentanyl,
pentobarbital, and thiopental), in cases where the patient was sampled after the
initial treatment.
1 case). The contents were identified by LC–quadrupoletime-of-flight-MS/MS (LC–QTOF-MS/MS) and nuclear
magnetic resonance (NMR; quantitative analysis was not
performed) spectroscopy at the Swedish Medical Products
Agency (personal communication, K-H. Jönsson, Swedish
Medical Products Agency, Uppsala, Sweden).16
Four patients brought zip-locked transparent plastic
bags containing a white powder that was demonstrated
to consist of 3-MeO-PCP (2 of the bags were labeled
500 mg and 1000-mg 3-MeO-PCP, respectively). One of
them also brought 4-MeO-PCP products (4 bags labeled
500 mg 4-MeO-PCP).
NPS identified in the other drug items were β-keto2,5-dimethoxy-4-bromophenethylamine (bk-2C-B), 4-acetoxyN,N-dimethyltryptamine (4-AcO-DMT), dibutylone,
flubromazolam, AB-FUBINACA, ketamine, 3’,4’methylenedioxy-α-pyrrolidinobutiophenone (MDPBP),
3-methylethcathinone (3-MEC), N-methyl-N-ethyltryptamine
(MET), α-methyltryptamine (AMT), 2-(4-bromo-2,5dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine
(25B-NBOMe), and 2-(2,5-dimethoxy-4-nitrophenyl)-N-(2methoxybenzyl)ethanamine (25N-NBOMe). None of these
drug items was labeled 3- or 4-MeO-PCP.
Clinical features
The case material was subdivided into two groups;
single-substance exposures (n ⫽ 7) testing positive for
only 3-and/or 4-MeO-PCP, and poly-substance exposures
(n ⫽ 52) testing positive for other psychoactive substances
in addition to a PCP analog. In the single-substance group,
2 intoxications were graded as severe (PSS 3), 4 as moderate (PSS 2), and 1 as mild (PSS 1). In the poly-substance
group, 20 intoxications (38%) were graded as severe
(PSS 3).
In both subgroups, hypertension (systolic pressure
ⱖ 140 mmHg), an altered mental status (confusion, disorientation, dissociation, and/or hallucinations), and tachycardia (ⱖ 100/min) were the most prominent clinical features
(Table 2). Nystagmus (vertical, horizontal, or both) was
equally frequent (∼30%) in both groups, whereas deep
unconsciousness (RLS ⬎ 5) was only registered for 17% of
the poly-substance cases. Agitation and dilated pupils were
more common among poly-substance patients (38% and
33%, respectively) compared with those who only tested
positive for 3-MeO-PCP (0% and 29%, respectively).
Besides observation and standard supportive therapy,
pharmacological treatment with sedatives was reported in
29 (49%) cases. Administration of benzodiazepines (primarily diazepam and/or midazolam) was specified in 26 (44%),
propofol in 13 (22%), and haloperidol in 5 (8%) medical
records.
The time of hospital medical care ranged between 1 and
9 (mean and median 2) days, but most patients (85%) stayed
for 1 or 2 days. For 28 of the 59 (47%) patients, ICU observation and treatment was considered necessary. All 7 patients
who only tested positive for 3-MeO-PCP were discharged
Clinical toxicology vol. 53 no. 9 2015
3-MeO-PCP and 4-MeO-PCP intoxications 861
Table 2. Clinical features in 59 analytically confirmed intoxications involving 3-MeO-PCP and/or
4-MeO-PCP.
Clinical features at any time during admission
Hypertension (systolic blood pressure ⱖ 140 mmHg)
Tachycardia (ⱖ 100/min)
Altered mental status (confusion, disorientation,
dissociation, hallucinations)
Normal-sized pupils
Agitation
Nystagmus
Renal deficiency (p-creatinine ⬎ 100 μmol/L)
Miotic pupils
Pupils with slow or no response to light
Rhabdomyolysis
Diaphoresis
Dilated pupils
Deep unconsciousness
Clinical significant hypothermia (⬍ 36°C)
Urinary retention
Clinical significant hyperthermia (⬎ 39°C)
Seizures in hospital
after 1–2 hospital days, and 2 (29%; both graded as PSS 3)
of those were observed at the ICU.
Cross-reactivity of 3- and 4-MeO-PCP in the CEDIA PCP
immunoassay
The cross-reactivity of methoxylated PCP standards in the
CEDIA PCP immunoassay was ∼14.5% for 3-MeO-PCP
(i.e., 175 ng/mL 3-MeO-PCP produced a test result of ∼25
ng/mL PCP) and ∼2.5% for 4-MeO-PCP (i.e., 1000 ng/mL
4-MeO-PCP produced a test result of ∼25 ng/mL PCP).
Of the 53 urine samples from the STRIDA project analytically confirmed to contain 3- and/or 4-MeO-PCP, 45 (85%)
tested positive for PCP (cutoff, 25 ng/mL) in the immunoassay screening. According to the confirmatory MS analysis,
the positive samples contained 21–52759 (mean: 5093,
median: 1725; n ⫽ 42) ng/mL 3-MeO-PCP and 61–71673
(mean: 18701, median: 10444; n ⫽ 8) ng/mL 4-MeO-PCP.
PCP itself was not detected in any sample. The 8 urine
samples that tested negative in the immunoassay screening
contained low concentrations of 3-MeO-PCP (4–60 ng/mL)
or 4-MeO-PCP (69 and 110 ng/mL).
Discussion
The increasing availability of NPS is a matter of great
concern, due to the wide range of new substances with
mostly unknown dose–response and toxicological effects
currently introduced through open online sale. In the
last years, several outbreaks of severe intoxications and
deaths caused by such novel drugs of abuse (e.g., 5-IT,
MT-45, and 3-MMC)3,4,14,17–19 have been documented in
Sweden, for which a subsequent legislative control usually
resulted in marked reductions in accessibility and number
of intoxications.3,4,14 However, it is also evident that other
structurally and/or pharmacologically related substances
Copyright © Informa Healthcare USA, Inc. 2015
Poly-drug
use (n ⫽ 52)
%
3-MeO-PCP
only (n ⫽ 7)
%
20
27
30
38
52
60
7
5
4
100
71
57
10
20
16
4
2
11
7
3
17
9
9
8
3
3
19
38
31
8
4
21
13
6
33
17
17
15
6
6
3
2
2
2
2
1
1
1
0
0
0
0
0
0
43
29
29
29
29
14
14
14
0
0
0
0
0
0
have rapidly replaced those restricted by law, forming
the characteristic market cycle with a rapid turnover rate
of NPS.
In 2013, the sudden increase in number of Swedish Poisons Information Centre consultations related to
alleged PCP poisonings was unexpected, because, according to experiences at the Poisons Information Centre
and elsewhere,11,20 PCP intoxications have been rare in
the last decades. However, although the vast majority
of urine samples collected in these cases tested positive
for PCP in the immunological screening, not one single
case was finally analytically confirmed to involve PCP
itself, but, rather, one or both of its methoxylated analogs
3- and 4-MeO-PCP. These two PCP analogs have been
sold as legal dissociatives (“PCP or ketamine substitutes”)
through online NPS trade, and discussed on Internet
drug chat forums since 2009 with a marked increase
in 2011.21–24 A UK arylcyclohexylamine ban covering
3- and 4-MeO-PCP came into effect on February 26,
2013,10 whereas in Sweden, where each new substance is
regulated individually,2 they did not become illegal until
January 16, 2015. However, introduction of an “analogs”
classification system or a similar system to prevent the
open online sale of NPS is currently under consideration
in Sweden. It may also be noted that most NPS introduced
on the recreational drugs market are already known to be
psychoactive in the scientific literature, which makes a
more proactive classification system possible. The “falsepositive” screening results for PCP is explained by the
cross-reactivity of both methoxylated analogs demonstrated in the PCP immunoassay, albeit the responses were
lower than that for the parent substance (∼7-fold lower
for 3-MeO-PCP and ∼40-fold lower for 4-MeO-PCP).
The degree of cross-reactivity in the PCP immunoassay
and the results for case samples indicated that metabolites
contributed to the response.
862 M. Bäckberg et al.
800
700
Substance concentration
in serum (ng/mL)
The present results highlight the often limited reliability
of self-reports of drug use, and the importance of analytical
confirmation in cases of NPS intoxication. Due to the large
number of substances of different drug classes introduced
in recent years,25,26 use of highly selective analytical techniques with the ability to distinguish structurally closely
related substances (i.e., confirmative methods based on MS)
is necessary. Relying solely on immunochemical screening
results may be misleading, due to the high risk for crossreactivity producing “false positive,” as was evident from
the present results, or false-negative test results.27–29 In this
context, whether a series of PCP intoxications reported in
the USA in 2014 was really due to PCP itself or to some
structural analog is unknown, because confirmative analysis
was not performed.20 It should also be noted that the true
psychoactive drug content of NPS products is sometimes
not given on the label, and contents can also vary over
time.30 Hence, NPS users may be unaware of which substance they take, leading to an increased risk for overdose
and fatalities.31
In the STRIDA project, 59 analytically confirmed intoxications involving 3- and/or 4-MeO-PCP were enrolled over
the 21-month study period, covering the time of the first
recorded cases during the second half of 2013 to the time
for national legislation of both substances in January 2015.32
Most cases involved 3-MeO-PCP, which was detected in
95% of cases. This likely reflects the prevalence of methoxylated PCP analogs use in Sweden but whether it was due
primarily to drug preference by users and/or simply to the
availability from NPS vendors is unknown.
So far there are only few publications on 3- or 4-MeOPCP-related intoxications,11,33 and information on associated
substance concentrations in body fluids is scarce. In Sweden,
5 deaths presumably associated with 3-MeO-PCP have been
identified since 2014, showing postmortem femoral blood
concentrations in the range 120–380 ng/g (roughly equivalent to ng/mL).34 In 2 of the cases, however, several other
psychoactive substances were also detected. In the present
series of non-fatal STRIDA cases, the serum 3-MeO-PCP
concentrations were typically below 110 ng/mL, but 1 case
showed a much higher level of 242 ng/mL, thus overlapping
the levels reported in the fatal cases (Fig. 4). The serum concentrations of 4-MeO-PCP were generally below 200 ng/mL,
although also here 1 case showed a much higher level of 705
ng/mL. There are no published 4-MeO-PCP values available for comparison, but the generally higher concentrations
compared with 3-MeO-PCP, and hence likely of drug doses,
agree with the lower affinity of 4-MeO-PCP on the glutamate
NMDA receptors.10,35 For PCP itself, serum concentrations
in the range 5–600 ng/mL have been reported.36,37
For direct comparison of concentration levels, however,
differences due to variable sampling times from drug exposure, routes of drug administration, patterns of exposure,
and possible effects of poly-drug exposure, should be taken
into account, but this information is often missing. In the
case of urine levels, variations in sample dilution (i.e.,
urinary creatinine concentration) should also be considered, but, even so, a very wide spread in normalized 3- and
600
500
400
300
200
100
0
3-MeO-PCP
4-MeO-PCP
Fig. 4. Serum concentrations of 3- and 4-MeO-PCP in non-fatal
acute intoxication cases enrolled in the STRIDA project. The shaded
area indicates the range of 3-MeO-PCP concentrations reported in
postmortem femoral blood from 5 Swedish autopsy cases.34.
4-MeO-PCP levels was noted. Highly variable urinary
concentrations have previously been reported also for PCP
(e.g., 200–142000 ng/mL).38 PCP is reported to be detectable for at least 48 h in urine,39 but the detection time for its
methoxylated analogs is unknown. However, in 1 STRIDA
patient that was sampled twice, the 3-MeO-PCP concentration in blood decreased from 73 to 30 ng/mL over 11 h, thus
suggesting a half-life of ∼10 h.
The 2 patients showing serum concentrations of 3-MeOPCP or 4-MeO-PCP in the”fatal range” (Fig. 4) were both
unconscious (RLS 8) on admission to the ED. Supportive
intensive care was required for 3 and 2 days, respectively,
and they were not discharged from hospital until after 9/7
days. In addition to 3- and 4-MeO-PCP, these patients also
tested positive for several other psychoactive substances;
in the 3-MeO-PCP patient, 4-MEC, 3-MeO-PCP, 4F-PVP,
cannabis, and conjugated ethanol metabolites were also
detected, and in the 4-MeO-PCP patient, also α-PBP,
methylphenidate and its metabolite ritalinic acid, and
flubromazepam, lorazepam, temazepam, and desmethyldiazepam were found.
Hypertension, an altered mental status (“dissociative
anesthesia”), and nystagmus have been suggested as clinical
hallmarks of acute PCP intoxication,36,38,40 and were also
reported in the intoxications involving 3- and/or 4-MeO-PCP.
In these cases, the most common features were tachycardia
and hypertension followed by an altered mental status, and
this was even more pronounced in the 3-MeO-PCP singlesubstance cases. One reason for this may be that some
patients with poly-substance exposure had also taken drugs
reversing the clinical signs of PCP (e.g., benzodiazepines),
or that the methoxylated PCP analogs were not dominantly
symptomatic. However, nystagmus, which is considered as
a characteristic of PCP intoxication,38 appeared almost
Clinical toxicology vol. 53 no. 9 2015
3-MeO-PCP and 4-MeO-PCP intoxications 863
equally frequently in both subgroups (∼30%), suggesting
that it may also be common in intoxications with methoxylated PCP analogs.
Overall, the clinical signs agreed with previous reports
on PCP and other dissociative drugs,11,20,36–38,41,42 but there
were difficulties in identifying a unique toxidrome related
to methoxylated PCP analogs, due to the high prevalence
of poly-substance use involving a large number of other
NPS (Table 1). This phenomenon is repeatedly seen among
NPS-positive patients in the STRIDA project,3,4,9,14,17 and
increases the risk for harmful consequences.
Limitations of the study that are inherent in the study
design relate to the collection of clinical samples with lack
of recorded clinical features, and the non-standardized times
of sampling. In addition, the total number of intoxications
involving methoxylated PCP analogs is likely underreported
and underestimated, because only severe cases treated in the
ED/ICU are covered. Furthermore, only part of all NPSrelated consultations to the Poisons Information Centre
eventually becomes STRIDA cases (i.e., both biological
samples and clinical data are available). Nevertheless, the
study emphasizes the importance of laboratory analysis
of all new psychoactive drugs which often have unknown
clinical and health effects when introduced.
Conclusions
This study presented the clinical features associated with
3-MeO-PCP and/or 4-MeO-PCP exposure in a case series
of 59 analytically confirmed non-fatal intoxicated patients
presenting at ED and ICU in Sweden. The adverse effects
noted in acute intoxications involving 3- and/or 4-MeOPCP resembled those of classical dissociatives such as PCP,
ketamine, and MXE. However, similar to intoxication cases
involving other NPS, poly-substance use was found to be
common which increases the risk for severe and unpredicted
consequences.
Declaration of interest
The authors report no declarations of interest. This work
was supported in part by grants from the Swedish National
Institute of Public Health.
References
1. EMCDDA. New psychoactive substances in Europe. An update from
the EU Early Warning System (March 2015). 2015. Available at:
http://www.emcdda.europa.eu/attachements.cfm/att_235958_EN_
TD0415135ENN.pdf.
2. The Public Health Agency of Sweden. Information about the Swedish
legislative action on drugs [in Swedish]. Available at: http://www.
folkhalsomyndigheten.se/amnesomraden/tillsyn-och-regelverk/
klassificering-av-missbrukssubstanser/. (Accessed on June, 2015)
3. Bäckberg M, Lindeman E, Beck O, Helander A. Characteristics of
analytically confirmed 3-MMC-related intoxications from the Swedish
STRIDA project. Clin Toxicol (Phila) 2015;53:46–53.
4. Helander A, Bäckberg M, Hultén P, Al-Saffar Y, Beck O. Detection
of new psychoactive substance use among emergency room patients:
Results from the Swedish STRIDA project. Forensic Sci Int
2014;243:23–29.
Copyright © Informa Healthcare USA, Inc. 2015
5. Berger ML, Schweifer A, Rebernik P, Hammerschmidt F. NMDA
receptor affinities of 1,2-diphenylethylamine and 1-(1,2-diphenylethyl)
piperidine enantiomers and of related compounds. Bioorg Med Chem
2009;17:3456–3462.
6. Wallach J, De Paoli G, Adejare A, Brandt SD. Preparation and
analytical characterization of 1-(1-phenylcyclohexyl)piperidine (PCP)
and 1-(1-phenylcyclohexyl)pyrrolidine (PCPy) analogues. Drug Test
Anal 2014;6:633–650.
7. Garey RE. PCP (phencyclidine): an update. J Psychedelic Drugs
1979;11:265–275.
8. Anis NA, Berry SC, Burton NR, Lodge D. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of
central mammalian neurones by N-methyl-aspartate. Br J Pharmacol
1983;79:565–575.
9. Helander A, Beck O, Bäckberg M. Intoxications by the dissociative
new psychoactive substances diphenidine and methoxphenidine. Clin
Toxicol (Phila) 2015;53:446–453.
10. Morris H, Wallach J. From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs. Drug Test Anal
2014;6:614–632.
11. Misselbrook GP, Hamilton EJ. Out with the old, in with the new? Case
reports of the clinical features and acute management of two novel
designer drugs. Acute Med 2012;11:157–160.
12. Helander A, Beck O, Hägerkvist R, Hultén P. Identification of novel
psychoactive drug use in Sweden based on laboratory analysis–initial
experiences from the STRIDA project. Scand J Clin Lab Invest
2013;73:400–406.
13. Persson HE, Sjöberg GK, Haines JA, Pronczuk de Garbino J.
Poisoning severity score. Grading of acute poisoning. J Toxicol Clin
Toxicol 1998;36:205–213.
14. Bäckberg M, Beck O, Hultén P, Rosengren-Holmberg J, Helander A.
Intoxications of the new psychoactive substance 5-(2-aminopropyl)
indole (5-IT): A case series from the Swedish STRIDA project. Clin
Toxicol (Phila) 2014;52:618–624.
15. Al-Saffar Y, Stephanson NN, Beck O. Multicomponent LC-MS/
MS screening method for detection of new psychoactive drugs,
legal highs, in urine–experience from the Swedish population.
J Chromatogr B Analyt Technol Biomed Life Sci 2013;930:
112–120.
16. Johansson M, Fransson D, Rundlöf T, Huynh NH, Arvidsson T.
A general analytical platform and strategy in search for illegal drugs.
J Pharm Biomed Anal 2014;100:215–229.
17. Helander A, Bäckberg M, Beck O. MT-45, a new psychoactive
substance associated with hearing loss and unconsciousness. Clin
Toxicol (Phila) 2014;52:901–904.
18. Kronstrand R, Roman M, Dahlgren M, Thelander G, Wikström M,
Druid H. A cluster of deaths involving 5-(2-aminopropyl)indole
(5-IT). J Anal Toxicol 2013;37:542–546.
19. Kronstrand R, Thelander G, Lindstedt D, Roman M, Kugelberg FC.
Fatal intoxications associated with the designer opioid AH-7921.
J Anal Toxicol 2014;38:599–604.
20. Dominici P, Kopec K, Manur R, Khalid A, Damiron K, Rowden A.
Phencyclidine Intoxication Case Series Study. J Med Toxicol 2014.
[Epub ahead of print]
21. Bluelight. Available at: http://www.bluelight.org/vb/content/. (Accessed
on June, 2015)
22. Drug-Forum. Available at: https://drugs-forum.com/forum/index.php.
(Accessed on June, 2015)
23. Erowid. Available at: http://www.erowid.org/. (Accessed on June,
2015)
24. Flashback. Available at: https://www.flashback.org. (Accessed on
June, 2015)
25. EMCDDA. Risk assessments of a various psychoactive substances
1999–2015. Available at: http://www.emcdda.europa.eu/publications/
searchresults?action ⫽ list & type ⫽ PUBLICATIONS & SERIES
_PUB ⫽ w12. (Accessed on June, 2015)
26. EMCDDA. European Drug Report 2015: Trends and Developments.
2015. Available at: http://www.emcdda.europa.eu/publications/edr/
trends-developments/2015 (Accessed on June, 2015)
864 M. Bäckberg et al.
27. Beck O, Rausberg L, Al-Saffar Y, Villen T, Karlsson L, Hansson T,
et al. Detectability of new psychoactive substances, ‘legal highs’, in
CEDIA, EMIT, and KIMS immunochemical screening assays for
drugs of abuse. Drug Test Anal 2014;6:492–499.
28. Reisfield GM, Goldberger BA, Bertholf RL. ‘False-positive’ and
‘false-negative’ test results in clinical urine drug testing. Bioanalysis
2009;1:937–952.
29. Schwartz RH. Urine testing in the detection of drugs of abuse. Arch
Intern Med 1988;148:2407–2412.
30. Davies S, Wood DM, Smith G, Button J, Ramsey J, Archer R, et al.
Purchasing ‘legal highs’ on the Internet–is there consistency in what
you get? QJM 2010;103:489–493.
31. Bäckberg M, Beck O, Jönsson K-H, Helander A. Opioid intoxications
involving butyrfentanyl, 4-fluorobutyrfentanyl, and fentanyl from the
Swedish STRIDA project. Clin Toxicol (Phila) 2015;53:609–617.
32. Läkemedelsverkets förteckning I över narkotika (LVFS 2014:11). [The
Medical Products Agency’s list of provisions on narcotics]. 2014. Available at: https://lakemedelsverket.se/upload/lvfs/LVFS_2014_11.pdf.
(Accessed on June, 2015)
33. Stevenson R, Tuddenham L. Novel psychoactive substance intoxication resulting in attempted murder. J Forensic Leg Med 2014;25:
60–61.
34. Johansson A, Thelander G, Roman M, Lindstedt D, Sandler H,
Rubertsson S, et al. Intoxications associated with the novel dissociative drug 3-MeO-PCP (abstract presented at the Nordic Conference on
Forensic Medicine. Stockholm, Sweden, June 10–13, 2015).
35. Roth BL, Gibbons S, Arunotayanun W, Huang XP, Setola V,
Treble R, et al. The ketamine analogue methoxetamine and 3- and
4-methoxy analogues of phencyclidine are high affinity and selective
ligands for the glutamate NMDA receptor. PLoS One 2013;
8:e59334.
36. Barton CH, Sterling ML, Vaziri ND. Phencyclidine intoxication:
clinical experience in 27 cases confirmed by urine assay. Ann Emerg
Med 1981;10:243–246.
37. Walberg CB, McCarron MM, Schulze BN. Quantitation of phencyclidine in serum by enzyme immunoassay: results in 405 patients. J Anal
Toxicol 1983;7:106–110.
38. McCarron MM, Schulze BW, Thompson GA, Conder MC, Goetz WA.
Acute phencyclidine intoxication: clinical patterns, complications,
and treatment. Ann Emerg Med 1981;10:290–297.
39. Yago KB, Pitts FN Jr., Burgoyne RW, Aniline O, Yago LS, Pitts AF.
The urban epidemic of phencyclidine (PCP) use: clinical and laboratory
evidence from a public psychiatric hospital emergency service. J Clin
Psychiatry 1981;42:193–196.
40. Bey T, Patel A. Phencyclidine intoxication and adverse effects: a
clinical and pharmacological review of an illicit drug. Cal J Emerg
Med 2007;8:9–14.
41. McCarron MM, Schulze BW, Thompson GA, Conder MC, Goetz WA.
Acute phencyclidine intoxication: incidence of clinical findings in
1,000 cases. Ann Emerg Med 1981;10:237–242.
42. Zawilska JB. Methoxetamine–a novel recreational drug with potent
hallucinogenic properties. Toxicol Lett 2014;230:402–407.
Clinical toxicology vol. 53 no. 9 2015