Chronic Fatigue or
Sagging Serotonin?
Successful clinical corrections for depression, fatigue
and mood disorders with adrenal and neurotransmitter
balancing
ROBYN KUTKA, ND
DIRECTOR OF CLINICAL SERVICES, LABRIX
Only 17% of US Adults
are considered to be in a state
of optimal mental health!
Centers for Diseas Control and Prevention. Mental Health Basics.
https://www.cdc.gov/mentalhealth/basics.htm . Accessibility verified 6/30/2016
Over 30% of the United States population will
experience Major Depressive Episodes (MDE) lifetime prevalence
•MDE = A period of two weeks or longer during which there
is either depressed mood or loss of interest or pleasure and
at least four other symptoms that reflect change in ADLs
(i.e. problems with sleep, eating, energy, concentration and
self-image)
•In 2014 an estimate 15.7 million adults in the US (6.7% of
the US Adult population) had at least one major depressive
episode in the past year.
Faris. Depression Statistics. March 28, 2012. http://www.healthline.com/health/depression/statistics#4. Accessibility verified 06/30/2016
National Institutes of Health. Major Depression Among Adults. http://www.nimh.nih.gov/health/statistics/prevalence/major-depression-among-adults.shtml Accessibility verified 6/30/2016
Cost of depression
•Individuals suffering from depression (diagnosed or otherwise)
consume considerably more health services than similar individuals
without depression symptoms.
•A study of 14,903 individuals on Medicare found those with a current
diagnosis of depression had double the healthcare costs compared to
those with no signs of depression:
• Depression dx: $22,960 in a 1 year period
• Depressed with no diagnosis: $14,365
• No signs of depression: $11,956
Faris. Depression Statistics. March 28, 2012. http://www.healthline.com/health/depression/statistics#4. Accessibility verified 06/30/2016
•Women are twice as likely to have depression, and symptoms of
depression, as men of the same age.
•12% of all women in the United States will experience symptoms
of clinical depression at some point in their lives.
•The Behavioral Risk Factor Surveillance System found that the rate
of diagnosed major depression increased with age from 2.8% for
adults 18-24 to a peak of 4.6% for adults 45-64 years.
Faris. Depression Statistics. March 28, 2012. http://www.healthline.com/health/depression/statistics#4. Accessibility verified 06/30/2016
About 50% of all adults
experiencing symptoms
of depression will not talk
to a doctor or seek help
for depression.
Over 80% of people with
symptoms of clinical
depression are not
receiving any specific
treatment for their
depression.
Faris. Depression Statistics. March 28, 2012.
http://www.healthline.com/health/depression/statistics
#4. Accessibility verified 06/30/2016
On the rise….
•Major depression is the number 1 psychological
disorder in the western world
•According to a Harvard study the number of
patients diagnosed with depression increases by
approximately 20% per year.
•It is projected that by the year 2020 it will be the
2nd most disabling condition in the world, second
only to heart disease.
Faris. Depression Statistics. March 28, 2012. http://www.healthline.com/health/depression/statistics#4. Accessibility verified 06/30/2016
Centers for Diseas Control and Prevention. Mental Health Basics. https://www.cdc.gov/mentalhealth/basics.htm . Accessibility verified 6/30/2016
The rate of antidepressant use in the United States has
increased nearly 400% over the last two decades.
Currently:
◦11% of Americans (over age 12) take
antidepressant medication
◦23% of women aged 40-59 take
antidepressants (more than any other age-sex
group)
Center for Disease Control and Prevention. Health, United States. Available at: http://www.cdc.gov/nchs/data/hus/hus10.pdf . Accessibility verified July 30, 2014.
Olfson M, Marcus SC. National patterns in antidepressant medication treatment. Arch Gen Psychiatry. 2009; 66: 848–56.
2007: $25 billion dollars were spent on antidepressants and
antipsychotics
2009: US doctors wrote more psychiatric prescriptions than there
were people in the USA
Whitaker R. Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs and the Astonishing Rise of
Mental Illness. New York, NY: Broadway Paperbacks; 2010.
Psychiatric drug overuse is
cited by federal study
•Federal investigators have found evidence of widespread overuse of
psychiatric drugs by older Americans with Alzheimer’s disease and
dementia and are recommending that Medicare officials take
immediate action to reduce unnecessary prescriptions.
•In addition to decline in memory, dementia can cause changes in mood
or personality and, at times, agitation or aggression. Antipsychotic drugs
have been prescribed to help manage these symptoms.
•However, according to the FDA, antipsychotic drugs are expensive,
costing hundreds of millions of Medicare dollars. They also increase the
risk of death, falls with fractures, hospitalizations and other
complications.
Pear, Robert. “Psychiatric Drug Overuse is Cited by Federal Study.” The New York Times. March 1, 2015.
Chronic fatigue, depression or both?
Chronic
Fatigue
Insomnia
Depression
Headaches, joint pain,
muscle pain
Headaches, cramps,
stomach upset, pains
Wants to participate
but too fatigued
Loss of interest in
activities
Numerous chief complaints/many
functional conditions...
Where to begin?
Treat root causes:
Neuroendocrine imbalances
◦ Hormonal
◦ Adrenal
◦ Neurotransmitter
A well established connection
Depression and altered neurotransmitter levels is a well demonstrated
connection
Times of hormonal transitions (peri/post-menopause, andropause,
etc..) often coincides with newly reported mood concerns.
CFS patients have been demonstrated to have a blunted cortisol
awakening response as well as lower cortisol output overall
◦ ACTH stimulation tests alone often lack the sensitivity to detect HPA Axis
dysfunction dysfunction. Salivary testing offers unique ability to capture
cortisol awakening response
Nater UM, Maloney E, Boneva RS et al. Attenuated morning salivary cortisol concentrations in a population-based study of persons with chronic fatigue syndrome and well
controls. J Clin Endocrinol Metab. 2008 Mar;93(3):703-9.
Cleare A et al. Hypothalamo-Pituitary-Adrenal Axis Dysfunction in Chronic Fatigue Syndrome, and the Cleare A et al. Hypothalamo-Pituitary-Adrenal Axis Dysfunction in
Chronic Fatigue Syndrome, and the Effects of Low-Dose Hydrocortisone Therapy. J Clin Endocrinol Metab. 2001. 86(8):3545–3554.
Cortisol
Estradiol
Testosterone
Why guess when you can test?
z
z
z
z
z
z
Urinary neurotransmitter testing
2nd void
•HPLC Triple Quadrupole MS/MS: the most accurate
methodology for measuring neurotransmitters
•Serotonin, GABA, glutamate, dopamine,
norepinephrine and epinephrine
•Urine testing has been employed clinically for over
10 years in US; 20 years in Europe
Hughes JW, et al. Depression and anxiety symptoms are related to increased 24-hour urinary norepinephrine excretion among healthy middle-aged women. J Psychosom Res. 2004; 57: 353-358.
Chekhonin VP, et al. Catecholamines and their metabolites in the brain and urine of rats with experimental Parkinson’s disease. Bull Exp Biol Med. 2000 130: 805-809.
Lynn-Bullock CP, et al. The effect of oral 5-HTP administration on 5-HTP and 5-HT immunoreactivity in monoaminergic brain regions of rats. J Chem Neuroanat. 2004; 27: 129-138.
Struys EA, et al. Determination of the GABA analogue succinic semialdehyde in urine and CSF by dinitrophenylhydrazine derviatization and liquid chromatography-tandem mass spectrometry:
Application to SSADH deficiency. J Inherit Metabol Dis. 2005; 28: 913-20.
Current medical literature
demonstrates:
•Urinary neurotransmitter levels significantly correlate to
plasma and CSF levels
•Correlation of neurotransmitter levels from first void urine
samples with 24 hour urine samples
•Significant alterations in neurotransmitter levels in
conditions including depression and autistic spectrum
disorders
•Alterations in urinary neurotransmitter levels in response to
both non-pharmaceutical treatments
References
• Dvorakova M, et al. Urinary catecholamines in children with attention deficit
hyperactivity disorder (ADHD): modulation by a polyphenolic extract from pine bark
(pycnogenol). Nutr Neurosci. 2007; 10: 151-57.
• Kaluzna-Czaplinska J, et al. Deterination of tryptophan in urine of autistic and healthy
children by gas chromatography/mass spectrometry. Med Sci Monit. 2010; 16: CR48892.
• Hushnir MM, et al. Analysis of catecholamines in urine by positive-ion electrospray
tandem mass spectrometry. Clin Chem. 2002; 48:323-31.
• Marc DT, et al. Neurotransmitters excreted in the urine as biomarkers of nervous system
activity: validity and clinical applicability. Neurosci Biobehav Rev. 2011; 35: 635-44.
• Moriarty M, et al. Development of an LC-MS method for the analysis of serotonin and
related compounds in urine and the identification of a potential biomarker for attention
deficit hyperactivity/hyperkinetic disorder. Anal Bioanal Chem. 2011; 401:2481-93.
• Nichkova MI, et al. Evaluation of a novel ELISA for sertonin: urinary serotonin as a
potential biomarker for depression. Anal Bioanal Chem. 2012; 402: 1593-600.
Signs and symptoms caused by imbalanced
NTs beyond mood and behavioral disorders
•Altered sleep
•Pain
•Decreased concentration
•Sweating
•Fatigue
•Dizziness
•Irritable Bowel Syndrome
•Heart palpitations
•Altered mental clarity
•Attention deficits
•Addiction
•Diminished energy / motivation
Capuron L, et al. Chronic low-grade inflammation in elderly persons is associated with altered tryptophan and tyrosine
metabolism: role in neuropsychiatric symptoms. Biol Psychiatry. 2011; 70: 175-82.
Main neurotransmitters
Serotonin
Dopamine
Norepinephrine
Epinephrine
GABA
Glutamate
Neurotransmitter pathways
Serotonin
•Functions include mood control, sleep, pain, GI
motility
•Imbalanced serotonin levels (high or low) are
associated with depression and loss of interest
•Biochemically derived from the amino acid
tryptophan
Whitaker R. Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs and the Astonishing Rise of Mental Illness. New York, NY: Broadway Paperbacks; 2010.
Maas JW, et al. Pretreatment neurotransmitter metabolite levels and response to tricyclic antidepressant drugs. Am J Psychiatry. 1984; 141: 1159-71.
Appetite change
•Moderately low serotonin
can cause your appetite to
change.
•Symptoms may include a lack of interest in eating,
or cravings for sweets and carbohydrates.
•The brain tries to use sweets and carbohydrates to
increase serotonin levels.
Wurtman RJ, et al. Brain serotonin, carbohydrate-craving, obesity and depression. Obes Res. 1995 Nov;3 Suppl 4:477S-480S.
Fat and sad?
Increasing insulin for a long period may trigger the onset
of insulin resistance, obesity, type 2 diabetes, and lower
serotonin levels.
Grossman, Mary H.; Hart, Cheryle R. (2008). The Feel-Good Diet. New York: McGraw-Hill. p. 64.
Clements RS, Darnell B (1980). "Myo-inositol content of common foods: development of a high-myo-inositol diet". Am. J. Clin. Nutr. 33 (9): 1954–67
How to increase serotonin in the
human brain without drugs
Positive mood induction
Light therapy
Exercise
Nutrition
Simon N Young. How to Increase serotonin in the human brain without drugs. J Psychiatry Neurosci. 2007 November; 32960:394-399.
Dopamine
•Enhances the reward response, especially if the reward is perceived as greater than
expected.
•Stimulates pleasure centers
•Enables us not only to see rewards, but to take action to move towards them
•Drive and motivation.
•Locomotion and coordination of movement
•Behavior and cognition
•Sleep
•Mood
•Attention and learning
•Inhibition of prolactin production (involved in lactation)
Schultz W. Dopamine signals for reward value and risk: basic and recent data. Behav Brain Funct. 2010; 6: 1-9.
Dopamine and Motivation
•Sometimes called the
“motivation molecule”
•Lab mice that are dopamine
deficient are so apathetic they’ll
literally starve themselves to
death, even when food is
readily available — that’s how
important dopamine is
to motivation
Angier, Natalie. “Molecule of Motivation, Dopamine Excels at its task. The New York Times. Oct. 26,
2009.
Dopamine imbalance
•Deficiency: mood swings/depression/anxiety,
isolation; Loss of interest and motivation, drop in
sex drive; forgetfulness; addictive states;
schizophrenia/autism/ADHD
•Excess: paranoia
Massage for serotonin and
dopamine support?
Studies suggest stress mediating affects of massage therapy:
• Salivary cortisol levels decreased by an average of 31%
• Urinary serotonin increased an average of 28%
• Urinary dopamine levels increased by an average of 31%
Norepinephrine and
epinephrine
•Regulate flight or flight response
•Control attention and arousal
•Regulate heart rate and blood pressure
•Release glucose from energy stores
Bear MF, Connors BW, Paradiso MA. Neuroscience. Exploring the Brain, second edition
Norepinephrine synthesis
•Norepinephrine is released by stress events
•Released from noradrenergic neurons in the locus coeruleus in the CNS
and from post ganglionic neurons in the SNS to stimulate fight or flight
response.
• The locus coeruleus is involved with the physiological response to stress and
panic. It is the principal site for brain synthesis of norepinephrine
•When norepinephrine is released from the adrenal medulla, it is
released into the blood and acts as a hormone
Epinephrine Synthesis
•Epinephrine is synthesized in the medulla
of the adrenal gland in an enzymatic
pathway that converts the amino acid
tyrosine into a series of intermediates and, ultimately,
epinephrine.
•ACTH stimulates the adrenal cortex to release cortisol which
increases expression of PNMT in chromaffin cells, enhancing
epinephrine synthesis.
•Epinephrine may be used as a neurotransmitter by some
neurons in the brain, but its most important role is in the
periphery
Coordinated fight or flight
response
•In the periphery, norepinephrine and epinephrine act as
regulators of carbohydrate and lipid metabolism.
•Norepinephrine and epinephrine are released from storage
vesicles in the adrenal medulla in response to fright,
exercise, cold, and low blood glucose levels.
•They increase the degradation of glycogen and
triacylglycerol, as well as increase blood pressure and
cardiac output.
Champe P, Harvey R, Ferrier D. Biochemistry. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2005.
Not so coordinated in CFS
Evidence suggests an altered sympathetic-neural and sympatheic adrenomedulla
reactivity in CSF, revealing a catecholaminergic hyporeactivity in CFS patients. “It
is conceivable that inadequate catecholaminergic responses to physical exertion
might contribute to CFS symptoms.”
Fritz
Strahler J1, Fischer S, Nater UM, Ehlert U, Gaab J. Norepinephrine and epinephrine responses to physiological and pharmacological stimulation in chronic fatigue syndrome.
Biol Psychol. 2013 Sep;94(1):160-6. doi: 10.1016/j.biopsycho.2013.06.002.
Glutamate
The most common excitatory neurotransmitter in the brain
High glutamate
•
•
•
•
•
Depression
Fatigue
Brain fog
Addiction/ dependency
Slowed learning
Low glutamate
•
•
•
•
•
•
•
Anxiety
Insomnia
ADHD/poor concentration
Seizure
ALS/MS
Autism
Alzheimer’s
Bear MF, Connors BW, Paradiso MA. Neuroscience. Exploring the Brain, second edition
Glutamate
Ingredients that ALWAYS contain free glutamic
acid
Ingredients that OFTEN contain or
produce glutamic acid
Ingredients SUSPECTED of creating glutamic acid in
sensitive people
MSG
Bouillon and broth
Corn starch, corn syrup
Yeast extract
Any “flavors” or “flavoring”
Dextrose
Anything “hydrolyzed”
Barley malt or malt extract
Rice syrup. Brown rice syrup
Textured protein (anything “protein”)
Soy sauce
Reduced fat milk (skim, 1%, 2%)
Soy or whey protein
Seasonings
Most things low fat or no fat
Gelatin
Carrageenan
Anything vitamin enriched
GABA
•The major inhibitory neurotransmitter in the brain
•Relaxing and calming
•Synthesized from glutamate and P5P
•Predominant receptor
• GABA A
• Utilized by neuroactive drugs like benzodiazepines
• Often used to treat anxiety, seizures, act as sedative or muscle relaxant
GABA imbalances
Low GABA levels have been found
in:
◦
◦
◦
◦
Panic/anxiety
Depression
Alcoholism
Bipolar disorders
Elevated GABA may contribute to:
◦
◦
◦
◦
◦
Drowsiness/lack of alertness
Difficulty concentrating
Diminished memory
Dampened mood
Decreased cognitive processing
Note: GABA levels may become
elevated as a compensatory
mechanism when excitatory
neurotransmitters are high
Vaiva G, et al. Low posttrauma GABA plasma levels as a predictive factor in the development of acute
posttraumatic stress disorder. Biol Psychiatry. 2004; 55: 250-54.
GABA impact
When sufficient or therapeutic, GABA may:
◦ reduce symptoms of alcohol withdrawal
◦ reduce symptoms of anxiety
◦ help some schizophrenics
◦ help to reduce high blood pressure
◦ suppress appetite
◦ help with premenstrual symptoms
◦ be helpful in some cases of depression
Yoga increases GABA
•All exercise can increase GABA, but Yoga stands out.
•Study of 8 yoga practitioners and 11 control subjects.
• Yoga practitioners did 60 minutes of yoga posturing and breathing
• Control group read quietly for an hour
• MRIs showed 27% increase in GABA compared to controls
• Second study compared 19 yoga practitioners with 15 walkers.
• Participants did yoga or walked for an hour three times a week for 12 weeks.
• Yoga practitioners had improved mood and anxiety compared to walking
controls, and MRI showed increased GABA in the thalamus.
Deans, Emily MD. Yoga (ba) GABA. Evidence that yoga can enhance anxiety-killing neurotransmitters in the
brain. Psychology Today. March 15, 2013. Accessibility verified 5/18/16.
Treatment
Pearls
Treatment for
neurotransmitter imbalances
Evaluation and targeted treatment approach
• Amino acids
• Co-factors
• Nervine and adaptogenic herbs
Amino acid precursors
•Taken on empty stomach at least 30 minutes away from food
•Cross the blood brain barrier and interact with HPA axis and
neurotransmitter regulation
Tryptophan
Tyrosine
GABA
Taurine
5-HTP
Glutamine
L-theanine
Hinz M. Depression. In Kohlstadt I, ed. Food and Nutrients in Disease Management. Boca Raton, FL: CRC Press: 2009.
Birdsall TC. 5-Hydroxytryptophan: a clinically-effective serotonin precursor. Altern Med Rev. 1998; 3: 271–80.
Pyle AC, et al. The role of serotonin in panic: evidence from tryptophan depletion studies. Acta Neuropsychiatrica. 2004; 16: 79–84.
GABA supplementation
Dysbiosis
◦ When dysbiosis is present, anxiolytic effects of GABA are observed, suggesting ability
to cross the BBB
Stress
◦ Stress can dramatically increase the ability of exogenous chemicals to pass through the
blood-brain barrier. During the Gulf War, Israeli soldiers took a drug to protect
themselves from chemical and biological weapons. Normally, it is not expected to
cross the BBB, but scientists observed that with the stress of war—had somehow
increased the permeability of the BBB...
◦ Nearly one-quarter of the soldiers complained of headaches, nausea, and dizziness –
symptoms which occur only if the drug reaches the brain.
Other causes for breakdown of the BBB
◦ Elevated glucose and diabetes
◦ Chronic environmental exposure
◦ Systemic inflammation
http://www.neurophysiology.ws/bbb.htm. Accessibility verified 12/10/13
Friedman A, et al. Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early
immediate transcriptional response. Nat Med. 1996; 2: 1382-85.
Kharrazian D, DHSc, DC, MS. Why Isn’t My Brain Working? A revolutionary understanding of brain decline and effective
strategies to recover your brain’s health. Carlsbad: Elephant Press, 2013. Print.
Phenibut (250-1,000 mg bid)
•A derivative of GABA which can cross the blood brain
barrier
•Phenibut will bind to GABA B receptors and has anxiolytic
effects
• Discovered in the Soviet Union in the 1960s, Phenibut is standard
issue in a cosmonaut’s medical kit.
Phenibut is able to lower stress levels without adversely affecting
performance.
Lapin I. Phenibut (beta-phenyl-GABA): a tranquilizer and nootropic drug. CNS Drug Rev. 2001: 7: 471-81.
Cofactors
Cofactors are substances essential for the activity of an
enzyme. For example, the conversion of dopamine to
norepinephrine is driven by the enzyme dopamine bhydroxylase, which requires vitamin C, copper and vitamin
B3 (niacin) to fuel the conversion.
Cofactors are often vitamins or
minerals. B vitamins are
especially important in
neurotransmitter pathways.
Cofactors
Activated forms of vitamins are essential when
providing cofactor support.
◦ For example, vitamin B6 should be given in the
form of pyridoxal-5-phosphate
◦ Folate and B12 should be given in the form of
methyltetrahydrofolate (MTHF) and
methylcobalamin
Mucuna pruriens (200-800 mg qd)
•Cowhage (mucuna pruriens) seeds have been used in
traditional Ayurvedic medicine
•Contains small amounts of L-dopa, a precursor to dopamine
• The bean portion of the plant has 3-6% L-dopa
• Inner layer (endocarp) is 5.3% L-dopa
•Proven to lessen symptoms of Parkinson’s disease
Prakash D, et al. Some nutritional properties of the seeds of three Mucuna species. Int J Food Sci Nutr. 2001; 52: 79-82.
Vadivel V, et al. Nutritional and anti-nutritional composition of velvet bean: an under-utilized food degume in south India. Int J Food Sci Nutr. 2000; 51: 279-87.
Vadivel V, et al. Nutritional and anti-nutritional characteristics of seven South Indian wild legumes. Plant Foods Hum Nutr. 2005; 60: 69-75.
HP-200 in Parkinson’s Disease study group. An alternative medicine treatment for Parkinson’s disease: Results of a multicenter clinical trial. J Alt Comp Med 1995;1:249-55.
L-theanine
“Adaptogen” to the neurotransmitter system
Many functions
◦ Acts as a GABA agonist (neuroinhibitory and
parasympathetic)
◦ Antagonistic effects on glutamate receptors
◦ Can modulate serotonin, GABA and dopamine levels
Nathan PJ, et al. The neuropharmacology of L-theanine (N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent. J Herb Pharmacother.
2006;6(2):21-30.
Wakabayashi C, et al. Behavioral and molecular evidence for psychotropic effects in L-theanine. Psychopharmacology (Berl). 2012 Feb;219(4):1099-109.
Weeks, BS. Formulations of dietary supplements and herbal extracts for relaxation and anxiolytic action: Relarian. Med Sci Monit. 2009 Nov;15(11)
L-theanine (100-500 mg bid)
•Amino acid found in green tea
•Produces a calming effect in the brain (boosts alpha waves)
•Helps modulate mood; creates a sense of well being
•Reduces mental and physical stress responses
•Improves cognition
•When combined with caffeine, has been shown to increase focus and
attention. “Mindful alertness.”
•Recommend divided dosing as L-theanine has a short ½ life (4-6 hours)
Gomez-Ramirez M, et al. The deployment of intersensory selective attention: A high-density electrical mapping study of the effects of Theanine". Clin
Neuropharmacol. 2007; 30: 25–38.
Kimura K, et al. L-Theanine reduces psychological and physiological stress responses. Biol Psychol. 2007; 74: 39–45.
Haskell CF, et al. The effects of l-theanine, caffeine and their combination on cognition and mood. Biol Psychol. 2008 ; 77: 113–22.
Vitamin D
Calcitriol activates the
gene expression of
the enzymes tyrosine
hydroxylase and
tryptophan
hydroxylase (the rate
limiting steps in the
production of
serotonin and the
catecholamines)
Puchacz E. Vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells. Brain Res Mol Brain Res. 1996 Feb;36(1):193-6.
Humble MB. Vitamin D, light and mental health. J Photochem Photobiol B. 1988 Jul; 2(1):1-19.
Methylation support
•Disruptions in methylation can impact both the
synthesis and breakdown of neurotransmitters
• Methylfolate is required for monomamine (serotonin,
dopamine, norepi) synthesis. When pan low monoamine
neurotransmitters are demonstrated on testing, question
MTHFR variant, low folate status, etc…
• SAMe is required for catecholamine metabolism
General considerations
•Adaptogenic herbs treat both the adrenal cortex and the medulla
•Can be beneficial to give tyrosine and macuna together, much like we
give adaptogenic herbs when giving hydrocortisone
•May be important to give a little tyrosine or L-dopa when giving 5-HTP,
and vice versa
Additional considerations
•Fish oil
• EPA more influential on behavior and mood; potent anti-inflammatory
• DHA contributes to fluidity of cell membranes
•Probiotics
•Nervine herbs to impact restoration of nervous system
• Valerian, passion flower, chamomile, lemon balm, oats, hops, California
poppy, lavender kava
•Adaptogenic herbs to tonify HPA axis
• Rhodiola, licorice, eleuthrococcus, ginko, ginseng, ashwaganda, astragalus,
schizandra
Neurotransmitter pathways
When addressing
neurotransmitter imbalances,
consider these obstacles to
cure…
Stress
•44% of Americans feel more stressed
than they did 5 years ago
•3 out of 4 doctors visits are for stress-related ailments
•Stress is the etiology of 60% of all illness and disease
•Stress related ailments cost the nation $100 billion
more every year than what obesity costs the nation
•1 in 5 Americans experiences extreme stress
• Shaking, heart palpitation, depression
Women
are more
stressed
than
men…..
HPA Axis
The main determinants of HPA axis activity are:
•Genetic background
•Early life environment
•Current life stress
Stress and the Brain
•Stress literally shrinks the brain and degrades the BBB
• Stressors: Environmental stress, but also smoking, food intolerances,
blood sugar imbalances, anemia, bacterial gut infections, gut
parasites, autoimmune dz, joint pain and inflammation, poor
digestion, etc.
•Excess fat is pro-inflammatory and a chronic stressor for
body and brain.
•Primary stress hormone is cortisol.
• Studies show that high cortisol in response to high stress damages
the hippocampus, which regulates our circadian rhythm. Eventually
the system becomes hyporeactive and less responsive to ACTH.
Esposito P, et al. Acute stress increases permeability of the blood-brain-barrier through activation of brain mast cells. Brain Res. 2001 Jan5;888(1):117-127.
Tavanti M et al. Evidence of diffuse damage in frontal and occipital cortex in the brain of patients with post-traumatic stress disorder. Neurol Sci. 2012 Feb;33(1):59-68.
Stress and the Brain
Stress (emotional, chemical or physical)
causes elevations in the inflammatory cytokine
IL-6 which enhances the sympathetic stress response.
Midbrain gets flooded with IL-6 during long periods of extreme stressors
making it extremely sensitive to stimuli. Eventually something as benign
as a loud sound or flash of light can trigger an inappropriately huge
stress response.
Chronic stress and inflammation make the brain highly efficient at
responding to stress.
Esposito P, et al. Acute stress increases permeability of the blood-brain-barrier through activation of brain mast cells. Brain Res. 2001
Jan5;888(1):117-127.
Tavanti M et al. Evidence of diffuse damage in frontal and occipital cortex in the brain of patients with post-traumatic stress disorder.
Neurol Sci. 2012 Feb;33(1):59-68.
Stress and the Brain
Treatment beyond cortisol support….
◦ Possible treatments: nutrients like omegas or B12,
balancing NTs, more positive stimulation, anemia or
blood sugar imbalances?
◦ In addition to modulating HPA axis dysfunction, herbal adaptogens work on
stress pathways in the brain, particularly in the hippocampus.
Esposito P, et al. Acute stress increases permeability of the blood-brain-barrier through activation of brain mast cells. Brain Res. 2001 Jan5;888(1):117-127.
Tavanti M et al. Evidence of diffuse damage in frontal and occipital cortex in the brain of patients with post-traumatic stress disorder. Neurol Sci. 2012 Feb;33(1):59-68.
Allostatic responses to stress
Allostasis is the process by which biological process attempt to restore
homeostasis in the face of stress.
Responses can involve alterations in the HPA axis function, the nervous
system and signaling molecules (i.e. neurotransmitters and hormones)
Allostatic alterations in HPA axis function contribute to depressed mood
Stephens Ph.D., Wand M.D. Stress and the HPA Axis; Role of glucocorticoids in alcohol dependence. Alcohol
Research Alcohol Res. 2012;34(4):468-83
Stephens Ph.D., Wand M.D.
Stress and the HPA Axis; Role
of glucocorticoids in alcohol
dependence. Alcohol
Research
Alcohol Res. 2012;34(4):46883
Blood sugar imbalances
Hypoglycemia/insulin resistance
• Low blood sugar stimulates the release of cortisol from the adrenal
glands. This triggers the breakdown of glycogen stored in the liver and
muscles to release glucose into the bloodstream.
• Low cortisol hapers this response and, instead, the adrenals release epi
and NE
•These are the fight or flight substances
that cause a person to wake at 3am
filled with anxiety, or to be nauseous
in the morning.
•Excess epi contributes to insulin resistance where excess insulin
(metabolic syndrome) increases norepi
Kharrazian, Datis DHSc, DC, MS. Why Isn’t My Brain Working? Carlsbad: Elephant Press, 2013. Print.
DePergola G Giogino F. Benigno R., et al. Independent influence of insulin, catecholamines and thyroid
hormones on metabolic syndrome. Obesity (silver Spring). 2008 Nove; 16(11):2405-11.
Gut-Brain-Microbiome Axis
An emerging concept…
•Alterations in gut microbial composition is associated with marked
changes in behaviors relevant to mood, pain and cognition.
•Dysfunction of the microbiome-brain-gut axis has been implicated in
stress-related disorders such as depression, anxiety, and irritable bowel
syndrome and neurodevelopmental disorders such as autism.
•Although not fully elucidated, accumulating data indicated that the gut
microbiota communicates with the CNS through neural, endocrine and
immune pathways.
•Probiotics attenuate anxiety and depressive like behaviors in
experimental animal and human models.
Borre YE, et al. The impact of microbiota on brain and behavior: mechanisms & therapeutic potential. Adv Exp Med Biol. 2014;817:373-403.
Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behavior. Nat Rev Neurosci. 2012 Oct;13(10):701-12.
Foster JA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013 May;36(5):305-12.
Wang Y, Kasper LH. The role of microbiome in central nervous system disorders. Brain Behav Immun. 2014 May;38:1-12.
“Leaky gut”
Gastrointestinal inflammation leading to a breach in GI integrity, aka
“leaky gut”, results in constant immune activation and may lead to
systemic inflammation.
Kharrazian, Datis DHSc, DC, MS. Why Isn’t My Brain Working? Carlsbad: Elephant Press, 2013. Print.
Inflammation
•Systemic inflammation (chronic joint pain, infections, food intolerances,
unmanaged autoimmune conditions, dysglycemia) releases immune
messengers (cytokines). These cytokines send messages across the BBB
that activate inflammation in the brain, altering function
• i.e. a person with a gluten intolerance who does not eliminate the food
experiences brain fog and mood concerns
•Likewise, inflammation in the brain can activate the body’s immune
system and trigger systemic inflammation which can manifest as joint
pain, gut pain, skin disorders, etc.
• i.e. a person who sustains a head injury suddenly develops an autoimmune
disease.
Kharrazian, Datis DHSc, DC, MS. Why Isn’t My Brain Working? Carlsbad: Elephant Press, 2013. Print.
Combination therapies
BHRT and amino acids provide targeted therapy,
and some supplements can support both hormone
and NT imbalances:
◦ Adaptogenic herbs tonify both the adrenal cortex
(cortisol) and the adrenal medulla (catecholamines)
◦ B vitamins support adrenal cortex secretion and also act
as co-factors for various NT pathways
The relationship between hormones and brain
chemistry strongly influences the severity of
presenting symptoms.
If optimal levels of neurotransmitters are not
present, their hormonal counterparts may not
adequately modulate, enhance or sensitize their
activity.
Mood and Hormones
•Emotional symptoms may be related to fluctuating hormone levels
rather than declining hormone levels
•Early menopause and surgical menopause may demonstrate increased
risk
•Women who have experienced PMS, PMDD and postpartum depression
may be at an increased risk of mood disturbance in peri/post
menopause.
•Mood concerns are exacerbated by hot flashes, night sweats and
resultant sleep disturbances
Carter, MBBS. Depression and emotional aspects of the menopause. BCMJ, Vol 43 No. 8 10/2001. pgs 463-466
Neurotransmitters, Hormones
and Mood
Estrogen:
◦ Increases production and synaptic concentration of serotonin
◦ Increases serotonin receptor levels
◦ Is a dopamine modulator, enhancing activity of dopamine
Progesterone:
◦ GABA agonist
Must have adequate levels
of hormones and NTs for successful relationships
Shepherd, Janet. Effects of Estrogen on Cognition, Mood and Degenerative Brain Diseases. J Am Pharm Assoc. 2001;41(2).
Example Cases
48 yo perimeno f
135 pounds, 5’4”
Mood is agitated and depressed
Hx of PTSD from childhood trauma being raised in a violent home. Has
been in counseling for more than 25 years and is now doing trauma
releasing exercises. Feels as if she’s dying inside a lot of the time
Sleep pattern: has gotten later and later. Now going to bed at 3-4 am
though she may go to bed at 6:30am. Sleeps 8 hours.
Energy 4/10 (10 bet)
Actively bulimic qd x 3 years; hides this from her partner
SHx remarkable for Nicorette use
Lab results
Optimal?
Treatment approach
Pg: 90mg sl hs days 7-menses
Theanine: 200 mg bid ac
Tyrosine with macuna: 2 capsules every am
B Complex with methyl B12 and methyl folate
2000 mcg B12
Vitamin D: 500 iu
Rhodiola and 100 mg phosphatidyl/phosphorylated serine: 1 capsule every “morning” and “noon”
Sleep support/Daytime regimen:
Every week, more bedtime up by 30 minutes. Start at 4:30am
No electronics for 2 hours prior to bed time
30 min before bed (4am this week) - 200mg phosphatidyl serine
Melatonin 2 hours prior to bed time: 2-5 mg with 200 mg 5HTP
Glutatmate is a future consideration
70 yo f
138 lbs, 5’3”
Pain x 35 years with dx of fibromyalgia and chronic fatigue. Pain can
cause depressed mood and suicidal ideations.
History remarkable for early childhood/teen years of trauma, abuse and
torture and anorexia and bulimia in later years
-currently using B vitamins, vitamin C and glandulars for HPA axis
support
Sleep disturbance. Utilizing Trazadone and Flexeril for sleep
Self-reported shallow breathing
Reports stress as “not a lot”
Energy 4/10 (10 best)
Lab results
Treatment approach
Anti-inflammatory diet with avoidances of any additional food
intolerances
DHEA: 10 mg PO q am
Hydrocortisone: 5 mg q am and 5 mg q noon
B Complex with adaptogenic herbs, vitamin C and low dose tyrosine am
and noon
5-HTP: 100 mg qhs
Referral to EFT practitioner
Self time (10+ min daily) and breathing exercises
6 Week follow up
Energy: Significantly better 6-7/10.
Pain: is also significantly better with more good days than bad.
Minimal change in sleep
Supporting Serotonin
Low serotonin
High serotonin
Tryptophan
◦ 500-2,000 mg
L-theanine
◦ 100-500 mg bid
5 HTP
◦ 50-600 mg
Co-factors (to support
metabolism and conversion)
◦ Vitamin B2: 50 mg
◦ Vitamin B3: 50 mg
◦ Iron: 25-50 mg
◦ SAMe: 250-500 mg
L-theanine
◦ 100-500 mg bid
Cofactors
◦ Iron 25-50 mg (citrate or
bisglycinate)
◦ P5P 50-200 mg
◦ Vitamin C 4,000-6,000 mg
◦ Vitamin D 2,000-10,000 IU
◦ MTHF
Supporting Dopamine
Low dopamine
N-acetyl l-tyrosine
◦ 250-1,500 mg
Macuna pruriens
◦ 200-800 mg
L-theanine
◦ 100-500 mg bid
Vitamin D
◦ 1,000-10,000 IU
Cofactors
◦
◦
◦
◦
◦
◦
Vitamin C 4-6 gm
Iron 25-50 mg
Vitamin B3 50 mg
P5P 50-200 mg
MTHF
Vitamin D 2,000-10,000 IU
High dopamine
L-theanine
◦ 100-500 mg bid
Co-factors (to support MAO/COMT)
◦ Vitamin B2: 50 mg
◦ Vitamin B3: 50 mg
◦ Iron: 25-50 mg
◦ SAMe: 250-500 mg
Co-factors (if Norepi low or low
range)
◦ Vitamin C: 4,000-6,000 mg
◦ Copper: 0.5-1 mg
◦ Vitamin B3: 50 mg
Supporting Norepinephrine
Low norepinephrine
N-acetyl l-tyrosine
◦ 250-1,500 mg
Macuna pruriens
◦ 200-800 mg
L-theanine
◦ 100-500mg bid
◦ Vitamin D
◦ 1,000-10,000 IU
Co-factors
◦ Vitamin C: 4-6 gm
◦ Copper: 0.5-1 mg
◦ Vitamin B3: 50 mg
High norepinephrine
• L-theanine
• 100-500 mg bid
• Co-factors (to support
MAO/COMT)
• Vitamin B2: 50 mg
• Vitamin B3: 50 mg
• Iron: 25-50 mg
• SAMe: 250-500 mg
• Co-factors (if epi low or low
range)
• SAMe: 250-500 mg
• Address hypoadrenia
Supporting Epinephrine
Low epinephrine
N-acetyl l-tyrosine
◦ 250-1,500 mg
Macuna pruriens
◦ 200-800 mg
L-theanine
◦ 100-500mg bid
Co-factors
◦
◦
◦
◦
Vitamin C 4-6 gm
SAMe 250-500 mg
Magnesium 150-500 mg
Must address adrenal dysfunction (hypoadrenia)
High epinephrine
• L-theanine
• 100-500 mg bid
• Co-factors (to support
MAO/COMT)
• Vitamin B2: 50 mg
• Vitamin B3: 50 mg
• Iron: 25-50 mg
• SAMe: 250-500 mg
Addressing GABA
Low GABA
L-theanine
◦ 100-500 mg bid
GABA
◦ 500-2,000 mg
Phenibut
◦ 250-1,000 mg bid
Glutamine
◦ 1,000-3,000 mg
Co-factors
◦ P5P: 50-200 mg
High GABA
L-theanine
◦ 100-500 mg bid
Supporting Glutamate
Low glutamate
L-glutamine
◦ 1,000-3,000 mg
High glutamate
L-theanine
◦ 100-500 mg bid
Taurine (reduces glutamate toxicity)
◦ 500-1,500 mg
Co-Factors (to support metabolism
and conversion)
◦ Vitamin B3: 50mg
◦ P5P: 50-200 mg
Magnesium (reduces glutamate
toxicity)
◦ 150-500 mg