Workshop

Integrative Medicine: Supplements and Herbal Therapies including

Medical Marijuana

Primary Care Internal Medicine

15 October 2018 4:00-5:10 PM

Donald B. Levy, M.D Medical Director

Osher Clinical Center for Integrative Medicine at Brigham and Women’s Hospital

Assistant Clinical Professor of Medicine Harvard Medical School

Disclosures

I have no financial relationship with a commercial entity producing healthcare-related services.

Any products depicted in this talk are examples for the purpose of education and do not represent an endorsement of any brand.

Donald B. Levy, MD

Learning Objectives After Today’s Discussion, Participants will be able to:

1. Compare and Contrast short latency and long-latency vitamin deficiencies 2. Name at least one dietary supplement for which there is evidence of benefit in the management of: Hyperlipidemia, Hypertension, an Incipient URI, Depression, Anxiety, “Burn-out” and Insomnia 3. Describe the potential medicinal benefit and rationale for using whole plant cannabis for help in the management of at least one chronic condition

Integrative Medicine

A.K.A. Holistic Alternative Complementary Complementary and Alternative (CAM) Complementary and Integrative (NCCIH)* *National Center for Complementary and Integrative Health

Modern Integrative Medicine

.…..health care with an attitude of mind that

seeks preferentially those therapies or therapeutic lifestyle changes (TLC) that enhance one’s innate ability to recover from illness and maintain good health.

(An incremental change in the approach and scope

of Primary Care Medicine)

Part 1: Dietary Supplements: Prevalence of Use in the United States

2011-2012: 52% of Adults 2003-2006: >50% of Adults > 32% of Children 1988 -1994: 40% of Adults Kantor ED et. al. Trends in dietary supplement use among US adults from 1999-2012. JAMA.

2016;316(4):1464-74 Gahche J. et, al. Dietary supplement use among U.S. adults has increased since NHANES III (1988-

1994). NCHS data brief, no.61. Hyattsville, MD: National Center for Health Statistics. 2011 Picciano et al. Dietary supplement use among infants, children and adolescents in the United States,

1999-2002; Arch Pediatr Adolesc Med. 2007:161(10): 978-985

Three Rational Uses of Dietary Supplements

1. Prevent or treat an acute (Short Latency) deficiency condition

2. Prevent or treat a chronic (Long Latency)

deficiency condition 3. Treat an acute or chronic disease (“Green Pharmacy”)

Preventing or treating an

Acute Deficiency or Short Latency Syndrome

May 1941—NAS Subcommittee established RDA’s to prevent acute deficiency syndromes in the general population. i.e. Take daily to prevent:

• Scurvy Vitamin C —75-90 mg • Rickets Vitamin D— 600 IU • Pellagra Vitamin B3 (Niacin) —16 mg • Beriberi Vitamin B1 (Thiamin) —1.2 mg However: What is the optimal life-long dose of

these vitamins?

Preventing or treating a Chronic Disease or Long Latency Syndrome

There is suggestive evidence that specific vitamins, minerals or

other supplements may prevent, delay or ameliorate : • Osteoporosis • Osteoarthritis • Coronary Heart Disease • Depression • Hypertension • Multiple Sclerosis • Alzheimer’s Disease • Prostate Cancer • Complications of Pregnancy

Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in adults: scientific review. JAMA. 2002 19;287(23):3116-26. Review

Holick MF. Vitamin D deficiency. NEJM. 2007;357(3):266-81. Review

Can We Really Prevent or Treat a Chronic

Disease with a Micronutrient ?

If so, how do we investigate

Long Latency Hypotheses

Without VERY LARGE, 10-30 Year Studies?

Hypothesis: Osteoporosis is Partially Due to a Long latency Vitamin D Deficiency Syndrome

Osteoporosis + Vitamin D Insufficiency

may be associated with:

• Increased risk of falls • Increased risk of vertebral and non-vertebral

fractures • Muscle weakness

Look at physiologic feedback loops to determine what levels exist when there is optimal homoeostatic balance

PTH levels fall and level off as 25(OH) D levels rise

Optimal Daily Dose of Vitamin D for Bone Health is likely When We See:

Lowest Parathyroid Hormone (PTH) level Maximal Calcium Absorption and Transport Greatest Muscle Strength Greatest Bone Density

All of the Above are Achieved When:

Serum 25 (OH) D= ~ 32 ng/mL* (80nmol/L) Hypothesis: Ballpark optimal dose is whatever it takes to achieve that level.

Holick MF. Vitamin D deficiency. NEJM. 2007;357(3):266-81. Review.

* Notes: ― I.O.M. Report says data more consistent with level of ~20 ng/mL ― No disagreement that 4,000 IU Vitamin D3 daily is safe ― In sunny countries 25 (OH) D levels = 54-90 ng/mL)

Rational Use of Dietary Supplements for some Common Conditions in Primary Care

Case #1: Hyperlipidemia Case #2: Hypertension Case #3: URI / Influenza Case #4: Depression (+ Dysphoria/ Burn-out) Case #5: Anxiety and Insomnia

Case # 1: Hyperlipidemia—Statin intolerant but patient really needs this medication and willing to try

Consider: Vitamin D—if deficient Red Yeast Rice (see 2b) Coenzyme Q10? —Current evidence suggests

no benefit for statin-induced myalgias

Hyperlipidemia—Statin intolerant: Vitamin D Supplementation

• Check 25(OH) D level • Supplement if level below 32 ng/mL (80nmol)

References: • Michalska-Kasiczak M, et. al. Analysis of vitamin D levels in patients with and without

statin-associated myalgia - A systematic review and meta-analysis of 7 studies with 2420 patients. Int J Cardiol. 2014;178C:111-116

• Waqas A et. al. Low serum 25(OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients. Translational Res 2009;153:11-16.

• Lee, P et. al. Vitamin D insufficiency--a novel mechanism of statin-induced myalgias? Clin Endocrinology 2009.71;151-156

Hyperlipidemia— Statin intolerant

Give Co-enzyme Q10 ? Safe, nutritionally reasonable, but latest trials speak against

significant benefit for statin-induced myalgias → Taylor BA et. al. A randomized trial of coenzymeQ10 in patients

with confirmed statin myopathy. Atherosclerosis. 2015 ;238 (2):329-35.

→ Banach M et. al. Effects of coenzyme Q10 on statin-induced

myopathy: a meta-analysis of randomized controlled trials. Mayo Clin Proc. 2015 ;90(1): 24-34

Caso G et. Al. Effect of coenzyme q10 on myopathic symptoms in patients treated with statins. Am J

Cardiol 2007;99(10): 1409-12 Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy: a systematic

review. J Am Coll Cardiol. 2007 ;49(23): 2231-7

Case # 1b: Hyperlipidemia― “No statin please!” The individual who cannot or will not take a statin

Therapeutic Lifestyle Changes--especially Diet-Classic Mediterranean (Lyon Diet Heart Study) + Soluble Fiber (Psyllium, oat, flaxseed) + nuts

Phytosterols: plant stanols and sterols Red Yeast Rice Niacin --still benefit if not already on a statin (Coronary Drug Project—1980’s) (? Theaflavin-enriched Green Tea Extract --only 1 RCT) Policosanol Guggulipid (Both unlikely to be helpful based on good studies)

Hyperlipidemia: Phytosterols (Plant Stanols and Sterols) (Present in Western diet in small amounts--250-500 mg/d)

• Can lower LDL cholesterol by 10-14% in doses of 2,000- 3,000 mg /daily —especially dietary cholesterol • Well tolerated; does not affect serum levels of fat-soluble vitamins

Effective formulations contain Phytosterol esters • Cabral CE Phytosterols in the Treatment of Hypercholesterolemia and Prevention of

Cardiovascular Diseases. Arq Bras Cardiol. 2017;109(5):475-482 • Gylling H, European Atherosclerosis Society Consensus Panel on Phytosterols. Plantsterols and

plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease. Atherosclerosis. 2014;232(2):346-60

• Amir Shaghaghi M. Cholesterol-lowering efficacy of plant sterols/stanols provided in capsule and tablet formats: results of a ststematic review and meta-analysis. J Acad Nutr Diet.2013;113(11): 1494-503

• Talati R et. al. The comparative efficacy of plant sterols and stanols on serum lipids: a systematic review and meta-analysis. J Am Diet Assoc. 2010

Hyperlipidemia: Phytosterols

Example: “….made with esterified Reducol®, a proprietary blend of plant-based sterols and stanols …”

Hyperlipidemia: Red Yeast Rice

Dietary staple in some countries and used for 13 centuries in China--contains plant sterols, isoflavones and naturally occurring statins (monacolins)

• Trials using a dose of 2.4 --3.6 grams daily lasting at least 6 months have shown it to be well tolerated even in patients who had previously been statin- intolerant

• 20-25% reductions in LDL cholesterol

• Study of almost 5,000 patients in China with previous MI; 4.5 years; Decreased Cardiac events and CVD mortality • Must be high quality product to avoid contaminant (citrinin)

Red Yeast Rice: References • Moriarty PM. Effects of Xuezhikang in patients with dyslipidemia: a multicenter,

rendomized, placebo-controlled study. J Clin Lipidol. 2014;8(6)568-75 • Li Y. A meta-analysis of red yeast rice: an effective and relatively safe

alternative approach for dyslipidemia. PLoS One. 2014;9(6):e98611 • Becker DJ et. al. Phytosterols, red yeast rice, and lifestyle changes instead of

statins: a randomized, double-blinded, placebo-controlled trial. Am Heart J. 2013;166(1):187

• Becker DJ et. al. Red yeast rice for dyslipidemia in statin-intolerant patients. Ann Intern Med. 2009;150:830-839.

• Verhoeven V et. al. Red yeast rice lowers cholesterol in physicians - a double blind, placebo controlled randomized trial. BMC Complement Altern Med. 2013;13(1):178

• Lu Z et al. Effect of Xuezhikang, an extract from red yeast rice, on coronary events in a Chinese population with previous myocardial infarction. Am J Cardiol. 2008;101(12):1689-93 And Note: • Cohen PA Variability in strength of red yeast rice supplements purchased

from mainstream retailers. Eur J Prev Cardiol. 2017;24(13):1431-1434. . • Dujovne CA. Red Yeast Rice Preparations: Are They Suitable Substitutions for Statins? Am J Med. 2017;130(10):1148-1150

Case #2: Hypertension Beyond Diet, Lifestyle and Medications

Mind-Body Therapies as Adjuvants Mindfulness Meditation, Biofeedback, Tai Chi; Yoga; Resperate device

Acupuncture Rational Supplements • Magnesium citrate • Lycopene /Tomato extract • Vitamin D (if low) • Potassium (if dietary deficiency) Brook RD et. al. Beyond Medications and Diet: Alternative Approaches to Lowering

Blood. Scientific Statement From the American Heart Association Hypertension. 2013;1360-83

Potassium Supplementation to reach DASH goals (?)

• DASH Goal= 4700 mg daily • Most people cannot get this much in diet • OTC supplements often 99 mg; some 200 mg • Easy to take 200 mg tid

Beware potassium-sparing diuretic (such as triamterene, spironolactone or amiloride) or ARBs, ACE inhibitors, NSAIDs

Potassium Citrate Supplements

99 mg cap (Approx 2.5 mEq) 200 mg (Approx 5 mEq)

Potassium Supplementation (OTC) for Hypertension

• Poorolajal J Oral potassium supplementation for management of essential hypertension: A meta-analysis of randomized controlled trials. PLoS One. 2017;12(4) • Rysz J . Hypertension - Current Natural Strategies to Lower Blood Pressure.

Curr Pharm Des. 2017;23(17):2453-2461.. Review. • Gijsbers L, Effects of sodium and potassium supplementation on blood

pressure and arterial stiffness: a fully controlled dietary intervention study. J Hum Hypertens. 2015;29(10):592-8.

• Binia A, Daily potassium intake and sodium-to-potassium ratio in the reduction

of blood pressure: a meta-analysis of randomized controlled trials. J Hypertens. 2015;33(8):1509-20.

• Houston MC Potassium, magnesium, and calcium: their role in both the cause and treatment of hypertension. J Clin Hypertens (Greenwich). 2008;10(7 Suppl 2):3-11

Mind-Body Techniques as Adjuvants Varying styles/approaches = Heterogeneity of Literature

Some great responders with multiple benefits

• Mindfulness Meditation; [Yoga]

• RESPeRATE TM [Biofeedback]

• Tai Chi / Qi Gong

Two Popular Types of Mindfulness Training

Jon Kabat-Zinn Herbert Benson

Common Aspects of Mindful Awareness Practice (i.e. Meditation)

Intention Focusing the attention via some form

of repetition or return to focus

Nonjudgmental attitude toward everything experienced

Mindfulness Practice (Meditation) Alters Brain Function and Structure

Function Changes reported in studies:

• Emotional regulation • Stress management • Anxiety • Depression • Insomnia • Sense of self

Structure Some of the areas changed on

Functional MRI:

• Posterior cingulate • Hippocampus • Pons • Amygdala

Mindfulness and Breathing RESPeRATE TM Device

RESPeRATE in Use Guided paced breathing: (1) monitoring breathing movements, (2) com posing breathing–guiding tones, and (3) synchronizing breathing From: Cernes. J Am Soc Hypertens 2014;S1933-1711(14) 00834-1

Magnesium for Hypertension • Magnesium Citrate or glycinate well absorbed • Often a good adjunct to ongoing care • Dose: 400-600 mg; May take 6 weeks to show effect References: DiNicolantonio JJ, Magnesium for the prevention and treatment of cardiovascular disease. Open Heart. 2018;5(2):e000775. Romani AMP. Beneficial Role of Mg(2+) in Prevention and Treatment of Hypertension. Int J Hypertens. 2018; 2018:9013721 Zhang X et. al. Effects of Magnesium Supplementation on Blood Pressure: A Meta-Analysis of Randomized Double-

Blind Placebo-Controlled Trials. Hypertension. 2016: 68(2):324-33 Afsar B. The relationship between magnesium and ambulatory blood pressure, augmentation index, pulse wave

velocity, total peripheral resistance, and cardiac output in essential hypertension patients. J Am Soc Hypertens. 2014 ;8(1):28-35

Kolte D. Role of magnesium in cardiovascular diseases. Cardiol Rev. 2014;22(4):182-92 Rodriquez-M M.. Arch Med Res. 2014;45(5):388-93 Oral magnesium supplementation improves the metabolic

profile of metabolically obese, normal-weight individuals: a randomized double-blind placebo-controlled trial Rosanoff A. Oral magnesium supplements decrease high blood pressure (SBP>155 mmHg) in hypertensive

subjects on anti-hypertensive medications: a targeted meta-analysis. Magnes Res. 2013;26(3):93-9 Bo S Role of dietary magnesium in cardiovascular disease prevention, insulin sensitivity and diabetes. Curr Opin

Lipidol. 2008;19(1):50-6.

Magnesium: “Side effects” Depends on dose and formulation

Magnesium Citrate Capsules 3 caps = 500 mg

Magnesium Citrate Laxative 1 bottle = 17,450 mg

Lycopene / Tomato Extract

• Lycopene content : 15-20 mg daily • Studies included tomato extract

• Mozos I. Lycopene and Vascular Health. Front Pharmacol. 2018 9:521 • Böhm V. Lycopene and heart health. Mol Nutr Food Res. 2012;

56(2):296-303. • Paran E. et. al. The effects of natural antioxidants from tomato extract in

treated but uncontrolled hypertensive patients. Cardiovasc Drugs Ther. 2009;23(2):145-51

• Engelhard YN et al. Natural antioxidants from tomato extract reduce blood pressure in patients with grade-1 hypertension: a double-blind, placebo-controlled pilot study. Am Heart J. 2006;151(1):100

Tomato Extract: Lyc-O-MatoTM

Is it the Lycopene or the whole extract?

Pharmaceutical vs. Herbal Remedies

Red Yeast Rice vs. isolated ‘statin’ Drug Tomato Extract vs. isolated lycopene

Are Herbal Remedies Simply

“Messy” Drugs? (See Medical marijuana)

No benefit from supplementing Vitamin D

deficiency on blood pressure

Scragg R, Long-term high-dose vitamin D3 supplementation and blood pressure in healthy adults: a randomized controlled trial. Hypertension.2014 ;64(4):725-30.

Arora P, et. al. Vitamin D Therapy in Individuals With Prehypertension or Hypertension: The DAYLIGHT Trial. Circulation. 2015 ;131(3):254-

________________________________________________________________________ Andrukhova O et al. Vitamin d as a regulator of endothelial nitric oxide synthase and arterial stiffness in

mice. Mol Endocrinol. 2014;28(1): 53-64 Banzato C et al. Hypovitaminosis d and nocturnal hypertension in obese children: an interesting link. J

Hum Hypertens. 2013;1-7 Min B. Effects of vitamin d on blood pressure and endothelial function. Korean J Physiol Pharmacol.

2013;17(5):285-92 Pilz S et al. Vitamin D status and arterial hypertension: a systematic review . Nat Rev Cardiol. 2009;6

(10): 621-30

Case # 3: Upper Respiratory Infection

“I am coming down with a cold; I need an antibiotic or something…now!”

• Herbal preparations…… many claims • Some have actually been tested and are

especially effective when just becoming ill with a viral-type URI….rather than the often unnecessary, inappropriate, but requested antibiotic

Black Elderberry Extract (Sambucus nigra)

• Clinically: reduces symptoms when administered to patients with influenza

• Anthocyanins readily detected in bloodstream following ingestion

• May inhibit neuraminidase to roughly same degree as prescription meds

• Studied by mass spectrometry and molecular docking in cell culture and in clinical trials

Anthocyanin Binding and Inhibition of Influenza Neuraminidase Anthocyanin (left) and zanamivir (right) docked onto the structure of influenza neuraminidase

Swaminathan 2013

Black Elderberry (Sambucus nigra)

One High Quality Extract Directions • Herbal dosing can be

confusing based on whether crude herb, extract, standardization, etc.

• Can take equivalent of 3-5 grams of crude herb

4x daily • Follow Label for minimal

effective dosing

SambucolTM Contains 3.8 g Black Elderberry Extract per 10 ml Buy the “Original Formula” (center) Take Q.I.D.

Black Elderberry: References

• Porter RS, Bode RF. A Review of the antiviral properties of Black

Elder (Sambucus nigra L.) products. Phytother Res. 2017; 31(4):533-554

• Shahsavandi S, Interfering with lipid raft association: a mechanism to control influenza virus infection by Sambucus Nigra. Iran J Pharm Res. 2017;16(3):1147-1154.

• Swaminathan K. Binding of a natural anthocyanin inhibitor to influenza neuraminidase by mass spectrometry. Anal Bioanl Chem. 2013;405(20) 6563-72

• Krawitz C. Inhibitory activity of a standardized elderberry liquid extract against clinically-relevant human respiratory bacterial pathogens and Influenza A and B viruses. 2011;25(11):16

• Barak V. The effect of Sambucol, a black elderberry-based, natural product, on the

production of human cytokines: I. inflammatory cytokines. 2001;12(2): 290-6

Upper Respiratory Infections Questionable Vitamin/Herbal products

• No study (or single study often by the manufacturer)

• Minimal or no scientific plausibility • Pseudo-scientific extrapolations • Minimal meaningful clinical result

Airborne TM

• Mixture of many vitamins,

amino acids (lysine and glutamine) and 7 herbs

(in very low doses) • No clear evidence of

efficacy • Perhaps helps those very

deficient in the vitamins provided (C, Zn, Se)

Oscillococcinum TM

• Homeopathic remedy tested against influenza-like illness

• 17.1% vs. 10.3% recovery w/in 48 hours*

*Ferley JP, et. al. A controlled evaluation

of a homeopathic preparation in the treatment of influenza-like syndromes. Br J Clin Pharmacol. 1989;27:329-335

Case #4 Burn-out / Dysphoria (What do you call this? Mild Fatigue, Low Energy..…)

“I am tired, burned-out, stressed and

depressed…. “I do not want (or tolerate or need ) an

antidepressant…..” Therapist Lifestyle changes Exercise What else?

Is this a question of enhancing Resilience ?

•Act of rebounding or springing back especially after being deformed • Power of recovery after strain

Hans Selye meant to say “Strain”

“Selye several times complained to me that had his knowledge of English been more precise, he would have gone down in history as the father of the ‘strain’ concept.”

Paul J. Rosch, M.D., F.A.C.P. REMINISCENCES OF HANS SELYE, AND THE BIRTH OF "STRESS“

Selye: General Adaptation Syndrome (GAS)

(Experiments with rats--1936 )

Adaptation to repetitive low level stress (strain); (low doses of stress results in increased resistance) Stage 1 “Alarm reaction”—initial stress recognition—

Symptoms emerge

Stage 2– Acquisition of non-specific resistance— Symptoms disappear Stage 3—Exhaustion—same symptoms reappear followed by Death

Lazarev and Brekhman

(1950’s and 1960’s) • Certain herbal extracts can prolong the duration of

non-specific resistance to stress and diminish the magnitude of the alarm phase

• Adaptogens: non-toxic compounds with polyvalent mechanisms of action

• Response occurs at multiple levels from the cellular to the whole organism

i.e. Neurons—adaptogens influence signaling to promote neuroplasticity and decrease vulnerability to neurodegeneration

Adaptogens

“Stress-response modifiers that increase an organism’s nonspecific resistance to stress by increasing its ability to adapt and survive”

* * Panossian, A Understanding adaptogenic activity: specificity of adaptogens and other phytochemicals. Ann N.Y. Acad Sci; 2017: 49-64

Rhodiola rosea for Stress/Fatigue (Dysphoria/ Burn-out)

Adaptogen (non-medical term) …A substance that can act to increase an organism's

resistance to physical, chemical and biological stressors

Long history of use in Eastern Europe and Asia for:

• Combating stress-induced fatigue and depression ("burnout")

• Improvement of mental performance

Rhodiola rosea: An Adaptogen

Rhodiola rosea • Studies in humans and animals: Some support for the claims made at doses

of 340 or 680 mg. of an extract known as SHR-5 • Effects can be seen after single dose • May reach maximal benefit in two weeks. • No significant adverse effects reported (theoretical risk of interaction with SSRI's)

Stress/ Fatigue: • Panossian A. Understanding adaptogenic activity: specificity of the pharmacological action of adaptogens and other

phytochemicals. Ann N Y Acad Sci. 2017;1401(10:49-64 • Cropley M, The effects of Rhodiola rosea L. extract on anxiety, stress, cognition and other mood symptoms. Phytother Res.

2015;29(12):1934-9. • Ishaque S . Rhodiola rosea for physical and mental fatigue: a systematic review. BMC Complement Altern Med. 2012;12:70 • Olsson EM A randomised, double-blind, placebo-controlled, parallel-group study of the standardized extract shr-5 of the roots

of Rhodiola rosea in the treatment of subjects with stress-related fatigue. Planta med. 2009;75(2): 105-12 Depression: • Mao JJ, Rhodiola rosea versus sertraline for major depressive disorder: A randomized placebo-controlled trial. Phytomedicine.

2015; 15;22(3):394 • Amsterdam JD, Rhodiola rosea L. as a putative botanical antidepressant. Phytomedicine. 2016 ;23(7):770-83. • Hung SK, The effectiveness and efficacy of rhodiola rosea L.: a systematic review of randomized clinical trials. Phytomedicine.

2011;18(4): 235-244 • Darbinyan V et. al. Clinical trial of Rhodiola rosea L. extract SHR-5 in the treatment of mild to moderate depression. Nord J

Psychiatry. 2007;61(5): 343-8

Ashwagandha (Withania somnifera)

Another adaptogen…..

• Used in traditional Ayurvedic medicine for over 3,000 years. • Clinical trials and animal research support its use for anxiety and cognitive and neurologic disorders

• Chandrasekhar K. A prospective, randomized double-blind, placebo-controlled study of safety and efficacy of a high-concentration full-spectrum extract of ashwagandha root in reducing stress and anxiety in adults. Indian J Psychol Med. 2012; 34(3): 255–262.

• Kuboyama T. Effects of ashwagandha (roots of withania somnifera) on neurodegenerative diseases. Biol Pharm Bull. 2014;37(6):892-7

• Monograph. Withania somnifera. Altern Med Rev. 2004;9(2):211-214 • Mishra LC. Scientific basis for the therapeutic use of Withania somnifera

(ashwagandha): a review. Altern Med Rev.2000;5(4):334-46 • Ashwagandha Supplements Review. ConsumerLab. July 2018

Case #4a Mild Depression:

S-Adenosyl Methionine (SAMe)

• Major methyl donor in the body-- involved with the metabolism of serotonin, norepinephrine and dopamine

• Onset of action: much more rapid than prescription or herbal antidepressants

• Monotherapy or can be used concurrently with other agents until the former take effect

• Small # of trials: superior to placebo; as effective as full doses of tricyclic antidepressants

• Prescription medication in Germany since 1989

SAMe for Depression

• Dose: 200 mg once or twice daily and titrated up

over 1-2 weeks to 800 mg. daily • Maintenance at 200 mg. twice daily • Well tolerated; some G.I. side effects (higher doses)

• Two week therapeutic trial should be sufficient to determine effectiveness

Sharma A…Work Group of the American Psychiatric Association Council on Research. S-Adenosylmethionine (SAMe) for neuropsychiatric disorders: a clinician-oriented review of research. J Clin Psychiatry. 2017;78(6):e656-e667 Freeman MP et. al. Complementary and alternative medicine in major depressive disorder: the

American psychiatric association task force report. J Clin Psychiatry. 2010;71(6): 669-81 Mischoulon D, Fava M. Role of S-adenosyl-L-methionine in the treatment of depression: a

review of the evidence. Am J Clin Nutr. 2002;76(5):1158S-61S. Review

S-Adenosyl Methionine (SAMe)

Widely Available Brand

Very Hydroscopic…

Case#5-- Anxiety/ Insomnia

The following have some degree of supportive literature for use either as a sole agent or an adjunct:

• Chamomile Extract • L-Theanine • [Acupuncture]

Chamomile Extract (Matricaria recutita)

for Mild to Moderate Anxiety

Eight week RCT, double-blind, placebo-controlled • Mild to moderate GAD • Extract standardized to 1.2% apigenin • Start: one 220 mg. capsule daily • dose once weekly based on HAM-A score (up to 5 caps/day) • Significant anxiolytic effect over placebo

Amsterdam JD et. al. A randomized, double-blind, placebo-controlled trial of oral Matricaria recutita

(chamomile) extract for generalized anxiety disorder. J Clin Psychopharmacol. 2009:29(4):378-82

Chamomile for Anxiety

Well tolerated More convenient/ reliable than tea Standarized 1.2% apigenin

L-Theanine for Anxiety Non-protein amino acid--constituent of Green Tea

• Balances some of the stimulatory effect of tea • 200 mg p.o. can produce a state of increased alpha

waves and a subjective sense of relaxation and improvement in concentration and learning ability in about 30-40 minutes

• Some people find it helpful for sleep • Can use 3-4 x daily

L-Theanine

Capsule 200 mg Chewable 100 mg

L-Theanine: References Natural Medicines Professional --database—Theanine. 2015 Ota M et. al. Effect of L-theanine on sensimotor gating in healthy human

subjects. Psychiatry Clin Neurosci.2014;68(5):337-43 Unno K et. al. Anti-stress effect of theanine on students during pharmacy

practice: positive correlation among salivary alpha amylase activity, trait anxiety and subjective stress. Pharmacol Biochem Behav.2013;111:128-35

Vuong QV et. al. L-theanine: properties, synthesis and isolation from tea. J Sci Food Agric. 2011;91(11):1931-9

Lu K et.al. The acute effects of L-theanine in comparison with alprazolam on anticipatory anxiety in humans. Hum Psychopharmacol. 2004;19(7): 457-65

Nutraceutical Information / Evidence

Medical Databases

1. Micromedex/PDR —becomes AltMedDex® when you type in a Nutraceutical

2. Natural Standard and Natural Medicines Comprehensive Database

joined to become:

Locating Quality Supplements (Nutraceuticals and botanicals)

• Quality, purity, potency and bioavailability vary tremendously!

• Some formulations may be more physiologic than

others (folate vs. methyltetrahydrofolate)

• Cost does not always reflect quality

Nutraceutical Regulation is generally focused on:

1. Safety and Labeling 2. Lesser emphasis on product claims and intended use

(as compared to pharmaceuticals) • Relies on Good Manufacturing Practice (GMP) regulations • FTC– watches claims made in Advertising • FDA – watches claims made in Labeling and packaging

• Consumers are largely responsible for determining the usefulness and value offered

A Start: Look for these Product Seals:

• Confirm the identity and quantity of some of the ingredients declared on the label

• Confirm product is free of selected contaminants and undeclared ingredients

• Demonstrate conformance to industry GMPs • On-going monitoring

l

• “ Quality Ratings and Product Reviews and Comparisons by Brand” • “ Expert Tips and Answers on Using Supplements” • ”e-Newsletter with Updates and Alerts” • “New and Archived Recalls and Warnings”

$42.00 / year for on-line membership ($69.00/ 2 years) A good resource. • (May not be as independent as claimed) • (Manufacturers can pay to be evaluated) • (Posts advertisements from manufacturers)

Example: Ashwagandha Choosing a product

ConsumerLab.com Nature’s Way • Brief Literature review • Safety / Quality Concerns • What they tested for • Daily dose minimum 6 mg

of withanolides—often 10-30 mg or more daily • Best Products….. #1—Nature’s way

One Independent Distributor’s Quality Program worth investigating: Emerson Ecologics

www.emersonecologics.com

Only those products meeting the highest standards get the Gold or Silver Seal

Some of the Quality Supplement Brands

That are Available Through Retail Outlets*

Enzymatic Therapies Gaia Herbs Nature’s Way NOW Vitamins Nordic Naturals (for fish oils, Omega-3 fatty acids) •

Cost: Look on-line; i.e. www.vitacost.com *Some of the highest quality brands of dietary supplements are available only through

health care

Part 2: Marijuana (Cannabis sativa or indica) From Medicinal herb to Recreational herb to Medicinal herb

Recreational Marijuana A Parking lot, Provincetown, MA

Recreational Use of Cannabis in the U.S.

• Most commonly used illicit substance • Each year 2.4 million people try it for the first time • 51% (males) 41% (females)—have tried it [2012] • Current prevalence of use in USA (varies by state) • Acute, life-threatening toxicity: very rare • Adolescents ― serious concerns about effects of

regular use on neurocognitive development and increased risk of dependence

Cannabis: Marijuana vs. Hemp

Growing Marijuana (indoors) Growing Hemp (outdoors)

Cannabis species are Diecious (have male and female plants)

They can be bred to produce different products:

Marijuana • Cannabis: annual flowering

herb • Trichomes or glandular

hairs grow mainly on the flowers of the female plants; harvested as buds; some people think of this as the “marijuana plant”

• very high in THC

Hemp • Cannabis: tall stalks , seeds

some of the leaves • Grown industrially for rope

and fabric and other uses; • Harvested before the plant

flowers • Legally defined as very low

in THC (0-0.3%) • Can be high in CBD

Cannabis Trichomes

Leaves with Trichomes Trichomes Magnified

Recreational Use―Street Terms

• Kief: Powdered preparation the trichomes (“buds”)from the flower; THC as high as 66%!

• Hashish: solid resinous preparation of the trichomes (“buds”)from the flower; high in THC

• Hash oil (“honey oil, dab, wax, budder”) further refined solvent extract; THC as high as 81% !!

• Dabbing = heating/vaporizing small amount (dab) of hash oil and inhaling

Recreational Use―How it looks

Kief (in a grinder) “Honey oil, “dab”…

Medical Marijuana Cannabis sativa (and Cannabis indica)

Recreational vs. Medical Marijuana Both use the Cannabis plant

Recreational # Current Users: (22 million?) Purpose: Mood altering state Product: High THC species Onset: Often early in life Cognitive Function: Impaired often Effect on Opiate Use: 25% reduction lethal overdose where legal

Medical 2.1 million registered [2017] Therapeutic Symptom Relief Lower THC /more CBD Often later- due to illness Improved- if symptom relief Report significant decreased opiate use when combined

Medical Use of Marijuana (Cannabis) A very short synopsis of over a very long time

2737 BC ― Chinese Emperor Shen-nung disappointed with the shortcomings of shamanism prescribed marijuana tea for gout, rheumatism, malaria , poor memory and more….

………….Approx. 4,600 years later: 1854—Listed in the U.S. Dispensary for legitimate medical use for

various ailments 1937 ― Cannabis tax act essentially criminalized it in the U.S. against

the advice of the American Medical Association submitted on record to Congress

1996―California legalized medical marijuana 2013―Massachusetts -- Approved Nov. 2012 by 63% of voters 2018―Legal in 30 states

Mainstream Physicians on Cannabis for headaches

• 1915—Sir William Osler, MD—The Principles and Practice of Medicine:

For migraine: “Cannabis indica is probably the most satisfactory remedy…” • 1942—Morris Fishbein, MD—Editor of JAMA Despite removal from pharmacopeia: Oral preparations of cannabis superior to ergotamine tartrate for menstrual migraine

Scheduled Drugs, Substances, or Chemicals

Schedule I --No currently accepted medical use and a high potential for abuse.

Examples: heroin, lysergic acid diethylamide (LSD), marijuana (cannabis), 3,4-methylenedioxymethamphetamine (ecstasy), methaqualone, and peyote

Schedule II --a high potential for abuse, with use potentially leading to severe psychological or physical dependence. These drugs are also considered dangerous.

Examples: hydrocodone (Vicodin), cocaine, methamphetamine, methadone, hydromorphone (Dilaudid), meperidine (Demerol), oxycodone (OxyContin), fentanyl, Dexedrine, Adderall, and Ritalin

Schedule III --moderate to low potential for physical and psychological dependence; abuse potential is less than Schedule I and Schedule II

Examples: Products containing less than 90 milligrams of codeine per dosage unit (Tylenol with codeine), ketamine, anabolic steroids, testosterone

Schedule IV : low potential for abuse and low risk of dependence. Examples: Xanax, Soma, Darvon, Darvocet, Valium, Ativan, Talwin, Ambien, Tramadol

Schedule 1 Status amended August 2016

• DEA says “no change” • “Entities” may apply for registration

to grow their own for research • No longer have to apply to get study

materials from the National Institutes of Drug Abuse (NIDA)

Cannabis Pharmacology 1.0

The Two “big” Cannabinoids

1. THC― Tetrahydrocanabinol 2. CBD― Cannabidiol

Cannabis Pharmacology 2.0

Endogenous Systems Opened the door to accelerated research (1990’s)

1. Cannabinoid receptors identified: • CB1 (CNS, peripheral nerves …many other places) • CB2 (Mostly in the immune system… other places too) Note : Almost no CB1 or CB2 receptors in brainstem (May explain why it rarely causes life-threatening autonomic

dysfunction) 2. Endogenous agonists identified: Endocannabinoids

Endocannabinoid System Demonstrated in Humans─ 1992

Pharmaceutical Cannabinoids

• dronabinol (Marinol®)—1985-synthetic THC

• nabilone (Cesanet®) —1985- synthetic analog of THC

• nabiximols (Sativex®) —2005- mouth spray

“Tincture of cannabis” that is standardized to 1:1 THC + CBD and has other cannabinoids— not yet available in USA • [Epidiolex® --(liquid, plant derived pure CBD for drug-

resistant pediatric epilepsy—compassionate use)]

Newer Pharmaceutical Cannabinoids

Does nabiximols (Sativex®) = Medical Marijuana?

Epidiolex® : Pure Cannabidiol (CBD) Oil for Infantile seizures

But…Pharmaceutical Cannabinoids

Are very different from Cannabis- the plant

• May not work as well as the whole plant

• Many patients report a very noticeable

difference • Why?

The Cannabis Plant Contains Hundreds of Other Compounds:

• 60+ different Cannabinoids • Terpenoids • Amino acids • Proteins • Sugars • Enzymes • Fatty acids • Esters • Flavonoids

Cannabis Pharmacology 3.0

The “Big Six” Cannabinoids

1. THC― Tetrahydrocanabinol 2. CBD― Cannabidiol

• CBG― Cannabigerol • CBN― Cannabinol • CBC― Cannabichromene • THCV―Tetrahydrocannabivarin

“Big 6” Cannabinoids (cont.)

• CBG: anti-inflammatory effects; inhibits GABA uptake; possibly enhances neurogenesis

• CBC: anti-inflammatory effects; enhances adult neural stem progenitor cell which may enhance neuroplasticity and neurogenesis

• THCV: inhibits some of the negative cognitive and physiologic effects of THC; neuroprotective

―Gruber et al. Frontiers in Pharm. 2016 (McLean, Harvard, Tufts)

Other Cannabis components: Terpenoids

• Known for Fragrance of different strains • Anti-inflammatory • Anxiolytic • Antioxidant • Anti-neoplastic • Antibacterial • Anti-malarial

Pharmaceutical vs. Herbal remedies

Are Herbal Preparations

simply “Messy” Drugs?

Pharmaceutical vs. Herbal remedies

Pharmaceuticals • Usually have 1 or 2 chemical compounds:

isolated, identified, measured • Impurities or less active ingredients removed Herbal extracts • Contain numerous chemical compounds • Not all identified, isolated, measured

The “Silver bullet”

• “The presence of several psychoactive compounds in one plant may have a ‘synergistic’ effect… Attempts to isolate the active principles from plant extracts may be ultimately self-defeating.”

• “The ‘silver bullet’ concept adopted by orthodox Western medicine for the drug discovery over the past 100 years, is now increasingly viewed as inadequate in many clinical situations…”

From: Sarris J et. al. Herbal medicine for depression, anxiety and insomnia: a review of

psychopharmacology and clinical evidence. Eur Neuropsychopharmacol. 2011;21:841-860

The “Entourage Effect” The synergistic interaction of numerous chemical constituents

1. THC considered the “Psychoactive ingredient” 2. CBD (cannabidiol) modifies the effects of THC

• May block anxiety caused by THC • High CBD = less psychotic experiences • Noted to have similarity to some anti-psychotic drugs • CBD/THC ratio—8:1 almost eliminates psychoactivity • Anti-seizure • Anti-inflammatory properties

High Quality Studies of Cannabis/ Systematic Reviews

• Often combine data from use of synthetic THC (dronabinol, nabilone) and /or THC+ CBD

oral spray (nabiximols). • Fewer studies use whole cannabis Suggested references:

Whiting PF et.al. Cannabinoids for medical use. A systematic review and meta-analysis. JAMA 2015;313(24):2456-2473

Hill KP. Medical marijuana for treatment of chronic pain and other medical and psychiatric problems. JAMA 2015;313(24):2474-2483

From Anecdotes, Case series, clinical and pre-clinical Studies: Observed Clinical Effects of Cannabis sativa

• Appetite stimulant • Anti-emetic • Analgesic • Anxiolytic • Antispasmodic • Anti-inflammatory

Cannabis cultivation: Beware of

rearranging the entourage

Rising Average THC content 1972: 1 -2 % 1990’s: 3 - 4% 2014: > 14% More potent strains are constantly being bred Mahmoud A. Biol Psychiatry, 2016 : 79, (7) 613-619

Cannabis Ingestion: Routes of Administration

• Inhalation—Smoked; Vaporized • Oral (ingested) • Oral (mucosal /sublingual) • Topical • Rectal

Vaporization —safer than smoking

• Heats the cannabis to a temperature where

active cannabinoid vapors form • Below the point of combustion (~ 450° F) • Produces fine mist, similar to steam • No carbon monoxide or noxious/toxic by-

products of smoke generated

Cannabis Vaporization Volcano Vaporizer by Storz and Bickel America, Inc.

Portable Vaporizers

One of Many Brands On-line

Vape with Travel kit

Cannabis Metabolism-Inhaled

Vaporized / Smoked

• Peak serum concentration: within 8 minutes “Wait a few minutes between puffs”

• Maximal “impairment” in about 20-40 minutes

• “Performance impaired” for a period of 4 hours (2.5 hours in 1 source)

Cannabis Metabolism—Oral

Edibles / Oral Pharmaceuticals

• Unpredictable absorption when eaten • Effects in 45-180 minutes • Peak concentration 2- 4 hours [75 minutes to 7 hours]

Wait 30-60 minutes between “doses” (bites)

• Sublingual / Mucosal: Effects felt in minutes; Peak concentration_____.

• Many look like familiar candies

Cannabis Edibles: Beware

From: MacCoun RJ N Engl J Med. March 12, 2015

Current Common Prescribed Indications

• Nausea and Vomiting (chemotherapy related) • Chronic Neuropathic Pain • Anorexia / Cachexia (esp. HIV/AIDS) • Spasticity (MS; Paraplegia) • Multiple Sclerosis--Bladder s/s; spasticity, pain, more… • Amyotrophic lateral sclerosis (ALS)—many symptoms • Insomnia—from any chronic condition) • Seizures– especially pediatric (CBD formulations)

Qualifying Conditions for Medical Marijuana in

Massachusetts The Debilitating Medical Conditions include (but are not limited to):

• Cancer • Glaucoma • AIDS or HIV positive • Hepatitis C • Amyotrophic lateral sclerosis (ALS) • Crohn’s disease • Parkinson’s disease • Multiple sclerosis (MS) •Other Debilitating Conditions determined by our doctors (not listed) Need to have the following symptoms... which are progressing to such an extent that one or more

major life activities is substantially limited:

• Intractable pain • Weakness • Cachexia • Nausea • Impaired strength or ability

Approved Debilitating Conditions

for Medical Marijuana Use in Colorado

Cancer Glaucoma AIDS or HIV positive OR … patient has a chronic or debilitating disease or medical condition

that produces one or more of the following...... • Cachexia • Persistent muscle spasms • Seizures • Severe nausea • Severe pain

Denied Debilitating Conditions: Asthma, Atherosclerosis, Bipolar Disease, Crohn’s Disease, Diabetes Mellitus-- types 1 & 2, Diabetic Retinopathy, Hepatitis C, Hypertension, Methicillin-Resistant Staphylococcus Aureus (MRSA), Opioid Dependence, Post Traumatic Stress Disorder (PTSD), Severe Anxiety, Clinical Depression, Tourette’s Syndrome

Some of the Problems or Concerns cited

regarding the

Medicalization of “herbal” Marijuana

Disorders / Side-effects

• Side-effects in some elderly—vertigo, xerostomia, hypotension, dysphoria; other side-effects if smoking; tachycardia

• Cannabis use disorder and other developmental problems—especially in adolescents

• Neurocognitive changes after long-term use in adults? —mixed evidence

Cannabinoid Hyperemesis Syndrome

• h/o regular long-term cannabis use—weekly • Cyclic nausea and vomiting; abdominal pain • Compulsive hot baths/showers—with

symptom relief • Resolution after stopping cannabis

Shusen S Cannabinoid Hyperemesis Syndrome. Hosp Pharm. 2013; 48(8): 650–655 [Possible 2018 ICD-10-CM Diagnosis Code: F12.188 --Cannabis hyperemesis syndrome co-occurrent and due to cannabis abuse]

Cannabis Addiction

Lifetime Risk of Dependence Marijuana ― 9% Alcohol ― 15% Cocaine ― 17% Heroin ― 23% Nicotine ― 32%

Cannabis Withdrawal [DSM-5 and ICD-10]

% Frequent users, on cessation, who report:

• Fatigue 31 % • Yawning 27 % • Hypersomnia 26 % • Psychomotor retardation 25 % • Anxiety 19 % • Depression 16 %

Research Science and Clinical Issues

• Rigorous comparative effectiveness trials lacking

• Composition, purity, concentration of whole plant active constituents (“entourage”) varies and needs to be studied)

• No clear optimal dose for various conditions/indications

• Unconventional patient-directed dosing

Pain Management Issue

May aggravate Opioid Usage and Overdose Crisis

Medical Cannabis and Opioid Use for Patients with Chronic Pain

• 64% decrease in opioid use –less effective if centralization of pain (Fibromyalgia-type)

Boehnke (2016)—retrospective survey—244 med cannabis pts with chronic pain

• Non-cancer pain (back, neck) on prescribed opioids. Self-prescribed cannabis– significant subpopulations greater pain relief with cannabis added

Degenhardt (2015)—Australia-1514 people—Interview/data collection

Opioid Overdose and Cannabis Legalization 1999-2010

• 13 states in U.S with medical cannabis laws • 24.8% reduction in mean annual opioid

overdose mortality compared with states lacking medical cannabis laws

• Mortality reduction effect strengthened over time

Bachuber MA. Medical cannabis laws and opioid analgesic mortality in the United States,1999-2010. JAMA Intern Med 2014;174(10):1668-1673

Advising a Patient--Discussion

• Explore medical indication / Goal of therapy • Monitoring / Assessing benefit (or harm) • Modes of Ingestion • Dosing: THC / CBD ratio • Other constituents (Entourage Effect) • Cautions; Unknowns • Discuss, Recommend—Do Not “Prescribe”

One Summary Article

Savage SR et.al. Cannabis in pain treatment: clinical and research considerations. J Pain. 2016;17(6):654-68

“This paper is a consensus document with input from clinical experts and researchers on pain who hold diverse opinions related to the appropriate roles of cannabis in medicine and society”

Integrative Medicine: Supplements and Herbal Therapies including Medical Marijuana

Key points 1. Use Natural Medicines Database for supplement information and evidence. 2. Use ConsumerLab.com to assess quality of supplement brands 3. Useful Supplements for several common conditions • Hyperlipidemia: Red Yeast Rice, Stanols/sterols • Hypertension: Magnesium, Potassium, Tomato ext./lycopene, Mind-Body • URI’s/ Influenza: Black Elderberry • Depression / Burnout: Rhodiola rosea; Ashwagandha; SAMe, • Anxiety/Insomnia: L-theanine, Chamomile extract For Cannabis: Nausea/vomiting, intractable pain, anorexia, cachexia, spasticity Next Best Steps Advising a patient on using supplements or medical cannabis: • Explore medical indication / Goal(s) of therapy • Mode of Ingestion; Dosage • How will we monitor / Assess benefit or harm? • Discuss, Recommend—Do Not “Prescribe”

Thank You for Listening! Questions are Welcome

Appendix

• Additional references • Further reading • Additional therapies

Mindfulness, Tai Chi, Yoga: References

Luberto CM, A Systematic Review and Meta-analysis of the Effects of Meditation on Empathy, Compassion, and Prosocial Behaviors. Mindfulness (N Y). 2018;9(3):708-724 Basso JC, Brief, daily meditation enhances attention, memory, mood, and emotional regulation in non-experienced meditators. Behav Brain Res. 2018. PMID: 30153464. Esch T. et. al. Mind/body techniques for physiological and psychological stress reduction: stress management via Tai Chi training - a pilot study. Med Sci Monit. 2007;13(11):CR488-497 Blom et al. Hypertension analysis of stress reduction using mindfulness meditation and yoga: results from the harmony

randomized controlled trial. Am J Hypertens. 2014;27(1):122-9. de fatima Rosas Marchiori. Decrease in blood pressure and improved psychological aspects through meditation training in

hypertensive older adults: a randomized control study. Geriatr Gerontol Int. 2014 Cramer H, et. al. A systematic review and meta-analysis of yoga for hypertension. Am J Hypertens. 2014; 27(9):1146-51. Cernes R. RESPeRATE: the role of paced breathing in hypertension treatment. J Am Soc Hypertens. 2014 Bisognano et. al. Beyond Medications and Diet: Alternative Approaches to Lowering Blood Pressure. Scientific Statement From

the American Heart Association Hypertension. 2013;1360-83 Wayne, Peter. Harvard Medical School Guide to Tai Chi. 2013; Shambala Publications Wang J et. al. Tai chi for essential hypertension. Evid Based Complement Alternat Med. 2013:215254 Wang F. et. al. The effects of tai chi on depression, anxiety, and psychological well-being: a systematic review and meta-

analysis.Int J Behav Med. 2013

Acupuncture for Hypertension

Some people respond―especially as an adjunctive therapy; worth a defined therapeutic trial

References: Zhao X-F. Is acupuncture effective for hypertension? A systematic review and meta-analysis. Plos One 2015 Longhurst J. Acupuncture's cardiovascular actions: A mechanistic perspective. Med Acupunct. 2013

;25(2):101-113. Review. Li DZ… . Acupuncture for essential hypertension: a meta-analysis of randomized sham-controlled clinical

trials. Evid Based Complement Alternat Med. 2014:279478. Longhurst JC, Acupuncture regulation of blood pressure: two decades of research. Int Rev Neurobiol.

2013;111:257-71 Yin C et. al. Acupuncture, a promising adjunctive therapy for essential hypertension: a double-blind,

randomized, controlled trial. Neurol Res. 2007;29 Suppl 1:S98-103 Wang J. Acupuncture for essential hypertension. Int J Cardiol. 2013;169(5):317-26

“More rigorous trials are warranted……….."

5-HTP (5-Hydroxytryptophan)

• Anxiolytic • Gentle sleep aide • Does not produce tolerance. • Usual dose range 100 mg –300 mg daily • No major side effects [Serotonin Syndrome]* 1. 1989--contaminated L-Tryptophan from single manufacturer (in Japan) caused eosinophilia-

myalgia syndrome in some; now available safely as 5-HTP * 2. Serotonin syndrome if also on high doses of serotonergic drugs

5-HTP (5-Hydroxytryptophan) Also some literature* to support: • Headache prevention • Fibromyalgia • Reduce Carbohydrate craving *Good recent literature hard to find • Bruni O, et.al. L -5-Hydroxytryptophan treatment of sleep terrors in children. Eur J Pediatr. 2004;163(7):402-7. • Schruers K. et. al. L-5-hydroxytryptophan administration inhibits carbon dioxide -induced panic in panic disorder patients. Psychiatry Res 2002;113:237-43 • Kahn RS et al. Effect of a serotonin precursor and uptake inhibitor in anxiety disorders; a double-blind comparison of 5-hydroxytryptophan, clomipramine and placebo. Int Clin Psychopharmacol 1987;2:33-45 • Wurtman RJ and Wurtman JJ. Brain serotonin, carbohydrate-craving, obesity and depression. Adv Exp Med Biol. 1996; 338:35-41

5-HTP (5-Hydroxytryptophan) for Anxiety

(from Griffonia simplicifolia seed Extract)

Acupuncture for Anxiety

Some people respond―especially as an adjunctive therapy: worth a defined therapeutic trial

Literature is heterogeneous--variable treatment points, number, duration and frequency of sessions, outcome measures… inconclusive but remarkably promising...

“…..More rigorous trials are warranted”……….."

References: • Errington-Evans N. Acupuncture for anxiety. CNS Neurosci Ther. 2012;18(4):277-84. Review • Pilkington K et. al. Acupuncture for anxiety and anxiety disorders--a systematic literature

review. Acupunt Med 2007;25(1-2): 1-10

Cannabis: Additional Selected References

• Nugent SM. Effects of cannabis among adults with chronic pain and an overview of general harms: a systematic review . Annals of Int Med; 2017

• Wilsey B et al. An exploratory human laboratory experiment evaluating vaporised cannabis in the treatment of neuropathic pain from spinal cord injury and disease. J Pain. Sep 2016 ;17(9):982-1000.

• Whiting PF et.al. Cannabinoids for medical use. A systematic review and meta-analysis. JAMA 2015;313(24):2456-2473

• Hill KP. Medical marijuana for treatment of chronic pain and other medical and psychiatric problems. JAMA 2015;313(24):2474-2483

• Bella JG Recreational cannabis use: pleasures and pitfalls. Cleve Clin J of Med. 2015;82(11):765-772

• Ulugol A. The endocannabinoid system as a potential target for pain modulation. Balkan Med J. 2014;31(2):115-20

• Lisdahl KM. Considering cannabis: the effects of regular cannabis use on neurocognition in adolescents and young adults. Curr Addict Rep. 2014;1:144-156

Cannabis Metabolism

• Cytochrome P 450 system: CYP2C9 and CYP3A4 • Urine metabolite testing—RIA; (confirmatory test: gas

chromatogaraphy + mass spectrometry)

• CBD/THC ratio—8:1 almost eliminates psychoactivity

Macdonald S . Testing for cannabis in the work-place: a review of the evidence. Addiction. 2010; 105(3):408-16 Meier U, Cannabinoid concentrations in blood and urine after smoking cannabidiol joints. Forensic Sci Int. 2018;291:62-67. Schlienz NJ, Pharmacokinetic Characterization of 11-nor-9-carboxy-Δ9-tetrahydrocannabinol in Urine Following Acute Oral Cannabis Ingestion in Healthy Adults. J Anal Toxicol. 2018;;42(4):232-247

Current Research: Cognitive Neuroscience

• 50 chronic MJ smokers • Early onset, late onset; healthy controls • Modified Stroop Color word test + fMRI Sagar KA, Dahlgren MK, Gonenc A, Racine MT, Dreman MW, Gruber SA. The impact of initiation: Early onset marijuana smokers demonstrate altered Stroop performance and brain activation Developmental Cognitive Neuroscience. 2015;16:84-92

Stroop: A Test of Directed Attention (A mental resource used to manage our thoughts by inhibiting one

response in order to say or do something else)