Medical Marijuana… Fact Versus Fiction

MEDICAL MARIJUANA…

FACT VERSUS FICTION

Thomas F. Jan, DO, FAOCPMR Subspecialty Certified– Pain Medicine Diplomate – American Board of Addiction Medicine

MASSAPEQUA PAIN MANAGEMENT AND REHABILITATION ADMINISTRATIVE DIRECTOR-CHRONIC PAIN MANAGEMENT

4200 SUNRISE HIGHWAY MATHER HOSPITAL-NORTHWELL HEALTH

MASSAPEQUA, NY 11758 PORT JEFFERSON, NY

516-541-1064 THE I LOVE ME SLIDE: THOMAS F. JAN, DO, FAOCPMR, FKIA

• 20 years private practice, board certified in pain medicine and addiction medicine • Current Chair, American Osteopathic Pain Medicine Conjoint Exam Committee • Administrative Director for Chronic Pain Management, John T. Mather Hospital, Port Jefferson, NY • Core faculty, PM&R residency program, Mercy Medical Center, Catholic Health System • Leadership Council, Long Island Council on Alcoholism and Drug Dependence (LICADD) • Medical Director, LICADD Opioid Overdose Prevention Program • Member, Nassau County, NY, County Executive's task force on Heroin and Prescription drug abuse • Former Medical Director, Town of Babylon Drug and Alcohol Program

Disclosures: Speaker Bureau, US WorldMeds, Lucemyra OBJECTIVES

A brief history of marijuana and its medical uses throughout history How does one get certified to prescribe medical marijuana Discussion about the endocannabinoid system (ECS) What receptors are there and what are they purported to do How do the various options affect the body through the ECS What are the risks involved and some discussion about the science MEDICAL MARIJUANA FOR OPIATE ADDICTION

“I prescribed the cannabis simply with a view to utilizing a well-known remedy for insomnia, but it did much more than procure sleep. I think it will be found that there need be no fear of peremptorily withdrawing the deleterious drug, if hemp is employed.”

Edward Birch, MD, 1889, The Lancet

2018-STATE MARIJUANA LAWS

http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx 2018-STATE MARIJUANA LAWS

http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx 2018 STATE MARIJUANA LAWS

http://www.governing.com/gov-data/safety-justice/state-marijuana-laws-map-medical-recreational.html 2018 STATE MARIJUANA LAWS

• Thirty states and the District of Columbia currently have laws broadly legalizing marijuana in some form.

• Eight states and the District of Columbia have adopted the most expansive laws legalizing marijuana for recreational use.

• Most recently, sales of recreational-use marijuana in California kicked off on Jan. 1 of this year

• In Massachusetts, retail sales of cannabis were legalized as of July 1st • The Cannabis Control Commission, the new state agency tasked with overseeing the burgeoning industry, has started issue the licenses needed for retail pot shops to open in Massachusetts • On July 9th, US Attorney Andrew Lelling, the top federal prosecutor in Massachusetts, stated that the three areas for potential marijuana prosecutions will include "overproduction," "targeted sales to minors," and "organized crime and interstate transportation of drug proceeds."

• Maine legalized recreational marijuana January 30th of this year http://www.governing.com/gov-data/safety-justice/state-marijuana-laws-map-medical-recreational.html 2018 STATE MARIJUANA LAWS (CONT’D)

• The vast majority of states allow for limited use of medical marijuana under certain circumstances • Some medical marijuana laws are broader than others, with types of medical conditions that allow for treatment varying from state to state • Louisiana, West Virginia and a few other states allow only for cannabis-infused products, such as oils or pills • Louisiana is considered to have legalized marijuana butit cannot be used in a form that can be smoked -- only oils, topical applications and other types. • Other states have passed narrow laws allowing residents to possess cannabis only if they suffer from select rare medical illnesses. • A number of states have also decriminalized the possession of small amounts of marijuana. http://www.governing.com/gov-data/safety-justice/state-marijuana-laws-map-medical-recreational.html 2018 STATE MARIJUANA LAWS (CONT’D)

Federal law, however, prohibits doctors from prescribing marijuana!!!

http://www.governing.com/gov-data/safety-justice/state-marijuana-laws-map-medical-recreational.html THE NEW YORK STATE MEDICAL MARIJUANA PROGRAM

On July 7, 2014, Governor Cuomo signed a medical marijuana bill into law. WHAT IS IT ALL ABOUT?

Requirements to become a registered medical marijuana physician: Be licensed physician and practicing in New York State The NYS Health Commissioner has the option of including nurse practitioners based on patient need and access Be qualified to treat the serious condition for which medical marijuana is being recommended Have completed a 2-4 hour training course approved by the NYS Department of Health Have registered with the NYS DOH as a recommending physician.

The NYS MMP overview; Compassionate Care New York | 347.781.5435 voice | [email protected] | www.compassionatecareny.org WHAT IS IT ALL ABOUT?

How does the physician recommendation work? Rather than write a prescription, the physician will issue a recommendation or certification that an eligible patient can obtain and use medical marijuana. A certification is good for one year (or less if the physician specifies a shorter time frame) or, if the person is deemed to be terminally ill, until their death. Once a patient has obtained a physician certification, s/he applies to the DOH for a patient registry card, which allows him or her to legally purchase and use medical marijuana obtained from a state-licensed dispensary.

The NYS MMP overview; Compassionate Care New York | 347.781.5435 voice | [email protected] | www.compassionatecareny.org WHAT IS IT ALL ABOUT?

Qualifying conditions:

Cancer Epilepsy HIV infection or AIDS Inflammatory bowel disease Amyotrophic lateral sclerosis (ALS) Neuropathy Parkinson's disease Huntington's disease Multiple sclerosis Post-traumatic stress disorder Spinal cord injury with spasticity Chronic pain

The NYS MMP overview; Compassionate Care New York | 347.781.5435 voice | [email protected] | www.compassionatecareny.org WHAT IS IT ALL ABOUT?

Must have one of the following clinically associated conditions, symptoms or complications: Cachexia or wasting syndrome severe or chronic pain resulting in substantial limitation of function severe nausea seizures severe or persistent muscle spasms such other conditions, symptoms or complications as added by the commissioner

Title 10, Department of Health 10 NYCRR §1004.2(a)(9)(i-vi) WHAT IS IT ALL ABOUT?

Chronic pain as defined by NYS:

Any severe debilitating pain that the practitioner determines degrades health and functional capability where the patient has contraindications, has experienced intolerable side effects, or has experienced failure of one or more previously tried therapeutic options and where there is documented medical evidence of such pain having lasted three months or more beyond onset, or the practitioner reasonably anticipates such pain to last three months or more beyond onset

Title 10, Department of Health 10 NYCRR §1004.2(a)(8)(xi) THE HISTORY 2900 BC - CHINESE EMPEROR FU HSI REFERENCES MARIJUANA AS A POPULAR MEDICINE

"The Chinese Emperor Fu Hsi (ca. 2900 BC), whom the Chinese credit with bringing civilization to China, seems to have made reference to Ma, the Chinese word for Cannabis, noting that Cannabis was very popular medicine that possessed both yin and yang."

Robert Deitch Hemp: American History Revisited: The Plant with a Divided History, 2003

Source: https://medicalmarijuana.procon.org/view.timeline.php?timelineID=000026 1450 BC - BOOK OF EXODUS REFERENCES HOLY ANOINTING OIL MADE FROM CANNABIS "Holy anointing oil, as described in the original Hebrew version of the recipe in Exodus (30:22-23), contained over six pounds of kaneh-bosem, a substance identified by respected etymologists, linguists, anthropologists, botanists and other researchers as cannabis, extracted into about six quarts of olive oil, along with a variety of other fragrant herbs. The ancient anointed ones were literally drenched in this potent mixture.“

Chris Bennett "Was Jesus a Stoner?," High Times Magazine, Feb. 10, 2003 "Marijuana proponents suggest that the recipe for the anointing oil passed from God to Moses included cannabis, or kaneh-bosm in Hebrew. They point to versions calling for fragrant cane, which they say was mistakenly changed to the plant calamus in the King James version of the Bible."

Shannon Kari "Cannabis Involved in Christ's Anointment?," National Post, Apr. 22, 2010

Source: https://medicalmarijuana.procon.org/view.timeline.php?timelineID=000026 1213 BC - EGYPTIANS USE CANNABIS FOR GLAUCOMA, INFLAMMATION, AND ENEMAS

Cannabis pollen is found on the mummy of Ramesses II, who died in 1213 BC. Prescriptions for cannabis in Ancient Egypt include treatment for the eyes (glaucoma), inflammation, and cooling the uterus, as well as administering enemas.

Lise Manniche, PhD An Ancient Egyptian Herbal, 1989

Source: https://medicalmarijuana.procon.org/view.timeline.php?timelineID=000026 1000 BC - BHANG, A DRINK OF CANNABIS AND MILK, IS USED IN INDIA AS AN ANESTHETIC

Bhang, a cannabis drink generally mixed with milk, is used as an anesthetic and anti-phlegmatic in India. Cannabis begins to be used in India to treat a wide variety of human maladies.

US National Commission on Marihuana and Drug Abuse

"Marihuana, A Signal of Misunderstanding," druglibrary.org, 1972

Source: https://medicalmarijuana.procon.org/view.timeline.php?timelineID=000026 700 BC - MEDICAL USE OF MARIJUANA IN THE MIDDLE EAST RECORDED IN THE VENIDAD

The Venidad, one of the volumes of the Zend-Avesta, the ancient Persian religious text written around the seventh century BC purportedly by Zoroaster (or Zarathustra), the founder of Zoroastrianism, and heavily influenced by the Vedas, mentions bhang and lists cannabis as the most important of 10,000 medicinal plants."

Martin Booth Cannabis: A History, 2005

Source: https://medicalmarijuana.procon.org/view.timeline.php?timelineID=000026 1621 - POPULAR ENGLISH MENTAL HEALTH BOOK RECOMMENDS CANNABIS TO TREAT DEPRESSION

English Clergyman and Oxford scholar Robert Burton suggests cannabis as a treatment for depression in his influential and still popular 1621 book The Anatomy of Melancholy.

Lester Grinspoon, MD

"History of Cannabis as a Medicine,“

Statement for hearing by DEA Law Judge, Aug.16, 2005

Source: https://medicalmarijuana.procon.org/view.timeline.php?timelineID=000026 1850 - MARIJUANA ADDED TO US PHARMACOPEIA

"By 1850, marijuana had made its way into the United States Pharmacopeia [an official public standards-setting authority for all prescription and over-the counter medicines], which listed marijuana as treatment for numerous afflictions, including: neuralgia, tetanus, typhus, cholera, rabies, dysentery, alcoholism, opiate addiction, anthrax, leprosy, incontinence, gout, convulsive disorders, tonsillitis, insanity, excessive menstrual bleeding, and uterine bleeding, among others. Patented marijuana tinctures were sold..." Cover of the 1851 United States Pharmacopeia Richard Glen Boire, JD and Kevin Feeney, JD Medical Marijuana Law, 2007

Source: https://medicalmarijuana.procon.org/view.timeline.php?timelineID=000026 1906 - PURE FOOD AND DRUGS ACT REQUIRES LABELING OF MEDICINE, INCLUDING CANNABIS

"An Act for preventing the manufacture, sale, or transportation of adulterated or misbranded or poisonous or deleterious foods, drugs, medicines, and liquors, and for regulating traffic therein, and for other purposes... That for the purposes of this Act an article shall also be deemed to be misbranded... if the package fail to bear a statement on the label of the quantity or proportion of any alcohol, morphine, opium, cocaine, heroin, alpha or beta eucaine, chloroform, cannabis indica, chloral hydrate, or acetanilide, or any derivative or preparation of any such substances contained therein.“ Pure Food and Drug Act (1906) National Center for Biotechnology Information website, June 30, 1906

Source: https://medicalmarijuana.procon.org/view.timeline.php?timelineID=000026

OCT. 1937 - "MARIHUANA (SIC) TAX ACT" LEADS TO DECLINE IN MARIJUANA PRESCRIPTIONS

"By the time the federal government passed the Marihuana Tax Act in [Oct.] 1937, every state had already enacted laws criminalizing the possession and sale of marijuana. The federal law, which was structured in a fashion similar to the 1914 Harrison Act, maintained the right to use marijuana for medicinal purposes but required physicians and pharmacists who prescribed or dispensed marijuana to register with federal authorities and pay an annual tax or license fee...

After the passage of the Act, prescriptions of marijuana declined because doctors generally decided it was easier not to prescribe marijuana than to deal with the extra work imposed by the new law."

Rosalie Liccardo Pacula, PhD "State Medical Marijuana Laws: Understanding the Laws and Their Limitations," Journal of Public Health Policy, 2002

Source: https://medicalmarijuana.procon.org/view.timeline.php?timelineID=000026 LET US NOT FORGET, WE ONCE THOUGHT OF MERCURY AS A “POWERFUL” MEDICINE

Mercury had long been used as a medicine to treat various diseases, such as syphilis and typhoid fever, or parasites. Certainly a treatment with such a "powerful" medicine impressed patients, and when poisoning symptoms appeared they could always be blamed on worsening of the original disease. LEGALITY

Cannabis is currently not FDA approved for any condition Cannabis is currently DEA Schedule 1 (Federal) As of 2018 Nine states and the District of Columbia allow recreational sales of marijuana as well as medical An additional 21 only allow medical use Others allow only for the sale of CBD, an extract which is non- psychoactive

https://www.cnn.com/2018/01/04/politics/marijuana-legalization-by-the-numbers/index.html THE HYPE

So, is it safe??? The following section is intended to illustrate the dangers of not following scientific thought. It is not a direct discussion of the benefits or detriments of cannabinoid prescribing/use. IS IT SAFE???

• One argument is that it a naturally occurring substance. • Some research shows increased efficacy with the “entourage effect by ingesting the whole plant. • Before deciding, remember that all of the following are naturally occurring… IS IT SAFE???

Wolfbane A highly poisonous flowering plant closely related to buttercups, the toxins can easily soak through the skin. Wolfsbane kills quickly, within six hours of consumption. IS IT SAFE???

Rhododendron Most the rhododendron plant contains the toxins andromedotoxin, grayanotoxin and rhodotoxin. Accidental consumption can cause weakness, difficulty in breathing, loss of balance and salivation in humans. IS IT SAFE???

Cat poop Do I really need to explain this??? IS IT SAFE???

The point here is that because it is naturally occurring is irrelevant to its potential benefit. Good objective science should be the only driving point in the debate IS IT EFFECTIVE???

Laetrile  Laetrile is another name for the natural product amygdalin, which is a chemical constituent found in the pits of many fruits and in numerous plants.  Laetrile has shown little anticancer activity in animal studies and no anticancer activity in human clinical trials. • Laetrile is not approved for use in the United States. • Inappropriate advertisement of laetrile as a cancer treatment has resulted in a U.S. Food and Drug Administration investigation that culminated in charges and conviction of one distributor.

National Cancer Institute (NIH): https://www.cancer.gov/about-cancer/treatment/cam/hp/laetrile-pdq, Updated: March 15, 2017 THE SCIENCE

The Endocannabinoid System (ECS) THE ENDOCANNABINOID SYSTEM

Two primary receptors known as the CB1 and CB2 These are G-Protein coupled receptors with 7 passes through the cell membrane THE ENDOCANNABINOID SYSTEM

CB1: Primarily in CNS and PNS in addition to reproductive, adipose, connective tissues and endocrine structures CB2: Primarily in the immune system but can be created and upregulated in tissues where they are not normally found with trauma/inflammation THE ENDOCANNABINOID SYSTEM

CB1 located in: CB2 located in:  CNS  Monocytes  Testes, uterus  Macrophages  Adipose tissue  B-cells  Connective tissue  T-cells  Endocrine glands  Liver  Exocrine glands  Spleen  Leukocytes  Tonsils  Spleen  CNS  Heart  Enteric nervous system  GI tract  Liver THE ENDOCANNABINOID SYSTEM

 CB receptors can activate different types of G- protein receptors in the cell  G-Protein receptors can open or close ion channels and promote or inhibit adenylate cyclase formation  This is the basis of “Agonist Trafficking”  Analogous to several keys opening the same lock, but different keys will open to a different room  “Entourage Effect” THE ENDOCANNABINOID SYSTEM

THC-phytocannabinoid HU-210 &WIN55, 212-synthetic cannabinoids Anandamide-endogenous cannabinoid OTHER CANNABINOID TARGETS

• GPR55 • TRPV1 “capsaicin receptor” • PPARs: Peroxisome proliferator-activated receptors • Voltage-gated ion channels • Ca2+, Na+, and various types of K+ channels • Ligand-gated ion channels • 5-HT3 and nicotinic ACh receptors ENDOGENOUS CANNABINOIDS

Anandamide (AEA) and 2-arachidonoylglycerol (2-AG): Retrograde messengers in nervous system Ananda means bliss in Sanskrit Autocrine or paracrine mediators elsewhere. Synthesized “on demand” from cell membrane precursors (arachidonic acid derivatives) and immediately released. Degraded by enzymatic hydrolysis AEA -> fatty acid amide hydrolase (FAAH) 2-AG -> monoacylglycerol lipase (MAGL)

J McPartland, DO, JAOA, October 2008, Vol. 108, 586-600 CB1 DISTRIBUTION IN THE CNS

 Most common G protein coupled receptor in the brain.

 Highest densities:  hippocampus  cerebral cortex  cerebellum  amygdaloid nucleus  basal ganglia.

 Accounts for effects:  short-term memory  cognition  mood and emotion  motor function  nociception  Virtually absent in brainstem cardiorespiratory centers - no known lethal overdose FUNCTION & REGULATION OF THE CANNABINOID SYSTEM

 Nervous system:  Nociception  Cannabinoid-opioid interactions  In a hyperstimulated glutaminergic presynaptic terminal, post-synaptic release of 2-AG will cause retrograde suppression of the release of glutamate .This is “Depolarization Induced Suppression of Excitation”  Bone  Connective tissues  Immune system  Neoplasm  Embryology  Digestive system  Hunger and feeding

J McPartland, DO, JAOA, October 2008, Vol. 108, 586-600 Guzmán, 2003; Bifulco et al., 2006; Sarfaraz et al., 2008; Hermanson & Marnett 2011; Velasco et al., 2016 ANTINOCICEPTIVE EFFECTS OF CANNABINOIDS ARE THOUGHT TO AT ALL LEVELS OF THE NEURAL PATHWAY

CNS Periaqueductal grey Ventral posterolateral nucleus of the thalamus Spinal Cord Specifically the dorsal horn. (Cannabinoids are thought to suppress GABA-releasing interneurons that inhibit neurons in the descending pathway.) CANNABINOID OPIOID SAFETY-SYNERGY

 Opioid and cannabinoid receptors are co-distributed in areas of the dorsal horn of the spinal cord and areas controlling nociceptive responses.  Cannabinoid receptors have low density in brainstem cardiorespiratory centers (no respiratory depression)  “Combination increases therapeutic index of opiates”  Opioid receptor proteins are upregulated in the spinal cord of chronic combination-treated animals

 CB1 and μ-opioid receptors are co-localized in areas important for morphine abstinence: nucleus accumbens, septum, striatum, PAG and amygdaloid nucleus  Cannabinoids may alter the expression of morphine antinociceptive tolerance and/or dependence.  Mice treated with low doses of THC and morphine in combination demonstrate avoidance of tolerance to the opioid with retention of the antinociceptive effect

Cichewicz DL, Synergistic interactions between cannabinoid and opioid analgesics, Life Science 2004 Jan 30;74(11):1317-24 ENDOCANNABINOID ACTIVITY AND THE DIGESTIVE SYSTEM CB1 Receptor:  Enteric nervous system  Inhibition of gastric acid secretion  Lower esophageal sphincter relaxation  Altered intestinal motility, visceral pain, and inflammation  Reduced gastric motility and delayed gastric emptying  (This appears to be paradoxical because delayed gastric emptying usually causes nausea. It is believed the anti nausea and anti emetic effects are secondary to a central and autonomic override of the delayed gastric emptying ENDOCANNABINOID ACTIVITY AND THE DIGESTIVE SYSTEM CB2 Receptor: Lamina propria, plasma cells, activated macrophages Myenteric and submucosal plexus ganglia in human ileum Likely involved in the inhibition of inflammation, visceral pain, and intestinal motility in the inflamed gut CANNABINOID DEFICIENCY SYNDROMES???

Dr. Russo, neurology, theorizes that after a review of the literature the following conditions may have an endocannabinoid component. He especially focused on “subjective” pain syndromes that lack objective signs and may be treatment resistant. He theorizes that treatment with specific cannabinoid receptor agonists or substances that inhibit the hydrolytic enzymes that break down the endocannabinoids may have a positive impact on this group of patients.

E. Russo, MD, Cannabis and Cannabinoid Research Volume 1.1, 2016 DOI: 10.1089/can.2016.0009 CANNABINOID DEFICIENCY SYNDROMES???

• Anorexia nervosa • Migraine • Chronic motion sickness • Motion sickness • Fibromyalgia • Multiple sclerosis • Huntington’s disease • Parkinson’s Disease • Irritable bowel syndrome • PTSD • Menstrual symptoms

E. Russo, MD, Cannabis and Cannabinoid Research Volume 1.1, 2016 DOI: 10.1089/can.2016.0009 CANNABINOID RECEPTOR POLYMORPHISMS HAVE BEEN ASSOCIATED WITH: Alcohol Dependence Schizophrenia Subtypes  Body Mass Index Impulsivity Central Obesity ADHD and PTSD Resting state theta wave power on EEG Bone mineral density Protection against major depressive disorder in methadone-maintained outpatients Response to hypocaloric Mediterranean diet Headache with nausea in the presence of life stress CANNABINOID RECEPTOR POLYMORPHISMS HAVE BEEN ASSOCIATED WITH: (references)  L. Schmidt, et al, Unequal Treatment Racial and Ethnic Disparities in Alcoholism Treatment Services NIAAA, 2002  Ujike, et al, CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia Molecular Psychiatry volume 7, pages 515–518 2002

 Pacher, et al, The Endocannabinoid System as an Emerging Target of Pharmacotherapy, Pharmacol Rev. 2006 Sep; 58(3): 389–462  Wiskerke, et al, Chapter 14 – The cannabinoid system and impulsive behavior, Cannabinoids in Neurologic and Mental Disease 2015, Pages 343–364

 Kirkham, et al, Endocannabinoids in the aetiopathology of obesity – Central mechanisms, Drug Discovery Today: Disease Mechanisms Volume 7, Issues 3–4, Winter 2010, Pages e163-e168  Lu, et al, Association of the cannabinoid receptor gene (CNR1) with ADHD and PTSD, Am J of Med Ethics, 2008  Heitland, et al, Genetic variability in the human cannabinoid receptor 1 is associated with resting state EEG theta power in humans, Behavioural Brain Research , Volume 274 – Nov 1, 2014  Woo, et al, Cannabinoid Receptor Gene Polymorphisms…, Menopause, Vol 22 Is 5 pp 512-519, 2015  Icick, et al, A cannabinoid receptor 1 polymorphism is protective against major depressive disorder in methadone‐maintained outpatients, Am J on Addiction, 2015

 de Luis, et al, Effects of Polymorphism rs3123554 in the Cannabinoid Receptor Gene Type 2 (Cnr2) on Body Weight and Insulin Resistance after Weight Loss with a Hypocaloric Mediterranean Diet, J of Metabolic Syn, 2016  Juhasz, et al, Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress, Genes, Brain and Behavior, 2016 EXOGENOUS CANNABINOIDS AND THEIR EFFECTS Δ9-THC MECHANISM OF ACTION ON THE ECS

THC mimics AEA and 2- AG by acting as an partial agonist at CB1 and CB2 Antagonism more likely at CB2 , and in CB1 when ECS is down-regulated It is theorized that an advantage of antagonism in obesity and endocannabinoid synthesis is causing increased appetite through the CB1 receptor in adipocytes THC: LOW AND ACUTE DOSES LEAD TO ECS UPREGULATION

 THC increases the production of endocannabinoids in brain cells.  THC upregulated CB1 receptors in mouse spinal cords.  Acute dose of THC increased cannabinoid receptor affinity in rats.  Sub-therapeutic doses of THC enhance the pain relief imparted by endocannabinoids in rats.  The implication is that endocannabinoids can widen their own therapeutic window by enhancing the ECS and upregulating the receptor production and sensitivity  Clinically, the implication is that keeping the dose at or below a certain threshold can sensitize and enhance the efficacy of the exogenous cannabinoid.  Tolerance to cannabinoids is due to ECS down regulation THC: HIGH AND REPEATED DOSES LEAD TO ECS DOWN REGULATION

 Persistent agonism  Phosphorylation by GRK or PKC  Binding by b-arrestin  Receptor pulled into a clathrin-coated pit  Endosome internalization  The resulting tolerance occurs at different rates and magnitudes in different part of the CNS. For example, in the hippocampus (memory regulation), it occurs faster and greater as opposed to the basal ganglia which regulates the euphoric effect. CBD MECHANISM OF ACTION

• Very low affinity for CB1 and CB2 receptors • Inhibits uptake • Antagonizes other CB1 & CB2 agonists • noradrenaline • dopamine • Non-competitive inverse agonist that modulates the affinity of ECS receptors • serotonin • GABA • Antagonizes • anandamide • GPR55 • alpha-1 adrenergic • Inhibits activity of fatty amide hydrolase (FAAH) • μ-opioid receptors • May act on mitochondria Ca2 stores • Activates • May block low-voltage-activated (T-type) Ca2 channels • 5-HT1A serotonergic • May stimulate activity of the inhibitory glycine-receptor • TRPV1-2 vanilloid receptors SYNTHETIC CANNABINOIDS

• Dronabinol, a synthetic THC, was approved as schedule II drug in 1986 and was moved to schedule III in 1999. • Nabilone, a THC analog, was approved by the FDA in 1985 but not marketed in the US until 2006 • Both are indicated for chemotherapy- induced nausea/vomiting and as an appetite stimulant for AIDS patients SYNTHETIC CANNABINOIDS, SOME WITH ULTRAPOTENCY

• Much higher affinity at the CB1 receptor compared to THC • Tend to have much stronger psychoactive effects and a greater side effect profile compared to herbal cannabinoids • These synthetics are often spray on to herbal products that look like cannabis and are sold over the counter as “K-2” or “Spice” and often result in acute psychiatric emergencies COMMON DRUGS THAT HAVE BEEN SHOWN TO HAVE ECS ACTIVITY

NSAIDs  Ibuprofen and ketorolac block the hydrolysis of AEA  COX2 inhibitors potentiated synaptic 2-AG release and CB1 signaling  some NSAIDs inhibit FAAH Acetaminophen  NAP blocks the breakdown of AEA by FAAH, inhibits COX1 and COX2, and acts as a TRPV1 agonist.  The analgesic activity of acetaminophen in rats is blocked by CB1 or CB2 antagonists MORE COMMON DRUGS THAT HAVE BEEN SHOWN TO HAVE ECS ACTIVITY

Glucocorticoids Preclinical rodent studies indicate that acute glucocorticoid administration enhances the activity of endocannabinoids "Corticosteroid mania" may have a cannabimimetic component. Chronic exposure to glucocorticoids downregulates the ECS, a scenario consistent with chronic stress. CB1 is thought to play pivotal role in anxiolytic action of benzodiazepines MORE COMMON DRUGS THAT HAVE BEEN SHOWN TO HAVE ECS ACTIVITY

Probiotics  Upregulate CB2 in colonic epithelial cells in mice.  Decrease pain behavior following colonic distension with butyrate, reversed by the CB2 antagonist Ethanol dampens the effects of the ECS. "Corticosteroid mania" may have a cannabimimetic component.  Chronic consumption and binge drinking likely desensitize or downregulate CB1 and impair endocannabinoid signaling, except perhaps in areas involved in reward and motivation to self- administer this substance of abuse. HERBAL MEDICINES THAT HAVE ECS ACTIVITY

Curcumin elevates endocannabinoid levels and brain nerve growth factor (NGF) in a brain region-specific fashion Echinacea alkylamides are potent agonists of CB2 (not CB1). This is why echinacea does have psychoactive effects Copal incense contains a pentacyclic triterpene with high affinity for CB1 and CB2 β-caryophyllene (principle terpenoid in black pepper) is a CB2 agonist. Protective effects in colitis and cisplatin-induced nephrotoxicity via CB2 mechanism LIFESTYLE EFFECTS ON THE ECS

Exercise Medium to high-intensity voluntary exercise increases ECS signaling, via increased serum AEA levels, and possibly increased CB1 expression Forced exercise does not increase AEA and can decrease CB1 Stress and Social Play Chronic stress impairs the eCB system, via decreased levels of AEA and 2-AG Social play in rats increased CB1 phosphorylation (a marker of CB1 activation) in the amygdala and enhanced AEA levels in the amygdala and nucleus accumbens THE CLINICAL EVIDENCE ASSOCIATION BETWEEN MEDICAL CANNABIS AND PRESCRIPTION OPIOID USE IN CHRONIC PAIN PATIENTS: A PRELIMINARY COHORT STUDY

21 month observational period Chronic pain patients, mainly LBP. Chronic opioid users. PMP was used Patient’s decision to use cannabis All patients had the opportunity to use medicinal cannabis, (37MCP) (29 non MCP) All opioids were first normalized into milligrams of IV MS using the GlobalRPH equivalency calculator and IV:Oral 3:1 was used to measure patient’s consumption levels.

Association between medical cannabis and prescription opioid use in chronic pain patients: a preliminary cohort study Jacob M Vigil et al. 2017;12(11), PLOS

Association between medical cannabis and prescription opioid use in chronic pain patients: a preliminary cohort study Jacob M Vigil et al. 2017;12(11), PLOS Association between medical cannabis and prescription opioid use in chronic pain patients: a preliminary cohort study Jacob M Vigil et al. 2017;12(11), PLOS CANNABIS AS A SUBSTITUTE FOR PRESCRIPTION DRUGS- A CROSS SECTIONAL STUDY

To examine whether and how often cannabis users reported substituting cannabis for prescription drugs Individuals were substituting cannabis for prescription drugs independent of whether they identified themselves as medical users 1,248 respondents reported 2,473 substitutions The comorbidity triad of pain, anxiety and depression was associated with greater substitution frequency

James M Corroon, jr et al. Cannabis as a substitute for prescription drugs- a cross sectional study Journal of Pain Research, May 2017 James M Corroon, jr et al. Cannabis as a substitute for prescription drugs- a cross sectional study Journal of Pain Research, May 2017 CANNABIS AS A SUBSTITUTE FOR PRESCRIPTION DRUGS- A CROSS SECTIONAL STUDY

Respondents were allowed to report up to three medications for which they substituted cannabis 59% reported substituting for a single class of medication  33% reported substituting for two classes 8% reported substituting for three classes The most common substitution was for opioids 32%, followed by benzodiazepines 16% and antidepressants 12% The reasons most frequently ranked as being most important for substituting cannabis for prescribed medications were “less adverse side effects” 39%, “cannabis is safer” 27% and “better symptom management” 16%

James M Corroon, jr et al. Cannabis as a substitute for prescription drugs- a cross sectional study Journal of Pain Research, May 2017 CANNABIS AS A SUBSTITUTE FOR PRESCRIPTION DRUGS- A CROSS SECTIONAL STUDY

Again, we need to be cognizant of our sources:

James M Corroon Jr,1 Laurie K Mischley,2 Michelle Sexton3

1Center for Medical Cannabis Education, Del Mar, CA, 2Bastyr University Research Institute, Kenmore, WA, 3Department of Medical Research, Center for the Study of Cannabis and Social Policy, Seattle, WA, USA BUT WE DO HAVE SOURCES THAT APPEAR MORE OBJECTIVE…

Two studies:  one supporting cannabis substitution for medicines  one showing some promise in the treatment of withdrawal/addiction MEDICAL CANNABIS ACCESS, USE AND SUBSTITUTION FOR PRESCRIPTION OPIOIDS AND OTHER SUBSTANCES: A SURVEY OF AUTHORIZED MEDICAL CANNABIS PATIENTS

A password protected 107 question online cross-sectional survey was made available in French and English for a 2 week period in July 2015 to patients of Tilray—a licensed producer of cannabis 1310 participants were notified of the opportunity to participate in this study via direct email to patients that had opted in to receive online communication from Tilray upon registration Participants were compensated $10 credit for Tilray cannabis The study was approved by Institutional Review Board Services, and gathered data on demographics, patient experiences, patterns of use, and cannabis substitution effects

Lucas and Walsh, International Journal of Drug Policy 42 (2017)30-35 Lucas and Walsh, International Journal of Drug Policy 42 (2017)30-35 MEDICAL CANNABIS ACCESS, USE AND SUBSTITUTION FOR PRESCRIPTION OPIOIDS AND OTHER SUBSTANCES: A SURVEY OF AUTHORIZED MEDICAL CANNABIS PATIENTS

“The high rate of substitution for prescription drugs among patients with pain-related and mental health conditions suggests that medical cannabis may be an effective adjunct or substitute treatment to prescription drugs used to treat these conditions.” Further research into the comparative efficacy of cannabis relative to front-line treatments for theses conditions is warranted, and longitudinal research would help elucidate the context of cannabis substitution effect, and the potential impact of cannabis substitution on the quality of life of patients (in-progress, Lucas) This study suggests that state laws allowing access to, and use of, medical cannabis may not be influencing individual decision making in this area

Lucas and Walsh, International Journal of Drug Policy 42 (2017)30-35 MEDICAL CANNABIS ACCESS, USE AND SUBSTITUTION FOR PRESCRIPTION OPIOIDS AND OTHER SUBSTANCES: A SURVEY OF AUTHORIZED MEDICAL CANNABIS PATIENTS

• Centre for Addictions Research of British Columbia • Department of Psychology, University of British Columbia • Centre for the Advancement of Psychological Science and Law, University of British Columbia

Lucas and Walsh, International Journal of Drug Policy 42 (2017)30-35 EARLY PHASE IN THE DEVELOPMENT OF CANNABIDIOL AS A TREATMENT FOR ADDICTION: OPIOID RELAPSE TAKES INITIAL CENTER STAGE

• THC has been shown to be rewarding and to enhance the sensitivity of other drugs • CBD • Low reinforcing properties • Limited abuse potential • Inhibit drug seeking behavior • CBD anxiolytic properties and minimal side effect profile supports its potential viability as a treatment option for a variety of symptoms associated with drug addiction • Most available medications used for treating addiction have low to moderate effects on relapse outcomes • CBD’s effects were prolonged, lasting two or more weeks after administration in its efficacy to reduce heroin reinstatement behavior triggered by drug-specific environmental cues. Even when it was administered during active heroin intake, the ability of CBD to inhibit relapse behavior was still apparent weeks after exposure

Yasmin L Hurd et al Early Phase in the Development of Cannabidiol as a Treatment for Addiction: Opioid Relapse Takes Initial Center Stage. Neurotherapeutics 2015 Oct15: 12(4): 807-815 EARLY PHASE IN THE DEVELOPMENT OF CANNABIDIOL AS A TREATMENT FOR ADDICTION: OPIOID RELAPSE TAKES INITIAL CENTER STAGE

 CBD decreases stress and exhibit anxiolytic-like effects via its 5HT1A receptor modulating properties  Studies indicate panicolytic properties  It acts as an antidepressant in animal models of depression and decreases compulsive behaviors in rodents  CBD seems to prevent cocaine-induced hepatotoxicity, reverse binge ethanol-induced neurotoxicity and mitigate the cardiac effects of THC  It is known to attenuate amphetamine-induced hyperlocomotion  These actions are hypothesized to be linked to CB1 related mechanisms

 “The fact that CBD and THC have divergent effects on behaviors linked to addiction vulnerability emphasizes the important need to educate the general public.”  “Medical marijuana represents a complex chemical mixture, all of which may not be an appropriate treatment for substance use disorders; while one cannabinoid constituent in the plant can alleviate negative symptoms, another may exacerbate them.”  “As such, it is important to make a distinction in the nomenclature and emphasize that it is specific cannabinoids, such as “CBD”, that may hold the psychiatric therapeutic promise, not the general marijuana plant.”  “As more research efforts are directed towards cannabinoids, we will soon be able to understand how best to leverage the potentially beneficial properties of cannabinoids to develop more targeted treatment interventions.”

Published online: 13 August 2015, The American Society for Experimental NeuroTherapeutics, Inc. 2015 Departments of Psychiatry, Neuroscience and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York Division of Medical Toxicology, Department of Emergency Medicine, Icahn School of Medicine at Mount Sinai, New York Department of Psychiatry, Karolinska Institutet, Stockholm, Sweden Research Center, Centre Hospitalier de l’Université de Montréal, Department of Psychiatry, Université deMontréal, Montreal, Canada

ADVERSE EFFECTS CANNABINOID HYPEREMESIS SYNDROME

 Characterized by chronic cannabis use, cyclic episodes of nausea and vomiting, and frequent hot bathing.  The clinical course of Cannabinoid Hyperemesis Syndrome may be divided into three phases: prodromal, hyperemetic, and recovery phase.  Occurs in individuals with long-term high-dose cannabis use, onset is years after initiating cannabis use.  Treatment is hot showers. Often compulsive bathing is seen in patients with this syndrome.  The hyperemetic phase usually ceases within 48 hours, and treatment involves supportive therapy with fluid resuscitation and anti-emetic medications. Patients often demonstrate the learned behavior of frequent hot bathing, which produces temporary cessation of nausea, vomiting, and abdominal pain.  The broad differential diagnosis of nausea and vomiting often leads to delay in the diagnosis of Cannabinoid Hyperemesis Syndrome  Cyclic vomiting syndrome shares several similarities with CHS and the two conditions are often confused.

Galli, et al, Cannabinoid Hyperemesis Syndrome Current Drug Abuse Rev, 2011 Dec;4(4):241-9 DRUG INTERACTIONS

Cytochrome P450 Enzymes  THC is a CYP1A2 Inducer  THC can potentially decrease serum concentrations of clozapine, duloxetine, naproxen, cyclobenzaprine CBD is a potent inhibitor of CYP 3A4 and CYP2D6  CBD via CYP3A4 may increase serum concentrations of Benzos, antihistamines, calcium channel clockers  CBD via CYP2D6 may increase serum concentrations of SSRI’s, TCA’s, b-Blockers, antipsychotics and opioids CONTRAINDICATIONS

Absolute contraindications Acute psychosis and other unstable psychiatric conditions Relative contraindications Severe cardiovascular, immunological, liver, or kidney disease especially in acute illness Cannabis may exacerbate arrhythmia or a history of arrhythmias

• Handbook on Cannabis, 2015 CONTAMINATION IN CANNABIS

Fungal contamination (Aspergillus and Penicillium species) in marijuana samples has been demonstrated. Contamination with fungal or bacterial pathogens could increase risk of pneumonia and other respiratory problems1 While medical cannabis may be safer than unregulated cannabis, testing for fungal or bacterial contamination varies by jurisdiction Pesticides may also pose risks in cannabis products2

1-Pruitt 1997, McLaren et al 2008 2- McLaren et al 2008 POTENTIAL LEGAL IMPLICATIONS IMPLICATIONS

• Precisely what medical professionals may prescribe medical marijuana and what standards of care must be met? • This question has implications for medical licensing and professional disciplinary procedures as well as medical malpractice litigation • May federal bankruptcy protection be denied medical marijuana businesses? • Yes, since the business is considered to be operated in violation of federal law • May federally regulated banks lawfully accept the proceeds of medical marijuana sales? • Banks are fearful of prosecution and want definitive legislation that provides a safe harbor. There are attempts to form state financial institutions to provide financial services to the medical marijuana industry • May criminal probation prohibit medical marijuana usage? • Generally courts say yes as judges have broad discretion in imposing conditions of probation