medical marijuana… fact versus fiction · recipe in exodus (30:22-23), contained over six pounds...

MEDICAL MARIJUANA…

FACT VERSUS FICTION

MASSAPEQUA PAIN MANAGEMENT AND REHABILITATION

4200 SUNRISE HIGHWAY

MASSAPEQUA, NY 11758

516-541-1064

ADMINISTRATIVE DIRECTOR-CHRONIC PAIN MANAGEMENT

MATHER HOSPITAL-NORTHWELL HEALTH

PORT JEFFERSON, NY

Thomas F. Jan, DO, FAOCPMR

Subspecialty Certified– Pain Medicine

Diplomate – American Board of Addiction Medicine

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

2018STATE MARIJUANA

LAWS

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

2018STATE 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


2018STATE 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.


2018STATE MARIJUANA LAWS (CONT’D)

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


THE NEW YORK STATEMEDICAL 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


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.




Qualifying conditions:

Cancer

HIV infection or AIDS

Amyotrophic lateral sclerosis (ALS)

Parkinson's disease

Multiple sclerosis

Spinal cord injury with spasticity

Epilepsy

Inflammatory bowel disease

Neuropathy

Huntington's disease

Post-traumatic stress disorder

Chronic pain




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)


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 HSIREFERENCES 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

https://medicalmarijuana.procon.org/view.source.php?sourceID=011036

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





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



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



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



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



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..."

Richard Glen Boire, JD and Kevin Feeney, JD Medical Marijuana Law, 2007


Cover of the 1851 United States Pharmacopeia



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


https://medicalmarijuana.procon.org/sourcefiles/Pure-Food-and-Drug-Act-1906.pdf

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



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


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


CB1 located in:

CNS

Testes, uterus

Adipose tissue

Connective tissue

Endocrine glands

Exocrine glands

Leukocytes

Spleen

Heart

GI tract

Liver

CB2 located in:

Monocytes

Macrophages

B-cells

T-cells

Liver

Spleen

Tonsils

CNS

Enteric nervous 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”


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 ANDTHE 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 ANDTHE 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

• Chronic motion sickness

• Fibromyalgia

• Huntington’s disease

• Irritable bowel syndrome

• Menstrual symptoms

• Migraine

• Motion sickness

• Multiple sclerosis

• Parkinson’s Disease

• PTSD

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

• Antagonizes other CB1 & CB2 agonists

• Non-competitive inverse agonist that modulates the affinity

of ECS receptors

• Antagonizes

• GPR55

• alpha-1 adrenergic

• μ-opioid receptors

• Activates

• 5-HT1A serotonergic

• TRPV1-2 vanilloid receptors

• Inhibits uptake

• noradrenaline

• dopamine

• serotonin

• GABA

• anandamide

• Inhibits activity of fatty amide hydrolase (FAAH)

• May act on mitochondria Ca2 stores

• May block low-voltage-activated (T-type) Ca2 channels

• May stimulate activity of the inhibitory glycine-receptor

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 BEENSHOWN 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 HAVEECS 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 ANDPRESCRIPTION OPIOID USE IN CHRONIC PAINPATIENTS: 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

CANNABIS AS A SUBSTITUTE FOR PRESCRIPTIONDRUGS- 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


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%




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


“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



• 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


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 TREATMENTFOR 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



SIDE EFFECTS AND INTERACTIONS

ADVERSE EFFECTS

CANNABINOID HYPEREMESIS SYNDROME

Galli, et al, Cannabinoid Hyperemesis Syndrome

Current Drug Abuse Rev, 2011 Dec;4(4):241-9

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.

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

Brad Reid: Numerous Legal Issues Surround Medical Marijuana

https://www.huffingtonpost.com/brad-reid/numerous-legal-issues-sur_b_6624554.html

IMPLICATIONS (Cont’d)

• May usage around children or reckless storage that allows children access to medical

marijuana be punished?

• Courts overwhelmingly say yes under a child endangerment standard

• May minor children be removed from a home in which medical marijuana is used?

• Courts frequently say yes in the best interest of the child

• May gun purchases or other permits be denied to medical marijuana users? TheFederal

Firearms Transaction Record Form 4473 asks questions concerning “unlawful” marijuana

and other drugs usage.

• Potential federal-state law conflict



http://www.atf.gov/files/forms/download/atf-f-4473-1.pdf


• What level of marijuana chemical (THC) blood concentration constitutes unlawful driving

under the influence?

• These standards are being created

• May federal Department of Housing and Urban Development regulations prohibit medical

marijuana use in federally supported public housing?

• Currently true

• May private sector tenants in medical marijuana states be prohibited in their lease agreement

from using any marijuana?

• Drug Courts:

• The impact of medical marijuana prescriptions in drug courts that frequently prefer abstinence from

all drug usage is to be determined




• May employers conduct marijuana screening as part of a zero tolerance

drug policy and enforce anti-marijuana policies with termination?

• While often the answer is yes, there is no uniform answer

• A difficult question involves off-work and off-employment-site medical marijuana

usage that produces a positive drug test result even when the individual is not

intoxicated

• State legislation varies in having reasonable accommodation and disability language

• The Colorado Supreme Court is considering this issue (Coats v. Dish Network)

• However, a Colorado decision will only be binding in Colorado




• Is an employee who is prescribed medical marijuana protected by

state or federal disability legislation?

• Disability legislation will typically not protect an employee who comes to

work intoxicated

• However, a disabled employee is typically entitled to reasonable

accommodation unless it produces an undue hardship for the employer.

• Precisely how state legislation defines “disability” is significant.

• Again, off-work usage of prescribed medical marijuana is a difficult issue




• Federal contractors must comply with the Drug Free Workplace Act. Federal law

considers marijuana an illegal drug and mandates a zero-tolerance workplace

policy

• As well, Department of Transportation regulations have similar requirements

• Some states exempt federally regulated employers from accommodation requirements.

However, the precise interplay between state and federal law is unclear.

• Does state legislation prohibiting employers from disciplining employees who

engage in lawful activities or use lawful products also apply to medical marijuana?

• These statutes were typically enacted with tobacco use in mind. Their application to

medical marijuana is uncertain




• May medical marijuana products be distributed in interstate commerce?

• Medical marijuana may not be distributed in a state that outlaws it

• Interstate transportation between states where medical marijuana is lawful is an open

question

• May one state successfully challenge the marijuana laws of another state?

• In December 2014 Nebraska and Oklahoma sued Colorado in the U.S. Supreme Court

asserting that Colorado was in violation of the federal Controlled Substance Act and that law

enforcement related expenses in their states were increased by Colorado’s actions

• Many commentators doubt that this litigation will succeed because of “standing” (a right to

sue) but the question is open




• On December 16, 2014, President Obama signed a federal spending bill containing

the following language :

• “None of the funds made available in this act to the Department of Justice may be used ... to

prevent ... states ... from implementing their own state laws that authorize the use, distribution,

possession, or cultivation of medical marijuana.”

• The interaction of this provision with the classification of marijuana as a Schedule I

substance under the Controlled Substances Act is uncertain



http://www.huffingtonpost.com/2014/05/30/dea-medical-marijuana-house-vote_n_5414679.html

CONCLUSIONS

CONCLUSIONS

Cannabis has been with man for thousands of years and the controversy continues…

There is significant scientific evidence supporting the Endocannabinoid System model and

its function in the human body

It is well documented that, as with all forms of medical treatment:

If it has an effect…it has a side effect!

As health care professionals we have an obligation to our patients to follow the maxim:

Primum non nocere

As well, we have an obligation to keep an open mind and to stay vigilant for therapies that

may benefit those we treat

medical marijuana… fact versus fiction · recipe in exodus (30:22-23), contained over six pounds...

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