mj presentation eav 032615

Marijuana: What every pharmacist should know

Elva Angelique Van Devender, PhD, PharmD, BCPS

Legacy Good Samaritan Medical Center

Pharmacy Clinical Skills Days

Spring 2015

What this talk is NOT…

Political

Legal

“Pro” or “con” marijuana

A reflection of my personal views

This presentation is meant to be a resource for practicing

pharmacists on marijuana—its pharmacology, clinical benefits/harms,

adverse effects, drug interactions, dosing issues, etc. so pharmacists

can educate our patients and colleagues about this drug if/when they

have questions about its use and its safety profile.

3/26/2015 LEGACY HEALTH 2

Learning objectives

Describe clinical pharmacology of marijuana and its active

components

Evaluate and discuss the clinical evidence supporting the medical

use of marijuana

Identify the adverse effects and drug interactions that can occur

with the use of marijuana

Understand the problems of marijuana dosing, testing, purity and

what this means for consumers of the drug

March 26, 2015 LEGACY HEALTH 3

Background

Federal Prohibition (1937-present)

Marijuana prohibited by Federal Law

Controlled Substances Act 1970—Schedule I

Still considered a federal offense to grow, sell, or purchase marijuana

Medical Use (1996-present)

Legal under a physician’s supervision

Twenty U.S. states and the District of Columbia now have medical

marijuana laws, and nearly one-half of those states joined the ranks in

the last 5 years.

Legalization (2012-present)

Requires state legislatures to regulate recreational use

Eliminates prohibition for possessing small amounts of marijuana

Four States--Washington, Colorado, Oregon, and Alaska—and the

District of Columbia have approved marijuana for recreational use

March 26, 2015 LEGACY HEALTH 4

Cannabis and cannabinoids

Marijuana, also known as Cannabis sativa, has been used since

ancient times for therapeutic, spiritual, and recreational purposes.

Plant-derived cannabinoids (80 identified to date)

Tetrahydrocannabinol (THC)

has a psychotropic effect and produces the “high” for which

marijuana is known.

Cannabidiol (CBD) and Cannabinol (CBN)

have anti-seizure, anti-inflammation, anti-anxiety, and anti-nausea

properties.

Endocannabinoids

Anandamide

2-arachidonoylglycerol (2-AG)


Cannabis pharmacology

Endocannabinoids are substances our bodies make naturally to

stimulate CB1 and CB2 receptors (and other non-cannabinoid

targets) throughout body.

CB1 receptors: highly expressed in the brain and nervous system but

poorly expressed in the respiratory center of the brainstem

CB2 receptors: expressed on immune cells but poorly expressed in

the brain and central nervous system

In each tissue, the cannabinoid system performs different tasks.

Endocannabinoids regulate and/or modulate pain, appetite, lipid

metabolism, gastrointestinal function, cardiovascular function, motor

function and mood.

Goal is always homeostasis!


Types of marijuana “drug mimics” available

Single molecule oral drugs (approved for

severe nausea, loss of appetite)

Patients report that these agents are slow-

acting and less effective than inhaled forms

of marijuana.

nabilone (Cesamet)—Schedule II

dronabinol (Marinol)—Schedule III

Oral mucosal spray (being studied for

cancer pain and neuropathic

pain/spasticity in MS)

Approved in 8 countries; in phase III trials in

the U.S.

nabiximol (Sativex)


Five general indications for marijuana use

Nausea and vomiting associated with cancer chemotherapy or

other causes

Weight loss associated with debilitating illnesses, including

HIV/AIDS and cancer

Spasticity associated with neurologic diseases, such as multiple

sclerosis

Pain syndromes

Other uses, including glaucoma


Therapeutic effectiveness of marijuana

Because of the federal criminalization of marijuana, evidence-

based research into its effectiveness has been hindered.

Supply of material for federally-funded research is limited.

University of Mississippi has the approved strain to supply

researchers – historically linked to the National Institute of Drug

Abuse (NIDA).

Drug grown here 10-20x lower potency than what you can buy at

dispensaries.

BUT we still have some good evidence in the areas of pain,

especially neuropathic pain and pain refractory to other treatments.

Study limitations:

Small numbers of patients studied

Different doses (THC content) of plant material

Different dosage forms

Difficulty of blinding patients


Marijuana for chronic pain

Systemic review and meta-

analysis of 18 double-

blinded RCT trials

Included synthetic

derivatives of THC

Objective: Evaluate clinical

effectiveness/side effects of

oral cannabis and cannabis

derivatives in chronic pain

Conclusion: Marijuana

offers moderate efficacy

against refractory pain but

risks (side effects) might be

greater than benefit.


Marijuana for neuropathic pain

Systemic review and meta-analysis of 14 RCT trials

Objective: evaluate clinical effectiveness of various

analgesics versus placebo against painful HIV-associated

sensory neuropathy

Conclusion: Smoked marijuana and capsaicin 8% both

found to be effective


Marijuana for adjuvant pain therapy with opiates

Marijuana potentiates analgesic effects when used with narcotics,

thereby diminishing the dosage of opioids needed for pain relief.

May help by preventing development to tolerance to and

withdrawal from opiates

Comparisons in analgesia

10 mg THC less effective than 60 mg codeine

20 mg THC more effective than 120 mg codeine

Potentially less dangerous than opiates (no respiratory

depression)

There is no risk of death by overdose from cannabis—even in

massive overdoses.


Short term side effects

Increased heart rate

Decreased blood pressure

Increased appetite

Coughing

Bronchitis/asthma

Sedation

Problems with memory and learning

Distorted perception and difficulty in thinking/problem-solving

Loss of coordination

High doses: confusion, paranoia, panic attacks, and hallucinations


Potential longer term side effects

Obstructive lung diseases

Heart disease/stroke

Risk of addiction and dependence

Psychosis/mental health problems


Marijuana use in the young: risk of addiction

Resurgence of marijuana use after more than a decade of decline

1 in 15 high school seniors are smoking marijuana on a daily or near

daily basis

High school seniors rate of use went up from 22% (1992) to nearly

40% (2011).

In Colorado, marijuana, not alcohol, is main reason adolescents are

admitted to substance abuse treatment programs.

9% of marijuana experimenters will become addicted.

1/6 teenagers; 25‐50% of daily users

Potential for addiction still less than users of nicotine (35%), heroin

(23%), and alcohol (15%).

Cannabis withdrawal makes cessation difficult and relapse likely.

Symptoms of withdrawal: anxiety, depression, nausea/decreased

appetite, insomnia/nightmares, headaches, irritability, muscle tension


Marijuana use in the young: brain development

Long‐term cannabis

exposure

produces structural brain

changes and lowers IQ

impairs neural

connectivity

reduces volume of

hippocampus

impairs learning and

memory

leads to loss of executive

function


The developing brain is more vulnerable to

extrinsic/environmental inputs than the mature brain.

Marijuana use: psychiatric consequences

Cannabis has a negative effect on pre‐existing psychiatric illness

and can lead to psychosis in predisposed individuals.

Acute cannabis psychosis

Typically when very large doses consumed

Agitation, confusion, sedation

Self-limiting

Acute schizophreniform reaction

Early and heavy marijuana exposure may increase risk of

developing a psychotic disorder such as schizophrenia

Patients with schizophrenia or bipolar disorder should be advised

to stay away from marijuana as it may exacerbate their symptoms.


Marijuana use: pregnancy and lactation

Research suggests that using marijuana

during pregnancy may result in

reduced fetal growth/lower birth weights?

birth defects?

decreased cognitive function/IQ?

behavioral issues/attention problems

diminished higher cognitive/executive

functions

Nursing mothers can transfer THC to their

babies through their breast milk which may

interfere with infant development.

Contraindicated in pregnancy—like many

other medicines


Marijuana use: cannabinoid hyperemesis

syndrome

Symptoms include cyclic vomiting (can last for hours or

days), abdominal pain, excessive thirst, nausea, gastric

pain and compulsive bathing to ease pain

Seen in recreational cannabis users who use drug chronically

and/or from an early age

Not usually seen in medical marijuana users

Paradoxical effect: marijuana can help with nausea and

appetite.

Marijuana drug mimics nabilone and dronabinol were

developed to help treat nausea.

Treatment is usually anti-nausea meds, hydration,

cessation of marijuana therapy.


Drug interactions

THC metabolized by CYP3A4 and CYP2C9 to several

hydroxylated metabolites

CYP3A4 mediated metabolism

sildenafil (heart attack or pulmonary hemorrhage)

protease inhibitors (reduction in indinavir and nelfinavir)

CYP2C9 mediated metabolism

selective serotonin reuptake inhibitors (manic symptoms)

tricyclic antidepressants (tachycardia, delirium)

Warfarin (increased INR with frequent marijuana use)

CNS depressants (additive depressant effects and impaired

cognitive/motor function)

Alcohol, benzodiazepines, barbiturates, tricyclics, narcotics,

sedatives/hypnotics, antihistamines


Drugs that can modulate marijuana’s effects

Steroids (case report data—increases side effects)

Hormones: women more sensitive to THC effects with higher

estrogen levels

Tobacco: greater increases in HR and carbon monoxide despite

lower THC concentrations

MDMA: greater increases in memory impairment; does not lessen

THC’s impairment of psychomotor function

Agents that can increase HR: amphetemines, anticholinergics,

tricyclics, naltrexone, theophylline

Agents that increase sedation: alcohol, benzodiazepines,

barbiturates, narcotics, sedatives/hypnotics, antihistamines

Agents that decrease feeling high: antipsychotics


Marijuana formulations

Typically three routes of administration

Lungs

Vaporized or smoked

Organic material (hash, hash oil)

Gut

Oral ingestion (edibles, tinctures, drinks)

Lipophilic, alcoholic, supercritical fluidic

extracts of plant material

Skin

Topical application of plant extracts (e.g.

creams)


Pharmacokinetics The pharmacokinetics of THC vary depending on the route of

administration.

Inhaled THC causes maximum plasma concentration after 15 to 30

minutes, with a duration of two to three hours.

Rapid onset (similar dose response curve to IV bolus)

Peak concentrations are high and are reached within minutes.

Bioavailability in lungs 10-25%

Following oral ingestion, effects begin in 30 to 90 minutes and can

last up to five to eight hours.

Variable absorption (due to gastric degradation and extensive first

pass metabolism)

Peak concentrations are low and reached in 1-3 hours.

Bioavailability ranges 5-20%

Cannabinoids are lipophilic – relatively long elimination!

It takes a week to one month for all the chemicals from one marijuana

cigarette to leave the body.

Can accumulate with chronic use


Marijuana potency: We’ve come a long way!

Today’s marijuana is NOT the marijuana of the 60s, 70s, or 80s!

Extremely potent: one “joint” today equivalent to smoking 3‐5 “joints”

in the 1960s.

THC levels up to 35% vs. single digits of a decade ago.

Marijuana concentrate is available: highly potent (75% THC or

higher).

One ounce of concentrate = approx. 2,800 servings of marijuana!


No clear optimal dose—concentration of THC is variable!

Review of 165 studies attempted to normalize THC dose.

Low <7 mg; medium 7-18 mg; high >18 mg

Variations in strain and phenotype of cannabis

Cannabis sativa, Cannabis indica, hybrids of both +/-CBD

Growers cultivate different strains of marijuana to yield higher

proportions of one cannabinoid than another.

Route of administration

Differing concentrations and ratios of cannabinoids based on route.

Amount of marijuana needed

Estimated 3–5x greater quantity required for oral products (assuming

equal efficiency and loss in both processes).

Dosing considerations


An unregulated industry with no controls!

No safeguards

Thousands of different strains– growers enrich and alter content

Pesticides, insecticides, and herbicides

Fungi content – dangerous to immunocompromised individuals

No recall mechanism for harmful or contaminated batches


Caveat emptor


Summary

THC is the best studied cannabinoid and achieves its

psychoactive effects by targeting CB1 receptors in the brain.

Clinical studies indicate marijuana might be useful to alleviate

chronic pain refractory to other treatments.

Marijuana, like any drug, is not benign—there are adverse events,

drug interactions, and patient populations for which this drug is

not appropriate and actually could be harmful.

There is no “standardization” for marijuana dosing. Marijuana

products come in many forms and strains (which are often

mislabeled and do not contain the potency of strains advertised on

the label), and patients/consumers will often “self-titrate” to effect.


Additional references 1. Bostwick JM. Blurred boundaries: the therapeutics and politics of medical marijuana. Mayo Clin Proc 2012;87:172-

186.

2. Borgelt LM, Franson KL, Nussbaum AM, Wang GS. The pharmacologic and clinical effects of medical cannabis.

Pharmacotherapy 2013;33:195-209.

3. Martin-Sanchez E, Furukawa TA, Taylor J, Martin JL. Systematic review and meta-analysis of cannabis treatment for

chronic pain. Pain Med 2009;10:1353–68.

4. Phillips TJ, Cherry CL, Cox S, Marshall SJ, Rice AS. Pharmacological treatment of painful HIV-associated sensory

neuropathy: a systematic review and meta-analysis of randomised controlled trials. PLoS ONE 2010;5:e14433.

5. Lucas P. Cannabis as an adjunct to or substitute for opiates in the treatment of chronic pain. J Psychoactive

Drugs 2012;44(2):125-33.

6. Volkow, ND, Baler RD, Weiss S. Adverse Health Effects of Marijuana Use. N Engl J Med 2014; 370:2219-27.

7. Wang T, Collet JP, Shapiro S, et al. Adverse effects of medical cannabinoids a systematic review. CMAJ

2008;178(13):1669-78.

8. Joffe A, Yancy WS; American Academy of Pediatrics Committee on Substance Abuse, American Academy of

Pediatrics Committee on Adolescence. Legalization of marijuana: potential impact on youth. Pediatrics 2004;113:e632-

e638.

9. Evins AE, Green AI, Kane JM. The effect of marijuana use on the risk for schizophrenia. J Clin

Psychiatry 2012;73(11):1463-8.

10. Wallace EA, Andrews SE, Carmany CL, et al. Cannabinoid hyperemesis syndrome: literature review and proposed diagnosis and treatment algorithm. South Med J 2011;104:659–664.

11. Email communications with Jane Ishmael, Ph.D. Associate Professor of Pharmacology, Department of

Pharmaceutical Sciences, College of Pharmacy, Oregon State University (January-February 2015).

12. Marijuana Science Forum. Marijuana and Fetal Harm. Available at: http://marijuanascienceforum.org. Accessed March 23, 2015.

http://marijuanascienceforum.org/

Thank you!

mj presentation eav 032615

Documents