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.

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