Medical Marihuana: Clearing the Air

Sara Feinauer, PharmD, BCPSNovember 2014

Google: Smoke. http://campbellpropertymanagement.com/blog/2014/08/05/159-new-laws-go-smoke-quick-look-medical-marijuana-smoke-foul/

Disclosure

• No disclosures concerning a conflict of interest with commercial entities that may be referenced in this presentation.

Objectives

• 1. Describe how medical marihuana may provide medicinal benefits

• 2. Compare and contrast the benefits versus risks of using medical marihuana

• 3. List usages and restrictions as applicable to the state of Michigan in regards to the use of medical marihuana

Overview

Medical Marihuana

Laws

RisksUses

Marijuana vs. Marihuana1

• Per Initiated Law 1 of 2008 and administrative rules:– “Marihuana is one of two acceptable spellings in

the dictionary and is consistent with the spelling in the Michigan Public Health Code, Act 368 of 1978, and Initiated Law 2008.”

Marihuana: A History2,3

• Prior to 1937, marihuana was commonly used as a bronchodilator– Used most often for asthma in the 1800s

• Dropped from the US pharmacopeia in 1941• Most commonly used illicit substance

worldwide– 3.9% of adult population (15-64 years old)

Marihuana: A Controversy2,3

• DEA states that there are legal products available

• AMA supports rescheduling to schedule II– “Known medicinal value, while acknowledging the

importance of proper medical supervision and accepting that more research is necessary into the side effects and possible dangers of medical marijuana use”

Limitation to Uses2

• Relief of symptoms, not cure

• Evidence often anecdotal

• Route of use

• Amount for use

How does it work?2,4

• Tetrahydrocannabinol (THC) is a partial agonist at cannabinoid receptors (CB1, CB2) in the endocannabinoid system– THC primary effect on CB1

How does it work?2,4

CB1

• Brain• PNS• ANS• Psychoactive

CB2

• Neurons• Immune cells

CB1 Effects2,4

Sedation Analgesic

Psychiatric

Anxiolytic

Appetite Stimulant

Uses

Medical Marijuana. Pharmacist’s Letter. January 2013.

Appetite Stimulant2

•Dronabinol < megestrol•Oral cannabis ≠ placeboCancer

•Smoking stimulates appetite•Dronabinol and THC (2% and 3.9%) > placebo

HIV

Chronic Pain5,6

• >45 studies– Cancer, diabetes, fibromyalgia, MS, HIV,

rheumatoid arthritis, spinal injuries– Majority show benefit– Quarter of studies showed no improvement

• No benefit in acute pain

Chronic Pain4,6,7

• THC 10 mg was better than placebo– Analgesically similar to 60mg codeine

• 3.56% THC cigarettes TID x 5 days decreased pain intensity over placebo– 3.56% and 7% studied– 9 cumulative “puffs” (240 minutes) = ½ cigarette– 19mg (3.56%) 34mg (7%) THC consumed

Multiple Sclerosis2,5

• Benefit shown from both oral intake and smoking – PO may reduce urge incontinence

• >24 studies– Relax rigid muscles– Decrease pain

Nausea and Vomiting2,7

• Modest anti-emetic• Different mechanism than commercially

available products• Possible adjunctive treatment• Most studies available look at commercial

products vs. medical marihuana• Smoking 8.4-16.9 mg THC had limited benefit

compared to 8 mg ondansetron

Glaucoma2,7

• Smoking marihuana reduces intraocular pressure short-term– 60-65% decrease for open angle glaucoma– Decreases blood flow to optic nerve– Linear relationship to amount smoked– Benefit for 3-4 hours = 8-10 marihuana cigarettes

smoke/day for continual benefit• Unknown benefit to visual function

Possible Benefit

Vaida B. Medical Marijuana: What the Research Shows. April 02, 2014. http://www.medscape.com/viewarticle/822942

Alzheimer’s Disease5,8

• 1 trial from 1997 showed THC could ease symptoms

• Participants showed less agitation and better appetites

• Decrease amyloid beta at low concentrations• Potential neuroprotective effect– Memory impairment only seen at “abuse”

concentrations

Autism5

• 2 animal studies show possible symptom benefit

• Study at University of California in progress

Cancer5

• Several human and animal studies

• Small study (9 participants) showed THC and other cannabinoids may slow brain cancer growth

• Lab studies of human cells show potential to slow breast and leukemia cancer cells

Epilepsy5

• Anecdotal and animal studies show cannabidiol (CBD) may help seizures in children

• New York University to begin studying marihuana benefit for epilepsy in children

Digestive Disorders5

• Anecdotal, early studies– Smoking marihuana can help with: colitis, irritable

bowel syndrome, and Crohn’s disease– Reduces bowel inflammation and decrease acid

reflux– Some patients retained more nutrients– Some had disease remission

Schizophrenia5

• 2 trials• THC and cannabidiol could help psychotic and

other symptoms

• Possible link to causing schizophrenia in adolescents who start

• National Institute of Health funding clinical trial to study ease of symptoms

Other possibilities7

• Tourette’s– Oral THC helped decrease tics after 6 weeks

compared to placebo

• Levodopa-induced dyskinesias in Parkinson’s Disease

Question 1

• Which of the following properties is an example of the possible beneficial aspects of using medical marihuana?a. Anxiolyticb. Analgesicc. Appetite stimulantd. All of the above

Risks9

“What the data are showing is for the majority of the population, cannabis is not associated with severe, long-term adverse outcomes, but there is a misconception that this means it is safe for nearly everyone, which is not true.”

Limitations to Risks

• Recreational use is not the same as medicinal use

• No consensus on definitions of low vs. heavy use

• Most studies use oral commercial forms

Abuse9-11

• States with legalized marihuana have higher rates of use/abuse/dependence

• Clinical and epidemiologic studies show link between early cannabis use and increased exposure to heavier drugs– No true causal relationship – genetic and

environmental influences– Screening processes

• Addiction potential 9-10%– Highest when starting as a teenager

Side Effects2

• Serious side effect risks low compared to many other prescription drugs

Common Side Effects6

Dry mouth, red eyes

Nausea/Vomiting

Sedation

Dizziness

Altered sense of time

Decreased GI motility

Confusion

Increased heart rate and BP fluctuations

Increased well-being

Muscle relaxation

Increased appetite

Cough

Chronic Use6

Apathy

Impaired memory

Sexual dysfunction

Bullous emphysema

Increased risk of MI in middle age

Ischemic stroke

Unknown Risks2

• Lung cancer• Testicular cancer• Increased risk of psychosis

Other risks6,9

• “Motivational syndrome”• Intoxicating doses impair reaction time, motor

coordination, and visual perceptions– Driving may be impaired for up to 8 hours

• Dependency similar to other pain medications

Lung Disease3

• Marihuana smoke contains 70% more carcinogenic ingredients than cigarette smoke

• Similar compounds to cigarette smoke• Research with lung cancer is conflicting• Combustive marihuana is a respiratory irritant

Lung Disease3

• Meta-analysis Tetrault et al.– Consistent association between short-term use

and bronchodilation• Increase FEV1, peak flow, and airway conductance

– Also found no consistent association with long-term smoking and airflow obstruction

– Benefit is non-linear, increase FEV1 with low levels of exposure, but decrease FEV1 at high levels

Lung Disease3

• CARDIA (Coronary Artery Risk Development in Young Adults)– 20 year follow up with no airflow obstruction with

occasional or low cumulative marihuana smokers• NHANES III (National Health and Nutrition Examination

Survey)– Both marihuana and tobacco increase respiratory symptoms

• Fligiel et al. suggests physical exam and spirometry may not be sensitive enough in asymptomatic smokers

Lung Disease3

• Associated with chronic bronchitis symptoms and airway inflammation, however low cumulative doses are not a risk factor for COPD

• Apical bullous lung disease– Linked to heavy smoking in young adults– Deeper and longer inhalations – Related to technique– Very rare and possibly coincidental

Lung Cancer3

• Research is conflicting– THC effects on cytokines suggest cancer cell

growth but cannabinoids seem to inhibit cell proliferation in vitro

• Histopathologic and immunohistologic evidence suggested molecular markers of pretumor progression, Moir et al.– Epidemiologic evidence linking is rare

Lung Cancer3

• Swedish study– > 50,000 men, 18-20 years old– Extended follow-up– Heavy cannabis smoking = >50 uses• Two-fold greater risk in developing lung cancer

• Article conclusion: “Any toxicity pales when compared to the greatest legalized killer in the world – tobacco.”

Study Flaws3

• Most people who smoke marihuana also smoke tobacco

• Most studies lack power to associate marihuana with COPD

• Under-reporting• Wide variety of definitions for “heavy” use

Question 2

• True or False: Smoking marijuana has been conclusively linked to lung cancer.

TrueFalse

Pharmacist stuff…

Medical Marijuana. Google. saintpetersblog.com

Drug Interactions6

• CYP450 3A4 and 2C inhibitor• Little evidence of clinically significant

interactions at medicinal doses• Unclear if risk equivalent when smoking

(undergoes less hepatic first-pass metabolism)• Use caution with anti-cholinergics and CNS

depressants (additive effects)

Contraindications/Precautions6

Contraindication• Abnormal sensitivity to marihuana

Precautions• Severe personality

disorders/psychoses• Pregnant/breastfeeding• Children/adolescents• Elderly• Cardiovascular disease• Addictive disorders

Pharmacokinetics6,7

• THC immediately in plasma following inhalation– Rapidly absorbed within seconds, peak

concentration 3-10 minutes• Low oral bioavailability improved when in oil-

based formulation• Active metabolites higher after oral use than

smoking

Pharmacokinetics7

• Cannabidiol (CBD) has extensive first-pass metabolism– Oral: peak 30-120 minutes and detected for 180-

240 minutes after ingestion

• Rapid onset and predictable decay allow for self-titration

• Overdose is rare

Medical Marihuana9,12

• “Not your parents’ pot”– Current cannabis more potent– Higher levels of THC• 1960-1970’s: <5% THC• Last 10 years: 15-20% THC

• Prescriptions should specify THC concentrations not greater than 9%

Types of Medical Marihuana

Sativa Indica

Leung L. Cannabis and its derivatives: Review of medical use. J Am Board Fam Med 2011;24:425-462.

Routes

Smoking

Vaporizing

EatingDrinking

Tincture

Topical

Methods, Forms and Routes of Medical Marijuana Administration. http://svphyto.org/wp-content/uploads/2013/06/Methods-Forms-and-Routes-of-Medical-Marijuana-Administration.pdf

Smoking3,4,6,13

Pros

• Most immediate relief• Refined control• Self-titration

Cons

• Respiratory irritation• Combustion creates additional byproducts• Possible contaminants• Amount delivered depends on individual techniques/lung capacity

Smoking13

• Potentially greater benefit in:– Tourette’s Syndrome– Glaucoma– Pain– HIV-induced neuropathic pain

Smoking2,3

• No FDA approved drug is available administered by smoking– Most studied route for medical marihuana

• Despite lack of marihuana standardization, smoking is an unpredictable route of administration– Dependent on user: time of inhale, method of

inhale, time of exhale

Vaporizing13

• Smokeless alternative– Considered safest route– Not the same as water pipes– Heat cannabis below point of combustion

producing less byproducts but allowing essential oils to volatize

• Similar effects to smoking

Marijuana Vaporizer. Google. lelandkim.com

Eating13

• Cannabinoids extracted into fats (butter/oils)• Ingested via baked goods/candy-like products• Active ingredients must be metabolized by liver– Can take 30 minutes – 2 hours before effects– Effects last 2-8 hours

• Side effects typically stronger than smoking• More difficult to regulate doses• Oral use potentially more beneficial in: MS

spasticity, peripheral/central neuropathic pain

Drinking13

• Tea– Boil water and pour over cannabis– Steep for 1.5 hours – not readily water soluble– Effects similar to eating

Tinctures13

• Alcohol used to extract cannabinoids• Effects similar to eating• Faster onset and quicker offset than eating– Effects in 5 minutes – 1 hour– Last up to 4 hours

• May drop or spray into mouth and absorb through mucous membranes

• Can drop in hot water to burn off alcohol

Topical13

• Can be absorbed through skin• Ideal for ointments

Commercially Available2

• Dronabinol (Marinol®) – schedule III• Nabilone (Cesamet®) – schedule II– Use: nausea with chemotherapy agents

• Nabiximols (Sativex®) – Buccal spray approved in Canada, currently studied

in US for neuropathic pain in adults with MS• Epidiolex®– FDA approved in 2013 for children’s epilepsy– Highly restricted use

Commercially Available2,13

• Typically these agents are too psychoactive– Narrow gap between therapeutic dose and

adverse effects• Euphoria, cognitive clouding, drowsiness

• Only based off of THC (psychoactive component)

• A combination of cannabinoids (cannabidiol and THC) as found in medicinal marihuana can have affect over benefit and side effect profile

Michigan Medical Marihuana Act9

• Department of Justice: Will not challenge state laws that legalize marihuana– Focus on:• Preventing distribution to minors• Stop drug trafficking by gangs/cartels• Prevent drugged driving• Prohibit public lands for growing

Michigan Medical Marihuana Act14

Patient

MI Resident

Debilitating qualifying medical

conditionRegistered with

MMMP

“Usable” Marihuana14

Leaves Flowers

Michigan Medical Marihuana Act14

Caregivers•Must meet state requirements for protection•May care for up to 5 patients

Physicians•Must meet state requirements for protection•Bona fide physician – patient relationship

MMMA: Updates14

•Limit transportationPublic Act 460

•Define bona fide physician-patient relationship•Further definitions: enclosed, locked facility, primary caregiver

Public Act 512

•Proof of residency•Further definitions•Add confidentiality

Public Act 514

Debilitating Medical Condition14

Cancer

Glaucoma

Positive HIV status

AIDS

Hepatitis C

Amyotrophic Lateral Sclerosis

Crohn’s disease

Agitation of Alzheimer’s disease

Nail patella syndrome

Debilitating Medical Condition14

Cachexia or wasting syndrome

Severe and chronic pain

Severe nausea

Seizures

Severe and persistent muscle spasms

Any other medical condition or its treatment approved by the department

Debilitating Medical Condition14

Approved•Parkinson’s Disease•PTSD

Denied•Asthma•Autism•Insomnia•Bipolar disorder

Question 3

• Which of the following is NOT a valid use for medical marihuana in Michigan?a. Glaucomab. Crohn’s Diseasec. Nail patellad. Schizophrenia

Updates15

• Dispensaries shutdown in February 2013 as “public nuisance”– House legislation to add new rules and limitations

for reopening• Michigan Court of Appeals in July 2013 said

“pot brownies” are not “usable marihuana” under the law, unless contain actual plant material– Legislation also to redefine to include edibles

Conclusions

• Marihuana has shown possible medicinal benefit in multiple indications

• Marihuana use does not come without risks

• Further studies need to be done

Resources1. Michigan Medical Marihuana Program. LARA. http://www.michigan.gov2. Medical Marijuana. Pharmacist’s Letter. January 2013.3. Manish J et al. Marijuana and Lung Diseases. Curr Opin Pulm Med. 2014;20(2):173-197.4. Leung L. Cannabis and its derivatives: Review of medical use. J Am Board Fam Med 2011;24:425-462.5. Vaida B. Medical Marijuana: What the Research Shows. April 02, 2014. http://www.medscape.com/viewarticle/8229426. Zanni GR. Medical marijuana potential and pitfalls. http://www.pharmacytimes.com7. Medical Marijuana. Clinical Pharmacology. 2014.8. Harrison P. Marijuana Compound a Novel Treatment for Alzheimer’s? September 05, 2014.

http://www.medscape.com/viewarticle/8311999. Melvil NA. Public in a haze about marijuana safety. September 04 2013.

http://www.medscape.com/viewarticle/81042710. Alcohol and Drug Information. National Council on Alcoholism and Drug Dependence, Inc. https://ncadd.org/for-the-

media/alcohol-a-drug-information. 11. Nicotine Addiction: Past and Present. How Tobacco Smoke Causes Disease. 2010. Available from:

http://www.ncbi.nlm.nih.gov/books/NBK53018/12. Collier R. MediData: How potent is medical marijuana. CMAJ. Aug 26, 2014. 13. Methods, Forms and Routes of Medical Marijuana Administration.

http://svphyto.org/wp-content/uploads/2013/06/Methods-Forms-and-Routes-of-Medical-Marijuana-Administration.pdf

14. Michigan Medical Marihuana Program. LARA. http://www.michigan.gov15. Oosting J. Michigan medical marihuana rule changes hit speed bump. October 01, 2014.

http://www.mlive.com/lansing-news/index.ssf/2014/10/michigan_medical_marijuana_rul.html

Questions?

Smoke. Google. http://textures8.com/smoke-abstract-background-sixty-five/