www.mghcme.org
Medical Marijuana: Friend or Foe?
Timothy E. Wilens MD
Director, Center for Addiction Medicine Chief, Division of Child and Adolescent Psychiatry,
Massachusetts General Hospital Harvard Medical School
www.mghcme.org
Disclosures*
Dr. Wilens has served as a consultant or has received grant support from the following:
• Grant Support: NIH (NIDA), Euthymics/Neurovance, Ironshore, Sunovion, TRIS, US National Football League (ERM Associates), U.S. Minor/Major League Baseball, Bay Cove Human Services, Phoenix House (Clinical Services)
• Royalties: Guilford Press, Cambridge Press, Elsevier, co/owner of a copyrighted diagnostic questionnaire (Before School Functioning Questionnaire), licensing agreement with Ironshore (BSFQ Questionnaire)
• Some of the medications discussed may not be FDA approved in the manner in which they are discussed including diagnosis(es), combinations, age groups, dosing, or in context to other disorders (e.g. substance use disorders)
* Past 3 years
Special appreciation to J Kelly PhD (MGH) for use of some of the slides.
www.mghcme.org
As of November 2016: Medical: 26 States and DC
Recreational: 7 States and DC
www.mghcme.org
www.mghcme.org
Main Effects of Marijuana
• Active ingredients: Delta-9 Tetrahydrocannabinol (THC), cannabidiol, tetrahydrocannabivarin
• Agonist to the cannabinoid (CB) receptors (CB1>CB2)
– G protein- decrease adenylate cyclase, inhibit calcium channels, and modify K+ channels
• Similar to naturally occurring anadamide (from arachidonic acid)
Pertwee, R (1997). "Pharmacology of cannabinoid CB1 and CB2 receptors". Pharmacology & Therapeutics 74 (2): 129–80; Tanda and Goldberg, Psychopharm (Berl) 2003: 169: 115-34
Delta 9-THC is converted rapidly to 11-hydroxy THC which is also active and outlasts measurable THC
www.mghcme.org
Photo courtesy of the NIDA Web site. From A Slide Teaching Packet: The Brain and the Actions of Cocaine, Opiates, and Marijuana.
Inhibitions
Major Brain Circuits Involved in Addiction
www.mghcme.org
Photo courtesy of the NIDA Web site. From A Slide Teaching Packet: The Brain and the Actions of Cocaine, Opiates, and Marijuana; Wilens et al. Contem Peds 2013.
Inhibitions
www.mghcme.org
THC Administration & FDA Approved THC-based medications
Compound Administration FDA Status Approved Locations
Purposes
Dronabinol (Marinol)
Oral capsule FDA-approved (1985)
USA, Germany
1. Nausea & vomiting related to cancer chemotherapy
2. Wasting associated with AIDS
Nabilone (Cesamet)
Oral capsule FDA-approved (1985) *Marketed in the US in 2006
USA, Canada, UK, Mexico
Nausea & vomiting related to cancer chemotherapy
Nabiximols (Sativex)
Oromucosal spray Almost FDA-approved; late-stage clinical trials
Canada, UK, other European countries
Multiple sclerosis spasticity, cancer pain, neuropathic pain
Marijuana Site Reclamation and Restoration Cost Analysis.” U.S. Department of Interior, National Park Service. December 9, 2010 (unpublished data). http://www.whitehouse.gov/ondcp/frequently-asked-questions-and-facts-about-marijuana#difference
www.mghcme.org
Effectiveness of THC compared to prochlorperazine (Compazine) for treating nausea and vomiting
0
5
10
15
20
25
Total Class A Class B Class C
Nu
mb
er
of
pat
ien
ts
Emetic Activity of Chemotherapeutic Agent
Patient Preference for Anti-Emetic Agent
THC
Prochlorperazine
No Preference
Sallan, S. E., Cronin, C., Zelen, M., & Zinberg, N. E. (1980). Antiemetics in patients receiving chemotherapy for cancer: a randomized comparison of delta-9-tetrahydrocannabinol and prochlorperazine. New England Journal of Medicine, 302(3), 135-138.
p=0.005
Of the 25 who expressed preference, 20 preferred THC to prochlorperazine; (degree of preference for either antiemetic not dependent on class of emetic activity related to patient’s chemotherapy); increased appetite
www.mghcme.org
Efficacy of orally-administered cannabis extract for appetite stimulation and quality of life for patients
with advanced cancer
Strasser, F., Luftner, D., Possinger, K., Ernst, G., Ruhstaller, T., Meissner, W., ... & Cerny, T. (2006). Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group.Journal of Clinical Oncology, 24(21), 3394-3400.
www.mghcme.org
Safety and efficacy of nabiximols
• 3 randomized, placebo-controlled, double-blind, parallel-group studies
• n=666 (363 randomized to nabiximols) patients with MS and spasticity
• Outcome: spasticity
• Adverse events were recorded
Wade, D. T., Collin, C., Stott, C., & Duncombe, P. (2010). Meta-analysis of the efficacy and safety of Sativex (nabiximols), on spasticity in people with multiple sclerosis. Multiple Sclerosis, 16(6), 707-714.
www.mghcme.org
Efficacy of smoked marijuana for MS patients with spasticity ( RCT; N= 30)
Corey-Bloom, J., Wolfson, T., Gamst, A., Jin, S., Marcotte, T. D., Bentley, H., & Gouaux, B. (2012). Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. Canadian Medical Association Journal, 184(10), 1143-1150.
Treatment with smoked cannabis resulted in a reduction in patient scores on the modifed Ashworth scale by an average of 2.74 points more than placebo (p < 0.0001). In addition, treatment reduced pain scores on a visual analogue scale by an average of 5.28 points more than placebo (p = 0.008).
www.mghcme.org
Comparative effectiveness of pharmacological treatments for pain
Snedecor, S. J., Sudharshan, L., Cappelleri, J. C., Sadosky, A., Mehta, S., & Botteman, M. (2013). Systematic Review and Meta‐Analysis of Pharmacological Therapies for Painful Diabetic Peripheral Neuropathy. Pain Practice.
Nabixomols (Sativex) least
effective for pain reduction among individuals with
diabetic peripheral neuropathy
www.mghcme.org
Efficacy of smoked THC for chronic neuropathic pain (N=23, cross-over RCT)
0
1
2
3
4
5
6
7
8
0.00% 2.50% 6.00% 9.40%
Pai
n S
core
†
THC Potency
Average Daily Pain
Highest Daily Pain
Lowest Daily Pain
Ware, M. A., Wang, T., Shapiro, S., Robinson, A., Ducruet, T., Huynh, T., ... & Collet, J. P. (2010). Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. Canadian Medical Association Journal, 182(14), E694-E701.
†Pain was scored on a scale from 0 (no pain) to 11 (worst possible pain)
p = 0.023 Participants receiving the 9.4% THC compared to the placebo. No other comparisons were sig. Secondary outcomes: Patients assigned to 9.4% THC had sig better outcomes compared to placebo with respect to getting to sleep, quality of sleep (less periodic wakefulness), and lower proportion anxiety depression on the quality of life measure.
www.mghcme.org
Efficacy of THC for HIV-positive patients with neuropathic pain
Abrams, D. I., Jay, C. A., Shade, S. B., Vizoso, H., Reda, H., Press, S., ... & Petersen, K. L. (2007). Cannabis in painful HIV-associated sensory neuropathy A randomized placebo-controlled trial. Neurology, 68(7), 515-521.
Significant benefit in reducing pain during
active treatment phase, lasting up to
8 days after stopping smoking
Over a 5-day inpatient intervention period, smoking cannabis cigarettes three times a day reduced HIV-SN pain by 34%, significantly more than the 17% reduction with placebo cigarettes. (p=.003) A 30% reduction in pain has been validated as a clinically significant level of improvement. In the current study, half (52%) of those randomized to cannabis experienced at least a 30% reduction in pain, while a quarter (24%) of those randomized to placebo experienced a similar reduction in pain. (p=.004)
www.mghcme.org
www.mghcme.org
Review: Cannabinoids reduce symptoms of Tourette’s syndrome
Expert Opinion on Pharmacotherapy, Volume 4, Issue 10, 2003, pages 1717-1725
Kirsten R Müller-Vahl
Abstract
Currently, the treatment of Tourette’s syndrome (TS) is unsatisfactory. Therefore, there is expanding interest in new therapeutical strategies. Anecdotal reports suggested that the use of cannabis might improve not
only tics, but also behavioural problems in patients with TS. A single-dose, cross-over study in 12 patients, as well as a 6-week, randomised trial in 24 patients, demonstrated that Δ9-
tetrahydrocannabinol (THC), the most psychoactive ingredient of cannabis, reduces tics in TS patients. No serious adverse effects occurred and no impairment on neuropsychological performance was
observed. If well-established drugs either fail to improve tics or cause significant adverse effects, in adult patients, therapy with Δ-THC should be tried. At present, it remains unclear whether herbal cannabis,
different natural or synthetic cannabinoid CB1-receptor agonists or agents that interfere with the inactivation of endocannabinoids, may have the best adverse effect profile in TS
www.mghcme.org
Medical Marijuana Extract in Pediatric Epilepsy
• N=213 subjects aged (pediatric/adult; mean age 11 years)
• DX: Dravet & Lennox-Gestault syndromes (seizures may lead to intellectual disabilities), and 11 other types of epilepsy
• Design: 12 week, open label study • Preparation: Oral suspension of cannabidiol (sponsored
by GW Pharma) • Findings: In 137 of 213 completers, mean 54%
reduction in seizure rate • Conclusion: Cannabidiol may offer treatment to
refractory seizures necessitating further RCT’s
(Devinsky et al, Am Acad Neurology Presentation, 2015)
www.mghcme.org
American Academy of Pediatrics: Position Statement on Medical Marijuana for
Children
• No accepted indications for medical marijuana in children
• Acknowledges that there may be exceptions for “compassionate use” of marijuana medically for children with debilitating diseases
• Recognizes small trials of CBD for seizures (Cochrane report 2012); work with dronabinol for nausea
• In general, does not support the legalization or medical use of marijuana in children
• Recommends scheduling from C- I to C-II to allow clinical trials
(Am Acad Peds: 2015)
www.mghcme.org
The controversy regarding medical marijuana
1.Health risks of smoked marijuana
2.Addictiveness of marijuana
3.Influence on youth drug use
www.mghcme.org
Health risks of smoked
marijuana
“3-4 cannabis cigarettes a day are associated with the same evidence of acute and chronic bronchitis and the same degree of damage to the bronchial mucosa as 20 or more tobacco cigarettes a day. Cannabis smoking is likely to weaken the immune system. Infections of the lung are due to a combination of smoking-related damage to the cells lining the bronchial passage and impairment of the principal immune cells in the small air sacs caused by cannabis.”
-- British Lung Foundation
Chronic bronchitis
Cough: most days
Phlegm
Shortness of breath
Wheezing
Chest sounds
Pneumonia
Overall chest finding
FEV1/FVC ratio <70%
Tobacco Users
Marijuana Users
0.0 1.0 2.0 4.0 6.0
Odds Ratio of Smokers vs. Non-smokers
Adjusting for gender, age, current asthma ; Marijuana analyses also controlled for tobacco
Moore, B. A., Augustson, E. M., Moser, R. P., & Budney, A. J. (2005). Respiratory effects of marijuana and tobacco use in a US sample. Journal of general internal medicine, 20(1), 33-37.
*
*
* *
* *
*
* *
* *
* *
*p<0.05
Res
pir
ato
ry S
ymp
tom
/Co
nd
itio
n
www.mghcme.org
Health risks of smoked
marijuana
All sites
Tobacco-related
Colorectal
Lung
Melanoma
Prostate
Breast
Cervix
Can
cer
Site
Women
Men
“There is very little evidence that smoking marijuana as a means of taking it represents a significant health risk…there have been no reported cases of lung cancer or emphysema….”
-- Lester Grinspoon, MD
Emeritus Professor of Psychiatry
Harvard Medical School 0.0 0.5 1.0 1.5 2.0
RR of cancer incidence comparing MJ users to non-users
Sidney, S., Quesenberry Jr, C. P., Friedman, G. D., & Tekawa, I. S. (1997). Marijuana use and
cancer incidence (California, United States). Cancer Causes & Control, 8(5), 722-728.
Adjusting for sociodemographic factors, alcohol and tobacco use
www.mghcme.org
Health risks of smoked
marijuana
Motor vehicle collision risk
Asbridge, M., Hayden, J. A., & Cartwright, J. L. (2012). Acute cannabis consumption and motor vehicle collision risk: systematic review of observational studies and meta-analysis. BMJ: British Medical Journal, 344.
www.mghcme.org
Health (and societal) risks of
smoked marijuana
Nutt, D. J., King, L. A., & Phillips, L. D. (2010). Drug harms in the UK: a multicriteria decision analysis. The Lancet, 376(9752), 1558-1565.
20 drugs ranked by overall harm along
16 criteria
www.mghcme.org
Getting the Jump on the Marijuana Problem
www.mghcme.org
Gray Matter Density (N=20/group; 18-25 yr olds) (Gilman et al. J Neurosci 34: 2014)
y = 66 y = 64
Marijuana > controls
Title
0 1 2 30.2
0.4
0.6
0.8
Joints per Occasion
VB
M
p = 0.002
Smoking Occasions per Day
VB
M
0 1 2 30.2
0.4
0.6
0.8
p = 0.001
Smoking Occasions per day Joints per Occasion
2.5
5.0
y = 68
Gray Matter Density in Nucleus Accumbens Increases with Marijuana Dose
www.mghcme.org
Lisdahl et al. Frontiers in Psychiatry. 2013. 4(53). Gruber et al. Drug Alcohol Depend. 2012 121, 159–162 Gruber et al. Exp. Clin. Psychopharmacol. 2011 19, 231–242.
The Impacts of adolescent marijuana use onset on cognition, brain structure, and function
www.mghcme.org
5 year Follow-Up of New Onset Cases of Any Drug Use Disorder (Largely Marijuana) and Current Executive Function Deficits in
Adolescence
Su
bje
cts
Wit
h C
urr
en
t Ex
ecu
tive
Dys
fun
ctio
n
(%)
Control
N=154
Pairwise Comparisons: a p < 0.05 vs. Controls; b p < 0.05 vs. ADHD
(Wilens et al J Am Acad Child Adolesc Psych: 2011)
a
a, b
www.mghcme.org
Summary
• Marijuana confers therapeutic benefit – FDA-approved medications addressing nausea in AIDS/cancer – May not be as effective as other meds for chronic pain – Specific components (e.g. THC vs cannabidiol) relationship to efficacy unclear
• Strong evidence of both oral and smoked marijuana alleviating spasticity among MS patients
• Lack of trials comparing smoked MJ to oral/spray THC:CBD – Thus, it is currently unclear whether the benefits of smoked MJ (net of
smoking-related risks) is greater than oral/other FDA-approved THC-based medications, and for which specific medical conditions
• Marijuana has substantial addiction potential • Use in adolescents <16 years of age particularly problematic for potential
structural brain changes and lasting neurocognitive dysfunction • Given the paucity of well conducted trials for specific indications,
physician recommendations for smoked MJ remains on a case-by-case basis