Marijuana:
What Does The Evidence Show?
Allen C. Bowling, MD, PhD
Physician Associate
Colorado Neurological Institute (CNI)
Marijuana and Neurological
Disease
Increasing legalization and availability
Neurologically relevant medical studies
BUT huge challenges for public and
professionals:
– Emotional response
– Political/media/business interests
– Difficult to find objective safety and
effectiveness information
Marijuana Information
 “Cannabis is effective for treating epilepsy,
Parkinson’s disease, depression, and migraine.”
 “[In MS], numerous studies have reported
improvement in tremor, sexual
dysfunction,…vision dimness, dysfunctions of
walking and balance (ataxia), and memory loss.”
 “Research has shown that medical
marijuana…can alleviate symptoms of Tourette’s.”
Summary
Basics of Marijuana
The Evidence
– Scientific studies
– Clinical studies
• MS, epilepsy, Parkinson’s disease and other
movement disorders
• Pain, anxiety, sleep
– Safety
Information Resources
States with Medical/Recreational
Marijuana (Illegal at Federal Level)
Proposed Marijuana Bills/Initiatives
in 2014
Medical Marijuana in Colorado:
“Approved Conditions”
“persistent muscle spasms,
including those that are
characteristic of multiple sclerosis”
“seizures, including those that are
characteristic of epilepsy”
“severe pain”
Variability of Marijuana Plants
and Products
Two major “subspecies”
– Cannabis sativa: mainly
THC
– Cannabis indica: THC and
CBD
Many different hybrids
Other variables
– Growing and storage
– State of maturity
– Processing/formulation
Forms of Marijuana
 Leaf
– Smoked, eaten (“edibles”), vaporized
 Plant resin: “hashish”
– Smoked, eaten
 Oil extracts
– Nabiximols (Sativex), Cannador, many others
that are unregulated and non-standardized
 Single molecule preparations
– THC: Marinol, dronabinol
– Chemical variant of THC: Cesamet, nabilone
“Cannabinoids”
Many different
potentially active
molecules:
– THC: delta-9tetrahydrocannabinol
– CBD: cannabidiol
– About 60 others
Marijuana
 Actions
– CB1 receptors
• Nerve cells
• “Homeostasis”
– CB2 receptors
• Immune cells
–Multiple other effects
-Antioxidant, excitotoxicity, calcium flux
“Endocannabinoids”
Analagous to endorphins
Two main
endocannabinoids
– Anandamide
• 100 times less potent
than THC
• ? “endorphin high”
– 2-AG
Full range of functions
unknown
“Endocannabinoids”
Analagous to endorphins
Two main
endocannabinoids
– Anandamide
• 100 times less potent
than THC
• ? “endorphin high”
– 2-AG
Full range of functions
unknown
THC
“Endocannabinoids”
Analagous to endorphins
Two main
endocannabinoids
– Anandamide
• 100 times less potent
than THC
• ? “endorphin high”
THC
– 2-AG
Full range of functions
unknown
Anandamide
Summary
Basics of Marijuana
The Evidence
– Scientific studies
– Clinical studies
• MS, epilepsy, Parkinson’s disease and other
movement disorders
• Pain, anxiety, sleep
– Safety
Information Resources
Neurological Relevance:
Scientific Studies
Nerve Cell Function
– Normalizes release of many different
neurotransmitters
Nerve Cell Survival
– Promotes survival by many
mechanisms
Immune System Function
– Anti-inflammatory effect
Neurological Relevance:
Clinical Studies
Multiple Sclerosis
Epilepsy
Parkinson’s Disease and Other
Movement Disorders
Pain
Sleep Disorders
Anxiety
AAN Classification Scheme:
Classes of Controlled Trials
Class I
– Randomized, controlled, objective outcome
– Extra criteria: concealed allocation, primary
outcome clearly defined, exclusion and
inclusion criteria clearly defined, adequate
accounting for dropouts and crossovers
Class II: lacks one criterion
Class III: all other controlled trials with
independent outcome assessment
Review of Alternative
Medicine and MS
 Summary of evidence-based guideline:
complementary and alternative medicine in
multiple sclerosis. Neurology 2014;82:1-10.
 Report of the Guideline Development Committee
of the American Academy of Neurology
– Yadav, Bever, Bowen, Bowling, Weinstock-Guttman,
Cameron, Bourdette, Gronseth, Narayanaswami
 Medline search: 1970-Sept 2013
Review of Marijuana and
Neurological Disorders
 Systematic review: Efficacy and safety of medical
marijuana in selected neurologic disorders.
Neurology 2014;82:1556-1563.
 Report of the Guideline Development Committee
of the American Academy of Neurology
– Koppel, Brust, Fife, Bronstein, Youssof, Gronseth, Gloss
 Medline search: 1948-Jan 2013
 Disorders
– MS: spasticity, pain, bladder dyfunction, tremor
– Dyskinesias: Huntington’s disease, levodopa-induced in
Parkinson’s disease
– Cervical dystonia, tics of Tourette syndrome, epilepsy
Studies of Marijuana and
Neurologic Conditions
Class I Class II Class III
TOTAL
MS
6
4
9
19
Epilepsy
0
0
0
0
Parkinson’s
1
0
1
2
Huntington’s
1
1
1
3
Tourette
0
1
1
2
Dystonia
0
0
1
1
MS: Two Recent Reviews
 The largest and most convincing research
 Formulations
–
–
–
–
THC: 4
Oral cannabis extract (Cannador): 8
Nabiximols (Sativex): 8
Smoked: 2
MS: Two Recent Reviews
Some level of effectiveness
– “Subjective spasticity,” pain
• Cannador, Nabiximols, THC
– Urinary frequency
• Nabiximols
Probably ineffective
– Objective spasticity, tremor
• Cannador, Nabiximols, THC
 Insufficient data: smoked
Epilepsy
Marijuana and THC: anti-convulsant or
pro-convulsant?
CBD: appears anti-convulsant
No Class I, II, or III studies
2 Class IV with no benefit, many anecdotes
Survey of 19 parents, CBD-enriched
– 84% improved: 11% seizure-free, 42% with
more than 80% decrease
– Porter, Epilepsy & Behav 2013;29:574-577.
Parkinson’s Disease
2 studies: one class I, one class III
CBD extract not effective for
“dyskinesia”
Class IV study
– “Open label,” smoked
– Improvement in tremor, rigidity, and
bradykinesia
Huntington’s Disease and
Others
Huntington’s
– 3 studies: Classes I, II, III
– Nabilone possibly effective for chorea,
but inconsistent results and limited
studies
Tourette and Dystonia
– Very limited studies
– No conclusions possible
Pain
18 controlled trials in pain
– Classes I, II, and III
Formulations
– Smoked: 4
– Extract: 7
– THC: 2
– Nabilone: 4
– Unique molecule: 1
Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer
pain; a systematic review of randomized trials. Brit J Clin Pharmacol
2011;72:735-744.
Pain
15/18 reported improvement in pain
– Especially central and peripheral nerve pain
– For painful HIV neuropathy, possibly the
most effective treatment
– Also fibromyalgia and rheumatoid arthritis
4/18 also reported improvement in sleep
No controlled studies in headache,
including migraine
Sleep Disorders
39 clinical studies
– Quality: extremely variable, generally poor
Formulations
– Smoked: 7
– THC or Nabilone: 14
– Cannador or Nabiximols: 14
– Other oral form: 4
Gates PJ, et al. The effects of cannabinoid administration on sleep: a
systematic review of human studies. Sleep Med Rev 2014;1-11.
Sleep Disorders
Impossible to make firm conclusions
– Many different conditions and
formulations
General observations
– “Recreational use”
• May interrupt sleep cycle and cause nonrestful sleep
– Use with condition that interrupts sleep
• May improve sleep quality and decrease nighttime disturbances
Anxiety
A very complicated story!
Marijuana use is significantly higher
in those with anxiety
Paradoxes
– Limited use: may cause relaxation but
also panic, paranoia, and psychosis
– Regular use
• Short-term: may decrease anxiety
• Long-term: may increase anxiety and
decrease effectiveness of anxiety meds
Tambaro S, et al. Cannabinoid-related agents in the treatment of anxiety
disorders: current knowledge and future perspectives. Recent Patents CNS
Drug Discov 2012;7:25-40.
Anxiety
Variable effects may be due to
different components
– Marijuana and THC
• Modest doses: decreased anxiety
• High doses: panic, psychosis, phobia
– CBD
• More consistent anti-anxiety effect
Marijuana:
Side Effects
 Generally well tolerated in neurological
clinical trials
 No risk of lethal overdose (unlike alcohol)
 No clear increase in risk of COPD or
cancer of lung, head, and neck (?anticancer effect)
Marijuana:Side Effects
Addiction
Decreased achievement
Motor vehicle accidents
Chronic bronchitis
Abnormal brain development
Progression to other drugs
Schizophrenia
Depression or anxiety
CONFIDENCE
High
High
High
High
Medium
Medium
Medium
Medium
Volkow et al, Adverse health effects of marijuana use. New Eng J
Med 2014;370:2219-2227.
Marijuana: Neurologically
Relevant Side Effects
Dizziness, impaired balance,
incoordination, visual difficulties,
seizures, leg weakness, sedation,
lightheadedness, psychosis,
hallucinations, associated with
strokes (and heart attacks)
Also, interactions with many
neurological meds
MRI Changes: Cognition
Recent MS study
– Users had more
cognitive
impairment and
more
abnormalities on
functional MRI
– Limitations of
study
– Pavisian B, et al. Effects of cannabis on cognition in patients with
MS. Neurol 2014;82:1879-1887.
MRI Changes: Cognition
?Neurotoxicity
– “Meta-analysis”--14 studies
– Consistently smaller
hippocampus size in users
• Is cannabis neurotoxic for
the healthy brain? A metaanalytic review of structural
brain alterations in nonpsychotic users, Rocchetti et
al, Psych Clin Neurosci
2013;67:483-492.
MRI Changes: Addiction?
Amygdala and Nucleus Accumbens:
emotion and motivation
• Cannabis use is quantitatively associated with nucleus
accumbens and amygdala abnormalities in young adult
recreational user, Gilman et al, J Neurosci
2014;34:5529-5538.
Marijuana:
Uncertain Potency and Purity
Study of edibles in Colorado (2014)
•
•
•
•
N=13
No products contained the amount of THC on label
1 product with 50% more
3 products with 0.2-0.4%
Colorado labelling
• “Warning: There may be health risks associated with the
consumption of this product…The product was produced
without regulatory oversight for health, safety, or
efficacy…The marijuana product contained within this
package has not been tested for potency, consume with
caution. The marijuana product contained within this
package has not been tested for contaminants.”
Unanswered Questions,
Unresolved Issues
Many studies are with standardized
preparations—not available in the US
Products that are available
– Many are non-standardized, non-regulated,
and high in THC
How to translate research studies with
oral preparations to smoked products?
Unanswered Questions,
Unresolved Issues
Are some hybrids more effective or safer?
What dose, frequency, and preparation?
“Combination therapy” with meds?
Relative safety and effectiveness of
marijuana vs conventional meds or
procedures?
Future Directions
Studies of specific strains
– Low, medium, and high THC
– Significant differences: anxiety, appetite,
others
– Brunt et al, 2014, J Clin Psychopharm
Increase endocannabinoid levels
– Many possibilities
– Promising studies in animals
– Pryce et al, 2013, Mult Scler J
Summary
Thousands of years of human use, but
scientific understanding and evidencebased medical use is in its infancy
Extremely complex pharmacology
Dozens of potentially active compounds
Complex neurological conditions
Limited safety information
Thoughtful, evidence-based risk:benefit
analysis
Summary:
Examples of Use
MS
– Reasonable?—moderate-severe disability
with severe pain and/or spasticity
– Unreasonable—college student, rare
spasms
Epilepsy
– Reasonable?—severe seizure disorder not
treatable with meds, surgery is next option
– Unreasonable—2 seizures, never taken
meds
Information Sources
Objective, updated, user-friendly
information resource for general
public and professionals
Information Sources
Objective, updated, user-friendly
information resource for general
public and professionals
–DOES NOT EXIST!
States with Medical/Recreational
Marijuana (Illegal at Federal Level)
Information Resources
 Lay articles
– King ME. Medical
marijuana: hype or
hope? Momentum Fall
2014, pp. 28-35.
– Bowling AC. Marijuana
and MS—an unfinished
story. Momentum Fall
2010, pp. 33-35.
 Book
– Iversen LL. The Science
of Marijuana. Oxford
Univ. Press: 2010.
References
 Books
– Bowling AC. Optimal Health With Multiple Sclerosis: A Guide to
Integrating Lifestyle, Alternative, and Conventional Medicine. New
York: Demos, 2014.
– Bowling AC. Complementary and alternative medicine: practical
considerations. In Rae-Grant A, Fox R, Bethoux F, eds. Multiple
Sclerosis and Related Disorders: Diagnosis, Medical Management, and
Rehabilitation. New York: Demos, 2013, 243-249.
– Iversen LL. The Science of Marijuana. New York: Oxford University
Press, 2008.
– Jellin JM, Gregory PJ, Batz F, et al. Pharmacist’s Letter/ Prescriber’s
Letter Natural Medicines Comprehensive Database. Stockton, CA:
Therapeutic Research Faculty, 2014.
References
 Journal Articles
– Aggarwal SK. Cannabinergic pain medicine. Clin J Pain 2013;29:162171.
– Anon. Adverse effects of marijuana. Prescrire Int 2011;20:18-23.
– Baca R. Labels fudge THC levels: with no standard for testing, buyers
can’t trust items’ potency. Denver Post 2014 March 9:1A, 17A.
– Baker D, et al. The therapeutic potential of cannabis. Lancet Neurol
2003;2:291–298.
– Borgelt LM, et al. The pharmacologic and clinical effects of medical
cannabis. Pharmacother 2013;33:195-209.
– Bowling AC. Cannabinoids in MS—are we any closer to knowing how
best to use them? Mult Scler 2006; 12:523-525.
– Bowling AC. Worthless weed or pot of gold? Int J MS Care
2004;5:138,166.
– Bowling AC. Marijuana and MS—an unfinished story. Momentum, Fall
2010, 33-35.
References
– Corey-Bloom J, et al. Smoked cannabis for spasticity in multiple
sclerosis: a randomized, placebo-controlled trial. CMAJ 2012;184:11431150.
– Devinsky O, et al. Cannabidiol: pharmacology and potential therapeutic
role in epilepsy and other neuropsychiatric conditions. Epilepsia
2014;55:791-802.
– Gates PJ, et al. The effects of cannabinoid administration on sleep: a
systematic review of human studies. Sleep Med Rev 2014;1-11.
– Gilman JM, et al. Cannabis use is quantitatively associated with nucleus
accumbens and amygdala abnormalities in young adult recreational
users. J Neurosci 2014;34:5529-5538.
– Gordon AJ, et al. Medical consequences of marijuana use: a review of
current literature. Curr Psych Rep 2013;15:419.
– Greenberg HS, et al. Short-term effects of smoking marijuana on balance
in patients with multiple sclerosis and normal volunteers. Clin Pharmacol
Ther 1994;55:324-328.
– Kedzior KK, Laeber LT. A positive association between anxiety disorders
and cannabis use or cannabis use disorders in the general population—a
meta-analysis of 31 studies. BMC Psychiatr 2014;14:136.
– King ME. Medical marijuana: hype or hope? Momentum Fall 2014:28-35.
References
– Koppel BS, et al. Systematic review: efficacy and safety of medical
marijuana in selected neurologic disorders: report of the Guideline
Development Subcommittee of the American Academy of Neurology.
Neurol 2014;82:1556-1563.
– Lotan I, et al. Cannabis (medical marijuana) treatment of motor and nonmotor symptoms of Parkinson disease: an open-label observational study.
Clin Neuropharm 2014;37:41-44.
– Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer
pain; a systematic review of randomized trials. Brit J Clin Pharmacol
2011;72:735-744.
– Pavisian B, et al. Effects of cannabis on cognition in patients with MS.
Neurol 2014;82:1879-1887.
– Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enriched
cannabis use in pediatric treatment-resistant epilepsy. Epil Behav
2013;29:574-577.
– Pryce G, et al. Control of experimental spasticity by targeting the
degradation of endocannabinoids using selective fatty acid amide
hydrolase inhibitors. Mult Scler J 2013;19:1896-1904.
– Rocchetti M, et al. Is cannabis neurotoxic for the healthy brain? A metaanalytical review of structural brain alterations in non-psychotic users.
Psychiatr Clin Neurosci 2013;67:483-492.
References
– Secades-Villa R, et al. Probability and predictors of the cannabis
gateway effect: a national study. Int J Drug Policy 2014;
10.1016/j.drugpo.2014.07.011
– Tambaro S, et al. Cannabinoid-related agents in the treatment of
anxiety disorders: current knowledge and future perspectives. Recent
Patents CNS Drug Discov 2012;7:25-40.
– Thomas G, et al. Adverse cardiovascular, cerebrovascular, and
peripheral vascular effects of marijuana inhalation: what cardiologists
need to know. Amer J Cardiol 2014;113:187-190.
– Volkow ND, et al. Adverse health effects of marijuana use. New Eng J
Med 2014;370:2219-2227.
– Yadav V, et al. Summary of evidence-based guideline: complementary
and alternative medicine in multiple sclerosis: report of the Guideline
Development Subcommittee of the American Academy of Neurology.
Neurol 2014;82:1-10.
– Zajicek JP, Apostu VI. Role of cannabinoids in multiple sclerosis. CNS
Drugs 2011;25:187-201.
– Zajicek J, et al. Effect of dronabinol on progression in progressive
multiple sclerosis (CUPID): a randomized, placebo-controlled trial.
Lancet Neurol 2013;12:857-865.
References
– Zajicek J, Fox P, Sanders H, et al. Cannabinoids for treatment of
spasticity and other symptoms related to multiple sclerosis (CAMS
study): multicentre randomised placebo-controlled trial. Lancet
2003;362:1517–1526.
– Zajicek J, Sanders HP, Wright DE, et al. Cannabinoids in multiple
sclerosis (CAMS) study: safety and efficacy data for 12 months follow
up. J Neurol Neursurg Psych 2005;76:1664–1669.