Transcript Cannabis and MS

Medical Marijuana
Denis J. Petro, MD
Cynosure Neuroscience
ANA Position Statement on
Medical Marijuana
1. The education of registered nurses and other health care
practitioners regarding appropriate evidence-based
therapeutic use of marijuana including those nonsmoked forms of delta-9-tetrahydrocannabinol (THC) that
have proven to be therapeutically efficacious
2. Protection from criminal or civil penalties for patients using
medical marijuana as permitted under state laws
3. Exemption from criminal prosecution; civil liability; or
professional sanctioning, such as loss of licensure or
credentialing, for health care practitioners who prescribe,
dispense or administer medical marijuana in accordance
with state law.
4. Reclassification of marijuana’s status from a Schedule I
controlled substance into a less restrictive category.
5. Confirmation of the therapeutic efficacy of medical
marijuana.
Context
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History of Cannabis as Medicine
How Science Works
Pharmaceutical Industry
Regulatory Authorities
Criminal Justice System
Media
Personal Experience
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Observations
1960s
TIRR, VA system
1970s
Penn State Univ.
FDA
1980s-00s
Research
Cannabis in Cancer
Chemotherapy
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Neurology. 1978 Feb;28(2):174-8.Neurologic complications of
acute myelomonoblastic leukemia of four years' duration.･Ballard
JO, Towfighi J, Brennan RW, Saleem S, Eyster ME.An adult
with acute nonlymphoblastic leukemia involving the central
nervous system is presented. Unusual features included: (1)
Focal signs and radiographic evidence of sagittal sinus occlusion
early in the course of disease; (2) progressive meningeal,
cranial nerve, and spinal nerve involvement despite a 4-year
bone marrow remission; (3) intracerebral tumor formation, and
(4) retrobulbar optic neuritis associated with microscopic
findings of herpeslike viral particles. The incidence of clinically
overt neurologic disease in adults with acute nonlymphoblastic
leukemia seems to have increased in tandem with improved
chemotherapy. The prophylactic treatment of the central
nervous system during prolonged remission of adult acute
nonlymphoblastic leukemia may prove of benefit to these
patients.PMID: 271773 [PubMed - indexed for MEDLINE]
Petro DJ. Marihuana as a therapeutic agent for
muscle spasm or spasticity.
Psychosomatics 1980 21: 81- 85.This is a
case report of two cases, one of whom had
MS. Nocturnal leg spasms were relieved by
smoking cannabis within five minutes.
Abstention led to increased spasticity and
pain, again relieved by use of cannabis.
THC
Petro & Ellenberger. Treatment of human spasticity with
delta 9-tetrahydrocannabinol
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J Clin Pharmacol 1981 21: (8-9 Suppl):
413S-416S.Nine patients with spasticity
related to MS were examined by a blinded
observer before and after 90 minutes
intervals after oral capsules with 10 mg g,
5 mg or no synthetic THC. THC, but not
placebo, was associated with a reduced
spasticity score lasting for about 4 hours.
Big improvements with 4/9 with THC and
1/9 with placebo. Subjective highs were
experienced by one patient after THC and
one after placebo.
Joseph Heller
Catch 22
• There was only one catch and that was Catch-22, which
specified that a concern for one's safety in the face of
dangers that were real and immediate was the process of
a rational mind. Orr was crazy and could be grounded. All
he had to do was ask; and as soon as he did, he would no
longer be crazy and would have to fly more missions. Orr
would be crazy to fly more missions and sane if he didn't,
but if he was sane he had to fly them. If he flew them he
was crazy and didn't have to; but if he didn't want to he
was sane and had to. Yossarian was moved very deeply
by the absolute simplicity of this clause of Catch-22 and let
out a respectful whistle."That's some catch, that Catch-22,"
he [Yossarian] observed."It's the best there is," Doc
Daneeka agreed.
U.S. Government
Compassionate Investigational
New Drug Program
Federal program created to fit within
scope of the 1961 UN Single
Convention on Narcotic Drugs
Malec et al. Cannabis effect on
spasticity in spinal cord injury.
Arch Phys Med rehabil 1982 63: 116-8.
Questionnaire to spinal cord injury patients.
9/24 users reported no spasticity while
using cannabis, 11/24 reported some
benefit.
Marinol 1986
Delta-9 THC in capsule formulation
Approved for Nausea & Vomiting due to Cancer Chemo
Appetite/weight loss due to AIDS
Oral use-in sesame oil (10-20% absorbed)
Onset in 1/2 to 1 hr, Peak 2-4 hr, 1/2 life 4hr
Single dose with detectable metabolites > 35 days
DEA Petition 1986-88
Request to move Marijuana to DEA Schedule II filed in 1972
-Hearings lasted from 1986 to 1988
-Affidavit filed by DJP, called to testify by DEA
-Judge Young ruled that Marijuana should be reclassified as a
Schedule II drug under CSA and made available for medical
purposes (September 6, 1988)
-DEA ignored ruling
Meinck et al. Effect of cannabinoids on spasticity and
ataxia in multiple sclerosis.
J Neurol 1989 263: 120-2.Chronic motor
handicaps of one MS patient improved
acutely while smoking cannabis cigarette.
Cannabinoid Drugs 1986
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delta-9-Tetrahydrocannabinol (Δ9-THC, THC) and delta-8-tetrahydrocannabinol (Δ8THC), mimic the action of anandamide. The THCs produce the high associated with
cannabis by binding to the CB1 cannabinoid receptors in the brain.
Cannabidiol (CBD), non-psychoactive. CBD has anti-inflammatory effects.
CBD shares a precursor with THC and is the main cannabinoid in low-THC
Cannabis strains.
Cannabinol (CBN), a degradation product of THC, produces a depressant
effect.
Greenberg et al. Short-term effects of
smoking marijuana on balance in
patients with multiple sclerosis and
normal volunteers. Clin Pharm Ther
1994 55: 324-8.
Randomised, double blind study of inhaled cannabis on
postural (balance) responses in normal subjects and MS
patients. Technical paper that says that cannabis gives
patients and MS sufferers worse balance control.
1990s
Cannabinoid receptors
USA State Propositions
Prosecutions
IOM report
Cannabinoid Receptors
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Two types identified.
CB1
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» Brain (also in lung, liver, kidney)
Brain areas include cortex (neocortex, pyriform cortex, hippocampus, amygdala)
Basal Ganglia, thalmic and hypothalamic nuclei.
Cerebellar cortex
Brain stem (periaqueductal gray)
CB2
» Immune system and Hematopoietic cellos
IOM Report 1998
White House Office of National Drug Control Policy (ONDCP)
requested a review of the scientific evidence re:health benefits
and risks of Marijuana and constituent cannabinoids.
Response to 1996 referenda in California and Arizona permitting
the use of Marijuana as medicine.
Three 2-day workshops (Irvine, New Orleans, Washington,DC)
gathering scientific input.
IOM Recommendations
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1. Research should continue into effects of synthetic and plant-derived
cannabinoids.Different cannabinoids have different effects. Focus on pain relief,
control of nausea and vomiting, and appetite stimulation.
2. Clinical trials should be conducted to develop rapid-onset, reliable, and safe
delivery systems.
3. Psychological effects such as anxiety reduction and sedation should be evaluated
in clinical trials.
4. Studies to define the individual health risks of smoking marijuana should be
conducted, particularly among populations in which marijuana use is
prevalent.Smoked marijuana is a crude delivery system and not recommended for
medical use.
5. Clinical trials should focus on short term use (less than 6 months) in conditions for
which there is a reasonable expectation of efficacy with IRB approval and with data
relative to efficacy. Isolated cannabinoids and their synthetic derivatives offer the
best choices for clinical study and clinical trials of smoked marijuana should serve as
a first step toward the development of nonsmoked, rapid-onset cannabinoid delivery
systems.
6. Short-term use of smoked marijuana (less than 6 months) for patients with
debilitating symptoms must meet the following conditions:
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Failure of all approved medications to provide relief
The symptoms can reasonably be expected to be relieved by rapid-onset cannabinoids
Treatment is administered under medical supervision with efficacy assessment; and
IRB guidance and oversight.
Mechanism of Action in Spasticity
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Nature 404, 84-87 (2 March 2000) | doi:10.1038/35003583; Received 18
August 1999; Accepted 20 January 2000
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Cannabinoids control spasticity and tremor in a multiple sclerosis model
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David Baker1, Gareth Pryce1, J. Ludovic Croxford1, Peter Brown2, Roger
G. Pertwee3, John W. Huffman4 and Lorna Layward1.Neuroinflammation
Group, Department of Neurochemistry, Institute of Neurology, University
College London, 1 Wakefield Street, London WC1N 1PJ and the Institute
of Ophthalmology, UCL, London EC1V 9EL, UK2.The Medical Research
Council Human Movement and Balance Unit, National Hospital for
Neurology and Neurosurgery , Queen Square, London, WC1N 3BG,
UK3.Department of Biomedical Sciences, Institute of Medical Sciences,
University of Aberdeen, Foresterhill , Aberdeen AB25 2ZD,
UK4.Department of Chemistry, Clemson University, Clemson, South
Carolina 29634-1905 , USA5.Multiple Sclerosis Society of Great Britain
and Northern Ireland , 25 Effie Road, London SW6
Mechanism (continued)
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Chronic relapsing experimental allergic encephalomyelitis (CREAE)
is an autoimmune model of multiple sclerosis. Although both these
diseases are typified by relapsing-remitting paralytic episodes, after
CREAE induction by sensitization to myelin antigens Biozzi ABH
mice also develop spasticity and tremor. These symptoms also
occur during multiple sclerosis and are difficult to control. This has
prompted some patients to find alternative medicines, and to
perceive benefit from cannabis use.
Although this benefit has been backed up by small clinical studies,
mainly with non-quantifiable outcomes, the value of cannabis use in
multiple sclerosis remains anecdotal. Here we show that
cannabinoid (CB) receptor agonism using R(+)-WIN 55,212, 9tetrahydrocannabinol, methanandamide and JWH-133 quantitatively
ameliorated both tremor and spasticity in diseased mice. The
exacerbation of these signs after antagonism of the CB1 and CB2
receptors, notably the CB1 receptor, using SR141716A and
SR144528 indicate that the endogenous cannabinoid system may be
tonically active in the control of tremor and spasticity. This provides
a rationale for patients' indications of the therapeutic potential of
cannabis in the control of the symptoms of multiple sclerosis, and
provides a means of evaluating more selective cannabinoids in the
future.
2000s
State Laws enacted for
patient access
GW PharmaceuticalsSativex
GW Pharmaceutical PLC
-UK-based pharmaceutical company developing Sativex
Oromucosal Spray.
-Available in 26 countries around the world.
-Sativex approved by Health Canada in 2005 for the relief of
neuropathic pain in MS (marketed by Bayer).
-Began clinical trial of Sativex in USA in 2007 as adjunctive
treatment of cancer pain.