The medical and legal challenges of cannabis …...The medical and legal challenges of cannabis...
Transcript of The medical and legal challenges of cannabis …...The medical and legal challenges of cannabis...
The medical and legal challenges of cannabis legalization
Daniele PiomelliAnatomy and Neurobiology, Biochemistry and Pharmacology
Center for the Study of Cannabis,University of California, Irvine
UC Center, SacramentoFebruary 27, 2019
Cannabis: a brief history
Cannabis is listed in the USP as analgesic, antispasmodic
1854-1942
1937 Marihuana Tax Act:Cannabis becomes illegal
Cannabis sativa L.
1944-1964 Discovery of THC
1970 Controlled Substance Act:Illegality is confirmed
1988-1990 Discovery of cannabinoidreceptors
1992-1999 Discovery of the brainendocannabinoid system
Cannabis is introduced inmodern science
1845
2018 Medical use of cannabis legal in 30 States and DC
How does cannabis work?
Cannabis sativa L.
Δ9-THC
Cannabinoid receptors
Brain, peripheral neurons,adipocytes, hepatocytes, etc.
Innate and adaptive immune cells(B lymphocytes, macrophages)
Two cannabinoid receptors
CB1 CB2
Stress, pain, energy balance Immune response?
CB1: main cannabinoid receptor in the human brain
Δ9-THC
The body’s own cannabis
painfeeding
emotioncognition
reward
Cannabinoid
receptors
Endocannabinoids
Sixteen-member panel, assisted by NASEM staff
NASEM reportJanuary 2017
Focus on ‘systematic reviews’
Twenty-four thousand primary studies from 1999-2016
468-page report;Fifteen conclusions and four recommendations
Therapeutic effects(Cannabis or cannabinoids)
Conclusive or substantial evidence of effectiveness:• Chronic pain in adults (substantial)
• Chemotherapy-induced nausea (conclusive)• Spasticity in MS (substantial)
Limited evidence of effectiveness:• Weight loss in persons with HIV/AIDS
• Tourette syndrome• PTSD
Moderate evidence of effectiveness:• Sleep apnea and sleep disturbances associated
with fibromyalgia, chronic pain and MS
Therapeutic effects
Insufficient evidence to support or refute effectiveness:• Cancers (including glioma)• Anorexia nervosa, cachexia• Irritable bowel syndrome
• Epilepsy*• ALS
• Huntington’s disease• Parkinson’s disease
Limited evidence of ineffectiveness:• Alzheimer’s dementia
• Glaucoma**
* Epidiolex® (CBD) approved for some forms of child epilepsy after Committee’s deadline.
** Due to short duration of action.
Qualifying conditions for cannabis use in California
CancerAnorexia
AIDSChronic pain
SpasticityCachexia
Persistent muscle spasms, including those associated with multiple sclerosisSeizures, including, but not limited to, those associated with epilepsy
Severe nauseaGlaucomaArthritis
Migraines
Any other chronic or persistent medical symptom that substantially limitsthe ability of the person to conduct one or more major life activities (asdefined by the Americans with Disabilities Act of 1990) or, if not alleviated,may cause serious harm to the patient’s safety or physical or mental health.
Cannabis as a Schedule-I substance
The Controlled Substances Act of 1970
Signing of the Controlled Substances Act, October 27, 1970
The Controlled Substances Act of 1970
Signing of the Social Security Act, August 14, 1935
The Marihuana Tax Act of 1937
Cannabis as a Schedule-I substance
The Controlled Substances Act of 1970
The term "marihuana" means all parts of the plant Cannabis sativa L., whether growing or not; theseeds thereof; the resin extracted from any part of such plant; and every compound, manufacture,salt, derivative, mixture, or preparation of such plant, its seeds or resin. Such term does not includethe mature stalks of such plant, fiber produced from such stalks, oil or cake made from the seeds ofsuch plant, any other compound, manufacture, salt, derivative, mixture, or preparation of such maturestalks (except the resin extracted therefrom), fiber, oil, or cake, or the sterilized seed of such plantwhich is incapable of germination.
Criminal plants
Opium
MDMAHeroin
LSDMethaqualone
HydromorphoneMethadoneOxycodone
FentanylMorphineCodeineCocaine
AmphetamineMethamphetamineMethylphenydate
etc…
Scheduled chemicals ‘Marihuana’Peyote
Scheduled plants
A botanical intermission
There is general scientific consensus that most, if not all, wildvarieties and cultivars of cannabis belong to a single plant species,Cannabis sativa L. (A cultivar is a plant variety generated by humanbreeding).
There is no such a thing as Cannabis sativa and Cannabis indica:Cannabis sativa is a single botanical species.
There are, however, hundreds (maybe thousands) of wild varietiesand cultivars of Cannabis sativa.
Who is the criminal?
D9-Tetrahydrocannabinol (THC)Cannabidiol (CBD)
CannabinolCannabichromene
CannabigerolD9-Cannabivarin
etc.
120 cannabinoids (2015)
445 non-cannabinoids(2015)
ActivatesCannabinoid
Receptors
IntoxicationLowers blood pressure
Increases heart rateDry mouthEuphoria
Oneiroid statesCalmness
DrowsinessAlters time perception
(characterized since the mid-1800)
D9-Tetrahydrocannabinol (THC)(discovered in 1944-1964)
A little bit more about THC
ActivatesCannabinoid
Receptors
Reduces nausea, vomitAlleviates MS symptoms
Alleviates neuropathic painReduces Tourette symptoms?
D9-Tetrahydrocannabinol (THC)
TherapeuticApplications
May cause dependence, but modest compared to other
drugs
A clarification about dependence, withdrawal, addiction
Words matter, because facts matter
Substance dependence: A state in which a person (organism)functions normally only in the presence of a substance, theremoval of which causes withdrawal.
Substance addiction: A state in which a person (organism) activelyseeks a substance, without control and despite harms thatoutweigh benefits.
Substance abuse: Use of a pharmacologically active substance forpurposes other than the medically intended reason.
ActivatesCannabinoid
Receptors
Reduces nausea, vomitAlleviates MS symptoms
Alleviates neuropathic painReduces Tourette symptoms?
D9-Tetrahydrocannabinol (THC)
TherapeuticApplications
May cause dependence, but modest compared to other
drugs
Cannabis as a Schedule I drug?
These facts contradict two basic tenets of the classification of cannabis in Schedule I :
No medical use and high potential for abuse
FDA implicitly agrees (THC is an approved drug)
What about ‘lack of accepted safety’?
What about ‘lack of accepted safety’?
The median lethal dose (LD50) of pure THC is between 666 mg and 1,260 mg per kg
Even in the lowest case scenario, I would have to ingest >53 g of THC to have a 50% chance of dying
What about other drugs? Caffeine has an LD50 of 192 mg per kg, nicotine has an LD50 of approximately 60 mg per kg
These facts contradict the last basic tenet of the classification of cannabis in Schedule I :
Lack of accepted safety
What do other cannabinoids do?Some examples…
Activates UnknownReceptors
Alleviates seizuresAlleviates psychoses
Alleviates anxiety Reduces inflammation
Cannabidiol (CBD)
D9-Cannabivarin
BlocksCannabinoid
Receptors
Modulates effects of THC?
Cannabidivarin
Activates UnknownReceptors
Alleviates seizures
An inexplicable inconsistency
ActivatesCannabinoid
Receptors
IntoxicationDecreased blood pressure
Increased heart rateDry mouthEuphoria
Dream-like stateCalmness
DrowsinessAltered time perception
Increased appetite
D9-Tetrahydrocannabinol (THC)
Man-made (‘synthetic’) THC is either in Schedule II or III(under different proprietary
names and different formulations)
Plant-derived THC and all other cannabinoids are in Schedule I
(even if they are not intoxicating)
But wait, it gets better…
Plant-derived CBD was recently placed in Schedule V
under the proprietary name Epidiolex
Plant-derived CBD remains in Schedule I
Activates UnknownReceptors
Alleviates seizuresAlleviates psychoses
Alleviates anxiety Reduces inflammation
Cannabidiol (CBD)
A state of confusion
King Crimson, ‘In the court of the crimson king’, 1969
Analytical chemists cannot study the chemical make-up of cannabis-derived productsavailable to the general public. This prohibition blocks, among other things, all chemicalanalyses aimed at complementing observational investigations on the health effects ofcannabis or at assessing the impact of cannabis cultivation and/or industrial treatment onnearby human and natural habitats.
Clinical and preclinical investigators are barred from examining the biological and healthimpact of cannabis products that are legally sold to millions of consumers across thecountry. Importantly, many of these products contain very high concentrations of THC orCBD and may thus be different from products available in the past.
Plant biologists are barred from cultivating cannabis in their campus facilities, and thuscannot investigate how genetic, epigenetic and environmental factors influence its growthand properties. If you think this is unimportant, think twice…
Research on cannabis: no country for old men
Why molecular studies on cannabis are important
In short, genetic and epigenetic studies can explain why ‘marijuana-type’ and ‘hemp-type’
cannabis cultivars are different
But wait, it gets better…
Cannabis must come fromthe University of Mississippi
The Mississippi monopoly
The cannabis produced at the University of Mississippi is substantially different from thecannabis found in commerce.
This difference is consequential because it narrows the extent to which results obtained byresearch laboratories can be generalized to real-life situations. This is called an ‘externalvalidity’ problem.
NIDA is trying to overcome this problem by contracting the University of Mississippi toproduce cannabis cultivars with varying concentrations of THC.
Along the same lines, in 2016 the DEA has adopted a policy that allows new entities toregister, under the CSA, to grow and distribute cannabis to legitimate researchers in theUnited States.
However, at this time (Jan 2019) many applications have been filed with the DEA, but nolicense has been issued.
A proposed path forward
Re-schedule cannabis away from the most restrictive designation, recognizing that harm potential is modest and that there are medical benefits. Schedule 3 is the most appropriate designation.
CBD is non-psychoactive and should be de-scheduled.
All other non-psychoactive phytocannabinoids should also be de-scheduled.
As a step toward accomplishing those changes, research institutions should be exempted from Schedule I compliance and from other laws that prevent them from studying cannabis and cannabinoids.
Thanks! Questions?
Daniele PiomelliAnatomy and Neurobiology, Biochemistry and Pharmacology
Center for the Study of Cannabis,University of California, Irvine
UC Center, SacramentoFebruary 27, 2019