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