When was marijuana first scheduled as an illegal drug in the US?

Marijuana was first scheduled around 1930 under the DEA as a narcotic drug, making it illegal. This was further emphasized by the Nixon administration's 'War on Drugs' policy, often for political purposes to disenfranchise certain populations.

How does THC affect the brain and body?

THC binds to CB1 receptors primarily in the brain and CB2 receptors mostly on immune cells. This binding can stimulate areas like the hippocampus to extinguish memory (beneficial for PTSD), interfere with pain signaling in the brain, and stimulate appetite centers (useful for wasting syndromes and chemotherapy side effects).

What is the key difference between THC and CBD's mechanism of action?

THC directly binds to CB1 and CB2 receptors, leading to its intoxicating effects. CBD, however, does not directly bind to these receptors but works indirectly by activating the endocannabinoid system or by interacting with completely different receptors, providing medicinal effects without intoxication.

What is the legal definition of hemp and how was it impacted by the Farm Bill?

Hemp is legally defined as a cannabis cultivar containing less than 0.3% THC by weight. The Farm Bill provided legal cover for farmers to grow hemp, recognizing its economic potential as a cash crop and promoting its study and development under agencies like the USDA and FDA.

What are the common industrial uses of hemp?

Beyond cannabinoids, hemp has various industrial uses, including making hemp seeds (rich in omega-3 and omega-6 and protein), strong fibers (used in textiles, for credit cards, and even in car parts like BMW door panels), and 'hempcrete' as a concrete substitute.

What are the health risks associated with THC use?

While generally low in toxicity, THC can cause anxiety, panic, rapid heartbeat, and elevated blood pressure in sensitive individuals. The psychological 'set and setting' can significantly influence the experience.

Is cannabis a 'gateway drug'?

The consensus, including from NIDA (National Institute of Drug Abuse), is that cannabis is not a gateway drug. While young people may experiment with it alongside other substances, there's no evidence it directly causes progression to 'hardcore' drug addiction. Instead, it may serve as an 'exit drug' to help people move off other addictive substances.

What is the difference between smoking and vaping cannabis?

Smoking involves combustion at high temperatures, leading to inhalation of burnt plant material and other byproducts. Vaping uses lower temperatures to heat the substance, reducing pyrolysis. Newer inhalers aim for no temperature gradient, delivering the product via an inert carrier gas for more controlled dosing.

Why is FDA oversight of cannabis products difficult despite potential dangers like the 'vaping crisis'?

The FDA's ability to regulate cannabis products is limited because cannabis remains federally illegal. State agencies, not accustomed to scientific regulation, police this, often leading to inconsistent rules, lack of testing requirements, and difficulty in identifying the causes of widespread adverse events like those seen in the vaping crisis.

How do edibles deliver their intoxicating effects, and why are their effects so variable?

Edibles get you high because the cannabis is heated during preparation, converting the acidic cannabinoids into active THC. After ingestion, THC is metabolized by the liver into an even more intoxicating metabolite. Dosage is highly variable due to inconsistent mixing, individual digestive processes, body mass, and circadian rhythm.

How does the body's tolerance to THC compare to opiates?

THC can cause receptor down-regulation with overconsumption, but this can be quickly reset by stopping for a few days, and studies show long-term users don't necessarily increase their dose. Opiates, conversely, cause rapid down-regulation, requiring increasing doses for the same effect and eventually leading to hyperalgesia (enhanced pain).

What is the 'entourage effect' in cannabis?

The 'entourage effect' refers to the synergistic action of various compounds in the cannabis plant—including over a hundred cannabinoids, 80+ terpenes, and flavonoids—working together to produce a combined therapeutic effect that is greater than any single isolated compound.

Why is highly purified CBD (like Epidiolex) used for epilepsy, and what are its limitations?

Epidiolex is a plant-derived, >90% purified CBD product approved for rare seizure disorders in children. It shows about 30% reduction in seizures but comes with notable side effects like gastrointestinal issues and liver problems at high doses, highlighting the trade-offs of isolating compounds.

How can patients protect themselves when purchasing cannabis products in a fragmented legal landscape?

Patients in legal states should buy from licensed dispensaries and ask for a certificate of analysis to verify purity and safety. It is recommended to avoid buying cannabis products online or from unregulated street sources due to the lack of testing standards and potential adulterants. Consulting a physician knowledgeable in cannabinoid medicine is advised.

Key Moments

#81 – Debra Kimless, M.D. & Steve Goldner, J.D.: Cannabis – the latest science on CBD & THC

Q: What is the historical use of cannabis as medicine?

Cannabis has been used medicinally for over 5,000 years, with historical applications ranging from gout and memory loss in Asia to topical use on war horses by ancient Greeks for inflammation. It was also mixed with heat and milk in India as an anesthetic.

Peter Attia MD

People & Blogs4 min read132 min video

Jan 14, 2020|3,657 views|74|8

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Key Moments

TL;DR

Cannabis science: THC vs. CBD, medical uses, safety, and future regulations.

Key Insights

THC is psychoactive and binds to CB1 receptors, impacting memory and pain. CBD is non-psychoactive and works through indirect mechanisms or different receptors.

Cannabis has a long history of medicinal use; its modern scheduling in the 1930s was influenced by prohibitionist policies.

The Farm Bill legalized hemp (defined as <0.3% THC), opening pathways for CBD products and industrial hemp uses.

THC and CBD have remarkably low toxicity profiles with very wide therapeutic indices compared to substances like alcohol or opioids.

Vaping-related lung injuries are a serious concern, potentially linked to additives like PG/PG-13 and combustion products, with the FDA's regulatory framework for cannabis being complex due to its federal illegal status.

Edibles can be hard to dose accurately due to decarboxylation and individual metabolism, leading to unpredictable and potentially more intense effects.

While THC can have negative effects on developing brains and individuals predisposed to addiction, evidence suggests it's not a definitive 'gateway drug' and may help with opioid withdrawal.

Water-soluble formulations and sublingual administration offer improved bioavailability and faster onset, potentially reducing the required dose and avoiding first-pass liver metabolism.

The 'entourage effect,' where various cannabinoids and terpenes work synergistically, is crucial, and pure compounds may require higher doses and cause more side effects.

Research into cannabis's therapeutic potential, including its role in cancer, sleep, and mitigating addiction, is progressing but hampered by federal illegality and regulatory hurdles.

Patient safety and avoiding predatory practices are paramount, emphasizing the need for regulated dispensaries and Certificates of Analysis.

Federal rescheduling of cannabis is anticipated, which would enable more robust, standardized research and regulatory oversight, similar to pharmaceutical drug development.

HISTORICAL AND MOLECULAR OVERVIEW

Cannabis has a history of medicinal use spanning over 5,000 years, employed by ancient civilizations for various ailments. The modern understanding distinguishes between THC (tetrahydrocannabinol), the psychoactive component that binds to CB1 receptors in the brain and nervous system, influencing memory and pain, and CBD (cannabidiol), which is non-psychoactive. CBD interacts indirectly with the endocannabinoid system or through different receptors, offering various therapeutic benefits without intoxication. Chemically, these compounds are often found in acidic forms in the raw plant and require decarboxylation (heat and time) to become active. The distinction between cannabis and hemp is primarily legal, with hemp defined as containing less than 0.3% THC by weight.

REGULATORY LANDSCAPE AND THE FARM BILL

The scheduling of cannabis as a controlled substance, originating around the 1930s and intensified during the Nixon administration, significantly impacted its research and accessibility for decades. The recent Farm Bill in the U.S. marked a pivotal shift by legalizing hemp cultivation and production. This legislative change has enabled the widespread availability of CBD products and spurred interest in industrial hemp applications, like fiber and seed production. While the Farm Bill legalized hemp, the FDA's regulatory framework for CBD in consumer products is still evolving, creating a complex legal environment.

SAFETY PROFILE AND TOXICITY CONSIDERATIONS

THC and CBD exhibit remarkably low toxicity, with extremely wide therapeutic indices, meaning a very large dose would be required to cause serious harm. This is in stark contrast to substances like alcohol or opioids, which have a much narrower safety margin and higher potential for acute and chronic toxicity. While excessive THC can cause anxiety or temporary psychotic effects, fatalities are virtually nonexistent due to the absence of CB1 receptors in vital cardiorespiratory centers of the brain. The primary safety concern highlighted is the recent surge in vaping-related lung injuries, potentially linked to additives, manufacturing processes, and combustion products.

ROUTES OF ADMINISTRATION AND DELIVERY METHODS

Various methods exist for consuming cannabis, each with distinct pharmacokinetic profiles. Inhalation, whether smoking or vaping, provides rapid onset of effects but carries risks related to combustion products or potential additives, especially with unregulated vaping products. Edibles offer a longer-lasting effect but are notoriously difficult to dose precisely due to decarboxylation requirements and individual metabolic variations, often leading to unpredictable and intensified experiences. Emerging methods focus on water-soluble formulations and sublingual delivery, aiming to improve bioavailability, speed up onset, and avoid first-pass liver metabolism, offering potentially more controlled and effective therapeutic outcomes.

THERAPEUTIC APPLICATIONS AND RESEARCH PROGRESS

Cannabis, particularly its cannabinoids like THC and CBD, is being investigated for a wide range of therapeutic uses. These include pain management, anxiety reduction, sleep improvement, and aiding in the withdrawal from addictive substances like opioids. Emerging research also suggests potential anti-cancer properties, affecting apoptosis, migration, and neovascularization. The concept of the 'entourage effect,' where multiple compounds in cannabis work synergistically, is gaining traction, suggesting that whole-plant or carefully formulated combinations may be more effective than isolated compounds. Despite promising anecdotal evidence and preliminary trials, robust large-scale clinical research is still constrained by federal regulations.

CHALLENGES AND THE FUTURE OF CANNABIS SCIENCE

The primary obstacle to advancing cannabis research and therapeutic application is its continued federal illegality and the resulting regulatory complexities. This hinders standardized testing, broad clinical trials, and consistent product quality across states. The proliferation of unregulated products and predatory schemes poses significant risks to patient safety, underscoring the need for greater oversight. Experts anticipate federal rescheduling, which would unlock opportunities for rigorous scientific study, standardized pharmacovigilance, and the development of well-regulated medicinal products, ultimately aiming to harness the therapeutic potential of cannabis responsibly.

Mentioned in This Episode

●Products

●Companies

●Organizations

●Drugs & Medications

●Concepts

●People Referenced

Common Questions

Cannabis has been used medicinally for over 5,000 years, with historical applications ranging from gout and memory loss in Asia to topical use on war horses by ancient Greeks for inflammation. It was also mixed with heat and milk in India as an anesthetic.

Topics

Sleep Optimization Health & Longevity Mental Health & Psychology Addiction Science Pain Management Anxiety Relief Medicine & Clinical Drug Regulation Medical Marijuana Vaping Safety

Mentioned in this video

People

Peter Attia

Host of the podcast, who sought out the guests to learn about cannabis, THC, and CBD due to his personal ignorance and patient demand.

Deborah Kimless

An anesthesiologist specializing in pain management and Chief Medical Officer of Pure Green, who was drawn to cannabis research after her mother suffered a complication from a pharmaceutical drug.

Steve Goldner

Founder and CEO of Pure Green, a forensic toxicologist and FDA attorney, who developed liquid methadone and became interested in cannabis as medicine decades ago to help a friend with PTSD.

Rick Doblin

Founder of the Multidisciplinary Association for Psychedelic Studies (MAPS), whose work is cited as an example of successful research advocacy for controlled substances.

Drugs & Medications

Methadone

A liquid drug formulated by Steve Goldner 47 years ago to help friends addicted after the Vietnam War, which has helped people globally.

Tetrahydrocannabinol

The primary intoxicating cannabinoid in cannabis, which binds to CB1 and CB2 receptors in the brain and peripheral nervous system to produce its effects, including altered memory and pain relief.

MDMA

A Schedule I controlled substance currently in Phase 3 studies by MAPS, showing how research on federally controlled substances can progress with dedicated effort and funding.

Nabilone

A synthetic THC that has been on the market since the 1980s, available by prescription across the country for chemotherapy-induced nausea and vomiting, though it can be uncomfortable due to pure THC effects.

Epidiolex

A plant-derived, highly purified CBD product from GW Pharma, approved for two specific types of refractory seizures in children, showing around 30% reduction in seizures but with side effects like GI issues and liver problems at high doses.

Fennelbut

An oral form of GABA that crosses the blood-brain barrier and was once an over-the-counter sleep aid, no longer easily available due to lack of FDA GRAS designation. Mentioned for its CNS GABA activation properties.

Supplements

Cannabidiol

A non-hallucinogenic cannabinoid that works indirectly on the endocannabinoid system or on different receptors, offering many medicinal applications without intoxication. It is higher in hemp cultivars.

Bisphosphonate

A pharmaceutical drug, specifically Fosamax, that caused a severe complication for Dr. Kimless's mother, leading to a fatal fracture.

Organizations

Drug Enforcement Administration

The law enforcement agency under which marijuana was originally scheduled as a narcotic drug, making it illegal.

Nixon Administration

The US presidential administration under which the 'War on Drugs' policy, including the demonization of marijuana, was largely promulgated.

Food and Drug Administration

A regulatory body towards what is medicine and food, which Steve Goldner worked for as an attorney. It is currently involved in discussions around CBD regulation.

Society of Cannabis Clinicians

An organization that maintains a list of physicians by state who are experts in cannabinoid medicine and can provide guidance to patients in legal states.

Multidisciplinary Association for Psychedelic Studies

An organization founded by Rick Doblin in 1986, which has successfully advanced MDMA into Phase 3 clinical trials, demonstrating a roadmap for funding and studying controlled substances.

Legislation & Policy

Farm Bill

A federal law that legalized hemp cultivation, pushed by legislators to provide a cash crop for farmers. It allowed for the processing of hemp into oils and other products.

Concepts

New Drug Application

The application required by the FDA to sell a new drug in the United States, which is the ultimate goal after successful IND clinical trials.

CB1 receptor

A docking station in the brain and peripheral nervous system that THC primarily activates, leading to its psychoactive and medicinal effects.

Investigational New Drug

An exemption from selling an unapproved drug, required by the FDA for companies to conduct clinical trials on new drug formulations. This is a crucial step in the drug approval pathway.

CB2 receptor

A docking station predominantly found on immune cells and other tissues, also activated by THC and playing a role in the anti-inflammatory effects of cannabis.

Hemp

Legally defined as a cannabis cultivar with less than 0.3% THC by weight. It is rich in CBD and can be used for industrial purposes like fiber, seeds, and building materials.

Entourage Effect

The synergistic effect of multiple compounds (cannabinoids, terpenes, flavonoids) in cannabis working together, often resulting in greater therapeutic benefits than isolated compounds.

Companies

Pure Green

The company founded by Steve Goldner, where Dr. Kimless serves as Chief Medical Officer, aiming to create the safest and most efficacious forms of cannabis delivery.

GW Pharma

A pharmaceutical company that produces Epidiolex, a plant-derived CBD formulation for epilepsy.

Products

Mouth dissolving tablets

A type of sublingual tablet developed by Pure Green that disintegrates quickly in the mouth to deliver water-soluble cannabinoids into the bloodstream, bypassing first-pass metabolism.