Introduction to Cannabis

• General Context: The course is designed to be timely and relevant to real-world applications, focusing on substances frequently encountered in everyday life. This means we'll be discussing materials that many people may have interacted with or heard about, especially in terms of their health, legality, and cultural significance.

• Course Structure:

  • Phase 1: Focuses exclusively on cannabis, a plant with a long history of use for various purposes, including recreation, medicine, and industrial applications.

  • Phase 2: Focuses on tobacco, another widely used plant that has significant health implications and cultural relevance.

  • Phase 3: Concludes with a specific focus on vaping, which is a modern method of consuming substances, especially cannabis and tobacco. Vaping differs from traditional smoking in that it often involves heating rather than burning the material, potentially reducing harmful byproducts.

• The Concept of Vaping:

  • Vaping is not considered a completely separate entity but rather a delivery method for substances. This means it's a way to inhale the active components of cannabis or tobacco without the risks associated with combustion.

  • Vaping serves as a vehicle for delivering both cannabis (including $THC$, the compound responsible for the high associated with marijuana) and nicotine derived from tobacco.

  • Understanding the fundamental properties of cannabis and tobacco is necessary before applying that knowledge to vaping at the end of the term. This ensures that you have a comprehensive grasp of what you are inhaling and the effects it can have on your body.

Defining Cannabis: Species and Terminology

• Botanical Classification: Cannabis is a classification of plant, not a single product. This emphasizes that there are different types and uses for cannabis, and it's essential to understand these distinctions.

• Relevant Species: There are three distinct species of cannabis relevant to human use:

  • Cannabis sativa: Known for its tall stature and uplifting effects, commonly associated with energy and creativity.

  • Cannabis indica: Typically shorter and bushier, often associated with relaxing and sedative effects, making it commonly used for nighttime use.

  • Cannabis ruderalis: Less known and usually lower in psychoactive components, often used for breeding purposes, especially in creating hybrid strains.

• Hemp vs. Marijuana: While the terms are used interchangeably in casual conversation, they have specific academic and legal distinctions.

  • Hemp:

  • Derived from a specific strain of Cannabis sativa.

  • Bred over time specifically to maintain very low $THC$ (tetrahydrocannabinol) levels, which means it won't produce a high when consumed.

  • Primarily used for structural qualities due to its fibrous nature. Applications include making products like rope, twine, paper, and clothing, highlighting its versatility beyond just drug use.

  • The vegetative portions (specifically the stems) are the primary source of hemp material. Hemp is also currently used extensively as a source for $CBD$ (cannabidiol) production, which has various therapeutic benefits without psychoactive effects.

  • Marijuana:

  • Derived from the flowering portion of specific strains of Cannabis sativa.

  • Bred for high concentrations of $THC$, leading to the intoxicating effects sought after by recreational users.

  • The psychoactive effect is typically accessed by burning or heating the plant material, which releases the active compounds into smoke that can be inhaled. This is how people experience the 'high' from marijuana.

  • Hashish:

  • A concentrated resin extracted from the flowering portion of the cannabis plant.

  • Contains extremely high levels of $THC$ compared to unprocessed plant material. This concentration means it can provide more potent effects with smaller amounts.

Historical Context and Cultural Significance

• Ancient History (8,000 BC - 3,000 BC):

  • Evidence of cannabis fiber (hemp) use dates back approximately $10,000$ years ($8,000 \text{ BC}$). This historical use indicates that cannabis has been integral to various human societies for many millennia.

  • Its use has been documented in all major ancient civilizations: China, India, Egypt, and Mesopotamia. This widespread evidence highlights cannabis's significance across different cultures and regions.

  • Medicinal Use: The first recorded instance was in China roughly $5,000$ years ago ($3,000 \text{ BC}$), which shows that the plant was valued not just as a recreational substance but also for its health benefits.

  • Recreational Use: The first recorded recreational use is also credited to China, suggesting that people have sought pleasure and relaxation from cannabis since ancient times.

• Religious and Cultural Use in India:

  • Cannabis appears in some of the oldest Hindu holy texts, showcasing its role in spiritual practices. This indicates that cannabis has been involved in significant cultural and religious rituals.

  • Bhang: A cannabis tea made using milk, often consumed during Hindu weddings and festivals—emphasizing its place in celebrations and communal activities.

  • Early $1900\text{s}$ research concluded that cannabis was an integral component of both the religion and culture of India, pointing to its deep roots in cultural identity.

• Western Medicine Integration:

  • Cannabis did not enter Western medicine until the $1800\text{s}$. This illustrates a delayed recognition of its medicinal properties compared to its historical use in other parts of the world.

  • It was used sporadically for about a century, indicating a gradual acceptance but also a lack of consistent understanding.

  • Phasing Out: In the early $1900\text{s}$, Western medicine shifted from herbal, complex plant-based medicines to isolated, purified individual molecules. This led to a movement away from cannabis as therapies became more standardized and focused on specific chemical compounds.

  • Modern Resurgence: Modern science is now returning to cannabis to study individual molecules like $THC$ and $CBD$ to understand how they can be used similarly to traditional small-molecule pharmaceuticals. This revival highlights an evolving appreciation for the complexities of cannabis as a therapeutic agent.

Legal Evolution and International Control

• 1961 Single Convention on Narcotic Drugs:

  • The first major international effort to control drugs. This marked a significant step in global drug policy that would have lasting impacts on cannabis legality worldwide.

  • Cannabis was listed alongside opium as a "bad drug." This classification has had profound effects on societal perceptions and legal regulations of cannabis.

  • Prohibited production, manufacturing, and supply except for specific medicinal purposes, illustrating the tension between recognizing medicinal value and controlling substance use.

• 1971 Convention on Psychotropic Substances:

  • Established the modern "Scheduling" system (Schedule I, II, III, etc.) based on the negative effects versus beneficial uses of substances. This allows for a structured approach to regulating various drugs, including cannabis.

  • Original Scheduling: $THC$ was placed in Schedule I, categorizing it as a drug with high potential for abuse and no accepted medical use. Other cannabinoids, including $CBD$, were not regulated by this international convention, showing discrepancies in the understanding of cannabis’s components.

• Regional Variations (United States):

  • Many countries expanded these definitions. In the U.S., $CBD$ derived from marijuana was classified as Schedule I, complicating access for users seeking its therapeutic benefits.

  • Historically, $CBD$ from hemp was restricted only to cosmetic uses, hindering its potential medicinal applications.

• The 2018 Farm Bill:

  • Legally declared $CBD$ derived from hemp to be legal in the United States. This significant legislation reflected a changing perspective towards hemp and its derivatives, allowing for broader access to $CBD$ products.

  • $CBD$ derived from marijuana remained Schedule I at the federal level. This shows the ongoing complexity of cannabis regulation within the United States, where state and federal laws can conflict.

  • This legislation triggered a massive expansion in the commercial $CBD$ market, providing no unbacked medicinal claims were made, thus encouraging a booming industry while maintaining some regulatory oversight.

Chemical Composition and Cannabinoids

• General Profile: Cannabis contains over $100$ distinct cannabinoids—compounds specific to the cannabis plant. This complex chemistry is key to understanding the different effects cannabis can have on users.

• THC (Tetrahydrocannabinol):

  • The primary molecule responsible for psychoactive effects, meaning it’s the main chemical that causes the high associated with marijuana.

  • Distribution in Plant:

  • Roots and Seeds: Completely absent.

  • Stems: Very small/negligible levels.

  • Leaves: Contains approximately 2-3\text{ }\text{%} of total compounds.

  • Flowers: Extremely high concentrations, making up to 25\text{ }\text{%} of molecules in the flower, emphasizing why the flower is the most sought-after part of the plant for psychoactive use.

• Delta-9 THC:

  • The specific isomer that is most important and the only psychoactive cannabinoid discussed. Understanding isomers is crucial as they can have different effects on the body.

  • Acid Conjugate Form: In its raw state in the plant, it exists as an acid, which is NOT psychoactive. This means that the plant must be heated for users to experience its effects.

  • Activation: When heated or combusted, the acid form converts to free Delta-9 $THC$, producing psychoactive effects. This is why methods of consumption, like smoking or vaping, impact the experience greatly.

• CBD (Cannabidiol):

  • Shares many properties with $THC$ but is NOT psychoactive. This distinction makes $CBD$ a popular choice for those seeking therapeutic benefits without the high.

  • Modulation: In the presence of $THC$, $CBD$ actually reduces the psychoactive properties of $THC$. This is intriguing because it suggests that strains with a balance of both could offer benefits without overwhelming effects.

  • Acid Form: Initially exists as an acid conjugate. This form is a potent antiemetic (preventing vomiting), being $100$ to $1,000$ times more potent than its non-acidic counterpart, indicating its significant therapeutic potential.

• Historical Potency Shifts:

  • $1960\text{s}$: Marijuana typically contained 2-5\text{%} $THC$. This data helps set a baseline for understanding how cannabis has evolved over the decades.

  • Current Day: Street marijuana averages roughly 12\text{%} $THC$, highlighting a significant increase in potency over the years.

  • Current street marijuana also has significantly lower levels of $CBD$ (often near zero), meaning there is more $THC$ and less $CBD$ to mitigate its effects, resulting in much higher potency. This shift raises discussions about safety and usage effects in today’s consumers.

Cannabis Research Constraints

• NIH Regulation: Researchers must obtain marijuana for studies from the National Institutes of Health ($NIH$). This centralization can create limitations in the diversity of strains available for study.

• The Mississippi Greenhouse: The $NIH$ maintains a single greenhouse facility in Mississippi that grows the supply for all U.S. research. This challenges researchers looking for modern strains as the supply is limited.

• Complication: The strain grown by the $NIH$ is the "old" version from the $1960\text{s}$ (2-5\text{%} $THC$). This makes it difficult to apply research findings to the modern, high-potency (12\text{%} $THC$) marijuana used today. This gap can result in outdated conclusions not applicable to current users.

Administration Methods

• Smoking:

  • Most common route of administration. This traditional method allows for quick absorption of cannabinoids but also introduces other harmful byproducts from burning plant matter.

  • Plant material is combusted, releasing cannabinoids into a vapor/smoke for inhalation.

• Vaporization:

  • Material is heated but not burned. This method avoids combustion and often leads to a smoother inhalation experience without as many harmful substances.

  • Converts cannabinoids from acid/liquid forms into a gas phase, showcasing the scientific understanding of effective administration.

  • Avoids combustion, which prevents the inhalation of smoke and specific carcinogens, which is better for lung health.

• Edibles:

  • Cannabis or purified cannabinoids are incorporated into food items consumed orally. Edibles can lead to longer-lasting effects but can also be harder to dose correctly.

• Oral Tinctures:

  • Liquid concentrates of plant extracts administered via a dropper into the mouth. This method offers a quick absorption route and can be more discreet than smoking.

• Topical Administration:

  • Creams or oils applied directly to the skin, often used for local inflammation (e.g., knee pain). This method does not produce psychoactive effects but can provide targeted relief.

Pharmacokinetics: Absorption and Metabolism

• Bioavailability and Inhalation:

  • Smoking provides approximately 25\text{%} bioavailability but is highly variable based on the strain, the individual, and how long vapor is held in the lungs. Understanding bioavailability helps measure how much of the substance enters the bloodstream.

  • Plasma concentration of $THC$ peaks in $6-10 \text{ minutes}$, meaning users feel the effects quite rapidly after inhalation.

  • Concentration drops rapidly: to 60\text{%} after $15 \text{ minutes}$ and to 20\text{%} after $30 \text{ minutes}$, which highlights the temporary nature of the effects.

• Bioavailability and Oral Consumption:

  • Bioavailability is much lower, approximately 6\text{%} (slightly higher if in oil form). This indicates that when consumed this way, much less of the substance reaches the bloodstream.

  • Absorption is much slower, taking $2-6 \text{ hours}$ to reach the bloodstream, making it critical for users to exercise patience when consuming edibles.

• Distribution:

  • $THC$ is highly lipophilic (fat-seeking), which means it moves into fatty tissues in the body, affecting how it is stored and metabolized over time.

  • Initially moves to organs with high blood flow, then quickly leaves the bloodstream to enter lipid-rich organs. This can result in prolonged effects in chronic users.

  • Retention: Because it stores in fats, it remains in the body for an extended period. In chronic users, $THC$ can be detected in the blood for more than a month after cessation as it slowly leaches back into the bloodstream from the organs, showcasing the potential long-term effects of cannabis use.

• Metabolism:

  • Primarily metabolized in the liver by Cytochrome P450 enzymes ($CYP \text{ P450s}$). This metabolism is crucial for understanding how the body processes cannabinoids.

  • Metabolites:

  1. 11-hydroxy THC: Remains psychoactive.

  2. THC-carboxylic acid and glucuronide conjugates: Inactive, signaling how different compounds can have divergent impacts in the body.

  • Genetics: Clearance is highly dependent on genetics. Individuals with specific variants of $CYP2C9$ show dramatically reduced clearance rates, indicating that personal biology can affect how someone experiences cannabis effects.

• Elimination:

  • Eliminated almost entirely as metabolites, demonstrating how the body gets rid of substances.

  • 65\text{%} excreted in feces; 25\text{%} in urine; the remainder through sweat and exhalation. This distribution can inform drug testing and usage implications.

  • Half-life: After a single low-dose exposure in a non-user, $THC$ is detectable for $2-5 \text{ days}$. Chronic use extends this to several weeks, indicating significant variances based on the frequency of use.

Tolerance and Dosing Strategies

• Mechanisms of Tolerance:

  • Down-regulation: Number of cannabinoid receptors decreases over time with heavy use. This leads to users needing more of the substance to achieve the same effect.

  • Desensitization: Remaining receptors become less responsive to the binding of $THC$. This means that long-term users may experience diminished effects or require higher doses.

• Dose Titration:

  • Inhalation is highly efficient for "titrating" a dose—inhaling until the desired effect is felt and then stopping. This method encourages users to be more mindful of their consumption.

  • Waiting $10-20 \text{ minutes}$ between puffs is recommended to avoid overconsumption, which can easily happen due to the rapid onset of effects.

• Edible Risks:

  • Due to the long delay in effect, overconsumption is common as users eat more before the first dose takes effect. People may not realize they’ve consumed enough until it's too late.

  • Users are advised to wait $3 \text{ hours}$ between bites, underscoring the importance of patience with edibles.

• Average Usage:

  • Medicinal users average $10-20 \text{ grams}$ of cannabis per week. This gives a benchmark for understanding how much cannabis is commonly used for therapeutic purposes.

  • Inhalation typically requires $6-7$ doses per day, whereas edibles only require about $2$ doses per day, showing how different forms require varied consumption strategies.

Safety and Adverse Effects

• Overdose Risk: There is an exceptionally low risk of life-threatening overdose. This is a key point of distinction when discussing cannabis relative to other substances.

  • Brain Physiology: Cannabinoid receptors have very low expression in the brain regions that control autonomous functions like breathing and heart rate. This biological fact contributes to the reduced overdose risk compared to substances that affect these critical functions.

  • There are no known instances of accidental fatal overdose from marijuana, which impacts ongoing debates about its safety and legality in various jurisdictions.

• Psychotic Effects:

  • Anxiety: Effects are biphasic. Low doses have been found to help reduce anxiety, whereas high doses frequently increase anxiety. This contradiction highlights the complexity of cannabis effects and necessitates careful dosing.