2.1 Overview of Bioactive Compounds in Cannabis sativa

The Cannabis sativa plant synthesizes a diverse spectrum of bioactive molecules, including:

• Phytocannabinoids (e.g., THC, CBD, CBG)

• Terpenes (e.g., limonene, pinene)

• Flavonoids (e.g., cannflavins)

• Volatile Organic Compounds (VOCs) & Volatile Sulfur Compounds (VSCs)

2.2 Key Phytocannabinoids

2.2.1 Tetrahydrocannabinol (THC)

• Psychoactivity: Principal agent behind the classic “high.”

• Receptor Affinity: Partial agonist at CB1 receptors in the CNS; modulates mood, appetite, and nociception.

• Therapeutic Indications:

  • Analgesia

  • Anti-nausea

  • Appetite stimulation

  • Muscle relaxation

2.2.2 Cannabidiol (CBD)

• Non-Psychoactive: Counterbalances psychoactivity of THC; minimal direct binding to CB1/CB2.

• Receptor Cross-Talk: Modulates 5-HT1A, TRPV1, and possibly GPR55.

• Clinical Utility:

  • FDA-approved for certain seizure disorders

  • Potential anxiolytic

  • Anti-inflammatory and neuroprotective properties

2.2.3 Cannabigerol (CBG)

• Often called the “Mother Cannabinoid” or “Grandmother of Cannabinoids” - Precursor to THC, CBD, CBN, et al.

• Pharmacodynamics: Moderate affinity for both CB1 and CB2; exerts antibacterial, anti-inflammatory, and neuroprotective effects.

• Like THC and CBD, the acidic form predominates in the raw plant (ie CBG-A → CBD-A, THC-A, et al)

2.2.4 Cannabinol (CBN)

• Degradation Product: Mildly psychoactive metabolite formed by THC oxidation.

• Clinical Potential: Sedative efficacy, possibly valuable for insomnia management.

2.2.5 Tetrahydrocannabinolic Acid (THC-A)

• Non-Psychoactive Precursor: Converts to THC upon decarboxylation (heat).

• Physiological Profile: Anti-inflammatory, anti-proliferative, and neuroprotective.

Clinical Insight: Over 120 phytocannabinoids have been identified in Cannabis sativa, but clinicians need not memorize every structure. Mastering the dominant cannabinoids— THC, CBD, CBG, CBN, and their acidic precursors—provides a robust start for learning medical cannabis therapeutics. Combine that with 3-5 major terpenes, expanding knowledge progressively as clinical needs dictate. In the beginning, I started with 5 cannabinoids and 5 terpenes, then continued to study another 3-5 every few weeks.

2.3 Pharmacokinetics and Pharmacodynamics

2.3.1 Absorption

• Inhalation: Rapid onset (minutes), high bioavailability; ideal for acute symptom management (e.g., breakthrough pain).

• Oral: Slower onset (30–90 min) due to first-pass hepatic metabolism; suitable for chronic or prophylactic therapies.

• Sublingual & Topical: Variable absorption rates and bioavailability; beneficial for localized or non-systemic treatment.

2.3.2 Distribution

• Lipophilicity: Cannabinoids sequester in adipose tissues and readily traverse cell membranes, accumulating in brain, liver, and muscle.

• Clinical Pearls: Chronic use elevates total-body cannabinoid burden, potentially altering drug elimination kinetics.

2.3.3 Metabolism

• Hepatic Enzymes: CYP2C9 and CYP3A4 primarily metabolize THC to its psychoactive metabolite 11-OH-THC.

• CBD Interference: CBD can modulate CYP activity, leading to potential drug interactions with anticoagulants, antidepressants, and more.

Clinical Insight: Genomic testing for CYP450 variants can help personalize dosing strategies and minimize side effects, particularly in patients taking multiple medications or presenting complex comorbidities.

2.3.4 Excretion

• Routes: Fecal and urinary pathways.

• Half-Life: Typically 1–2 days in infrequent users; accumulates to longer elimination times with chronic usage.

2.4 Bioavailability depends on the route of administration:

Note: You will see a range of bioavailability for each route due to the physical and biological complexities of the medicine and the patient consuming the medication.

Inhalation

• THC: Bioavailability ranges from 10%–35%, or higher.

• CBD: Bioavailability ranges from 11%–45%, or higher.

Because the medicine rapidly enters the bloodstream and is distributed to the brain and other tissues, the onset of effects occurs quickly.

Sublingual

• CBD: Bioavailability in the range of 12%–35%, or higher; likely similar for other cannabinoids (THC, CBN, CBG, et al). These values are close to those found via inhalation but likely for different reasons (e.g., variable sublingual contact time, local temperature, and vascular anatomy).

  
  

Oral (Enteral) Consumption

• THC: Bioavailability of approximately 4%–12% due to extensive first-pass metabolism (THC → 11-OH-THC).

• CBD: Oral bioavailability of approximately 6%, primarily undergoing hydroxylation (CBD → 7-OH-CBD and 7-COOH-CBD) and mainly excreted in feces.

More studies are needed to further define absorption of the following routes. Even in the presence of robust studies, for several factors, these levels will likely vary throughout the day in the same person.

Topical

Systemic bioavailability through the skin is likely < 10%, varying widely based on:

• Skin thickness and local temperature

• Formulation (balms, creams, gels, lotions, patches, etc.)

• Carriers, emulsifiers, and other permeation enhancers

• Hydrophobicity of cannabinoids and presence of other components (e.g., multiple cannabinoids, terpenes, flavonoids)

Rectal

The rectal route of administration can offer certain advantages over oral delivery, particularly by reducing first-pass metabolism when the formulation is retained in the lower rectum (i.e., below the hepatic portal circulation). However, this advantage depends on suppository placement and local circulation. This may be useful for some cancer and GI patients, however, follow-up is recommended to ensure the benefits continue to exceed the risks of placing the suppository for this route.

• THC: Early studies using modified THC formulations (e.g., THC-hemisuccinate) reported bioavailability as high as >50% in animals . However, results in humans can vary, and simpler cannabis extracts (without specialized modification) may yield lower systemic availability.

• CBD: Research is limited, but suppositories containing CBD may also benefit from partial avoidance of first-pass metabolism.

• Formulation Dependence: Various excipients (fats, oils, or other carriers) may greatly alter absorption.

Estimated Rectal Bioavailability: While some studies point to moderate or high percentages with modified cannabinoid preparations, human data on unmodified cannabis extracts are still limited and likely result in lower numbers, if properly placed, in a vascular environment, bioavailability is likely approximates that of sublingual, or possibly higher. Care must be taken to consider the comfort of the patient and unique sanitation risks associated with this route.

Vaginal

Although research on the vaginal administration of cannabinoids is relatively limited, early data and anecdotal reports suggest that absorption can be significant due to the abundant vascular supply of the vaginal epithelium. Factors that may affect bioavailability include:

• Formulation (suppositories, creams, gels)

• Local pH and mucosal environment

• Extent of first-pass metabolism (vaginal route may partially bypass the liver, but not as effectively as rectal)

Estimated Vaginal Bioavailability: Studies remain sparse and estimates vary considerably. Systemic absorption is likely similar or less than rectal administration. More human clinical studies are needed to confirm reliable percentages.

Clinical Insight: Note that the faster onset routes have higher bioavailability (inhalation and sublingual) than the slower onset routes (oral - sublingual and enteral).

Clinical Insight 2: Consider recommending the oral (enteral) and topical as the long acting and the inhalation/sublingual faster onset as a PRN.

Lipid Solubility: Both THC and CBD are highly lipophilic, quickly accumulating in fat tissues. Clinically, believed to be responsible for Urine Drug Tests being positive for nearly 30 days with chronic use, based on body habitus and metabolism.

• THC Half-life: 1–3 days in occasional users; 5–13 days in chronic daily users.

• CBD Half-life: 18–32 hours.

2.5 Role in Modulating Homeostasis

The Endocannabinoid System (ECS) facilitates physiological equilibrium:

1. Immune Modulation: Balances pro- and anti-inflammatory cytokine cascades.

2. Neurological Processes: Regulates synaptic plasticity, mood, and motor function.

3. Pain and Inflammation: Modulates nociceptive signals and immune response.

4. Metabolism and Stress Resilience: Affects energy uptake, hormonal regulation, and stress-adaptive responses.

2.6 Specific Receptor-Ligand Interactions

1. THC → CB1 Receptors (Partial Agonist)

   • Elicits psychoactive and analgesic effects, modifies neurotransmitter release (e.g., dopamine, GABA).

2. CBD → Indirect Modulation

   • Inhibits the enzyme FAAH, sustaining endogenous anandamide levels and subtly shaping CB1/CB2 tone.

3. Beta-Caryophyllene → CB2 Receptors

   • A terpene with potent anti-inflammatory and analgesic properties through direct CB2 receptor binding.

2.7 Mechanisms of Action

1. Cellular Pathways

   • The ECS is primarily mediated by G-protein coupled receptors, altering intracellular cAMP and Ca2+ levels.

   • These shifts orchestrate signal transduction cascades that modulate neurotransmitter release and gene expression.

2. Neurotransmitter Effects

   • GABA & Glutamate: Decreased presynaptic release helps attenuate excitatory impulses, promoting anxiolysis and analgesia.

   • Dopamine & Serotonin: Cannabinoid-mediated changes can enhance mood, appetite, and antiemetic effects.

2.8 The Role of Terpenes, VOCs, and VSCs in the “Entourage Effect”

2.8.1 Terpene Synergy

Traditionally overshadowed by cannabinoids, terpenes are increasingly recognized for modulating cannabinoid activity via receptor-binding optimization, blood-brain barrier permeability changes, and immunomodulatory pathways. This synergy is commonly referred to as the “entourage effect.”

Major Terpenes

1. Limonene

   • Aroma: Bright, citrusy

   • Effects: Mood elevation, potential anti-inflammatory properties

2. Pinene

   • Aroma: Sharp, pine-like

   • Effects: Bronchodilation, memory retention support, anti-inflammatory

3. Myrcene

   • Aroma: Earthy, musky

   • Effects: Sedation, muscle relaxation; may enhance THC’s CNS penetration

4. Linalool

   • Aroma: Floral, lavender-like

   • Effects: Anxiolytic, anticonvulsant, sedative

5. Beta-Caryophyllene

   • Aroma: Spicy, woody

   • Pharmacology: Selective CB2 agonism, robust anti-inflammatory effects

6. Humulene

   • Aroma: Woody, earthy

   • Effects: Appetite suppressant, anti-inflammatory

7. Terpinolene

   • Aroma: Floral, herbal

   • Potential: Antioxidant capacity, emerging antineoplastic research

8. Eucalyptol

   • Aroma: Minty, camphor-like

   • Effects: Anti-inflammatory, antibacterial

     
     

2.8.2 Volatile Organic Compounds (VOCs) & Volatile Sulfur Compounds (VSCs)

• VOCs: Broader class of aromatic hydrocarbons that can be natural or synthetic.

  • Natural - terpenes in cannabis, volatile sulfur compounds found in cannabis, garlic, onion, broccoli, brussel sprouts, wines, cheeses.

  • Synthetic - Benzene Toluene, Formaldehyde, Xylene, Styrene

• VSCs: Sulfur-containing molecules that impart the characteristic “skunky” notes.

  • Potential Therapeutic Role: Ongoing studies suggest immunomodulatory or neuroprotective capacities, though clinical data remain preliminary.

  • Synergistic Dimensions: May amplify or modulate the therapeutic profile of cannabinoids and terpenes when used in concert.

Clinical Insight: Harmful Synthetic VOCs—such as benzene, formaldehyde, and toluene— pose significant health hazards, particularly with chronic exposure in poorly ventilated settings. Health risks include respiratory tract irritation, neurotoxic effects, and carcinogenic potential. Clinicians should advise patients working in high-exposure industries or living in environments with elevated VOC levels to implement mitigation strategies—such as improved ventilation, personal protective equipment, and regular health screening—to minimize adverse outcomes.

2.9 Putting It All Together

For the advanced clinician, cannabis pharmacology transcends single-molecule focus on THC or CBD, underscoring instead a comprehensive “entourage” of cannabinoids, terpenes, VOCs, and VSCs that interact with the ECS. This holistic view highlights the importance of tailoring formulations to patient needs—considering genetics, comorbidities, and treatment goals—to optimize cannabis-based interventions.

1. Combining Cannabinoids and Terpenes: Enables targeted therapy with reduced side effects.

2. Monitoring CYP Interactions: Crucial for polypharmacy and complex patient scenarios, especially with CBD.

3. Emerging Research on VSCs: Calls for greater scrutiny and possible integration into therapeutic practice as evidence evolves.

Key Takeaways

• Multifactorial Pharmacology: No single compound defines cannabis therapy; synergy is the key to success.

• Dynamic ECS Modulation: Cannabinoids and terpenes fine-tune homeostasis, affecting immunity, mood, and metabolism.

• Pharmacokinetics: Recognize how absorption, distribution, metabolism, and excretion impact clinical outcomes.

• Terpenes, VOCs, and VSCs: Factor these into chemical variety (chemovar) product selection for enhanced therapeutic specificity.

Armed with this integrated perspective, the advanced practitioner can confidently guide cannabinoid-based interventions, pushing the frontier of patient-centered care and contributing to a rapidly evolving medical discipline.