3.1 Common Adverse Effects of Cannabinoids

3.1.1 Mild to Moderate Side Effects

• Drowsiness, Dizziness, Dry Mouth (Xerostomia): Commonly reported, often transient and dose-dependent.

• Increased Appetite (“Munchies”): Heightened by THC; may benefit patients with cachexia but present issues for obesity or metabolic disorders.

• Psychoactive Effects (Euphoria/Dysphoria): Primarily driven by THC; patient- specific factors (e.g., mental health history) can modulate presentation.

3.1.2 Severe but Rare Reactions

• Paranoia, Anxiety, Hallucinations: Linked to high-THC products or predisposed psychiatric vulnerability.

• Hypotension or Tachycardia: Observed in sensitive individuals; can exacerbate underlying cardiac conditions.

• Cannabinoid Hyperemesis Syndrome (CHS): Characterized by cyclical vomiting and abdominal pain, typically emerging with chronic cannabis use.

Clinical Insight: Adequate patient education regarding possible side effects—including practical strategies (e.g., hydration, pacing intake)—can mitigate the above side effects and improve therapeutic adherence.

Clinical Insight 2: Biphasic Effects of Cannabis

Cannabis exhibits a biphasic effect profile, meaning that in low to moderate doses, it can alleviate symptoms such as pain, anxiety, insomnia, and nausea; however, at higher doses or with chronic use, it may paradoxically exacerbate or even induce these same conditions.

3.2 Risk Management for MDs, DOs, and PharmDs

3.2.1 Comprehensive Patient History

• Screen for Mental Health Disorders: History of psychosis, bipolar disorder, or severe anxiety can increase susceptibility to adverse psychoactive reactions.

• Cardiovascular Assessment: Patients with arrhythmias or coronary artery disease require thorough risk-benefit evaluation.

• Substance Use and Tolerance: Prior cannabis exposure and other substance use can predict individual pharmacodynamic responses.

3.2.2 Documented Consent

• Informed Consent Forms: Detail the potential risks (e.g., psychoactivity, sedation), benefits (e.g., pain relief, antiemetic effects), and alternatives.

• Patient Understanding: Confirm comprehension of storage, administration methods, and the importance of follow-up.

3.2.3 Regular Monitoring

• Scheduled Follow-Ups: Assess efficacy, tolerability, need for dose adjustments.

• Validated Tools: Incorporate pain scales, quality-of-life metrics, or mental health inventories to quantify therapeutic outcomes.

Clinical Insight: Genomic testing for these specific CYP450 variants (CYP3A4*22 and CYP2C9*3) enables personalized dosing of cannabinoids, enhancing efficacy while minimizing potential side effects.

CYP3A4*22 Variant and CBD: Individuals with the CYP3A4*22 allele have reduced CYP3A4 enzyme activity. This leads to slower metabolism of CBD, resulting in higher plasma levels and an increased risk of side effects such as drowsiness or liver enzyme elevations 🧬🌿.

CYP2C9*3 Variant and THC: Those carrying the CYP2C9*3 allele exhibit significantly decreased CYP2C9 enzyme activity. Consequently, THC is metabolized more slowly, causing prolonged psychoactive effects and a higher likelihood of adverse reactions like anxiety or dizziness 🔬💉.

See the appendix for other common drugs metabolized by these cytochromes.

3.3 Contraindications and Precautions

3.3.1 Absolute Contraindications

1. Severe Psychosis or Schizophrenia: High-THC products may exacerbate delusions or hallucinations.

2. Allergic Reactions: Rare hypersensitivity to specific cannabinoids or terpenes demands absolute avoidance.

Clinical Insight: Some patients may experience IgE-mediated allergic reactions (e.g., contact dermatitis, conjunctivitis, rhinitis, anaphylaxis) triggered by cannabis pollen or extracts, which can cross-react with botanicals such as tomato, peach, or latex. Perform a detailed allergy history and consider referral for testing, especially if there is occupational/ environmental exposure, pollen sensitivity, or a history of atopic disease.

3.3.2 Relative Contraindications

1. Cardiovascular Disease: Hypotension or tachyarrhythmias can be triggered or worsened by certain cannabinoids.

2. Pregnancy & Lactation: Potential neurodevelopmental impacts on the fetus or neonate remain incompletely understood; prudent avoidance recommended unless clearly indicated.

3.4 Patient Populations Requiring Extra Care

3.4.1 Pediatric Patients

• FDA-Approved Uses (e.g., Epilepsy Syndromes): Rigorously follow evidence-based dosing.

• Avoid THC Dominance: High-THC regimens raise concerns for altered neurodevelopmental trajectories.

3.4.2 Geriatric Patients

• Start Low, Go Slow: Reduced metabolic clearance, polypharmacy, and fall risk mandate cautious titration.

• Monitor Sedation & Cognitive Changes: Even moderate doses can potentiate confusion or dizziness.

3.4.3 Patients with Psychiatric Disorders

• Favor CBD-Dominant Products: Minimizes exacerbation of psychotic or anxiety disorders.

• Close Symptom Monitoring: Watch for mood destabilization or paranoia with any increase in THC content.

3.5 Drug Interactions and Safety Considerations

3.5.1 CYP450 Interactions

• Inhibitors:

  • CBD: Inhibits CYP3A4 and CYP2C19, elevating plasma concentrations of anticoagulants (e.g., warfarin) and antiepileptics (e.g., clobazam).

• Inducers:

  • Chronic THC Use: May induce CYP1A2, potentially reducing the efficacy of co-administered drugs like theophylline.

3.5.2 Sedatives and CNS Depressants

• Additive Effects: Concomitant use with benzodiazepines, opioids, or alcohol can increase sedation and respiratory depression risk.

• Clinical Caution: Monitor sedation levels, especially in polypharmacy or fragile patient populations.

3.6 Monitoring and Managing Side Effects

3.6.1 Clinical Tools for Adverse Event Tracking

• CTCAE (Common Terminology Criteria for Adverse Events): Useful for standardized grading of adverse reactions.

• Patient Diaries: Encourage patients to record symptom onset, duration, and triggers to facilitate precise intervention strategies.

• Other scales: Visual Analog Scale, PTSD Checklist (PCL-5), et al

3.6.2 Intervention Strategies

• Dose Reduction or Route Modification: Lowering THC percentage or switching from inhalation to oral could reduce adverse events.

• CBD-Rich Formulations: Mitigate psychoactivity while preserving analgesic or anti-inflammatory benefits.

Clinical Insight: Early recognition of CHS is crucial. Patients should be educated on the symptoms (e.g., persistent nausea, morning retching) and the need for temporary cessation. Warm showers or topical capsaicin may provide symptomatic relief.

3.7 Clinical Pearls

1. CBD-Dominant Formulations\

   • Ideal for patients with complex polypharmacy profiles to minimize potent CYP450 interactions and psychoactive adverse effects.

2. Recognizing and Managing CHS

   • Patient education about cyclical vomiting and abdominal pain is essential; treatment includes cessation, IV fluids if needed, and antiemetics.

3. Genomic Tailoring

   • Where feasible, genotype CYP2C9, CYP2C19, or CYP3A4 to pinpoint individualized dosing strategies and reduce toxicity in sensitive patients.

4. Low-THC, High-CBD Strains

   • A prudent initial approach for elderly, pediatric, or psychiatric patients. Titrate gradually to achieve therapeutic effect with minimal psychoactivity.

Key Takeaway

Mastery of cannabinoid safety entails a thorough understanding of patient-specific risk factors, adverse effect profiles, and the nuanced interplay between cannabinoids and co-administered medications. Leveraging genomic insights and vigilant monitoring can further refine therapeutic outcomes while minimizing harm.