The Development of Cannabinoids as Therapeutic Agents in the United States

Abstract

Cannabis is one of the oldest and widely used substances in the world. Cannabinoids within the cannabis plant, known as phytocannabinoids, mediate cannabis' effects through interactions with the body's endogenous cannabinoid system. This endogenous system, the endocannabinoid system, has important roles in physical and mental health. These roles point to the potential to develop cannabinoids as therapeutic agents, while underscoring the risks related to interfering with the endogenous system during non-medical use. This scoping narrative review synthesizes the current evidence for both the therapeutic and adverse effects of the major (i.e., Δ9-tetrahydrocannabinol and cannabidiol) and lesser studied minor phytocannabinoids, from nonclinical to clinical research. We pay particular attention to the areas where evidence is well-established, including analgesic effects after acute exposures, and neurocognitive risks after acute and chronic use. In addition, drug development considerations for cannabinoids as therapeutic agents within the United States are reviewed. The proposed clinical study design considerations encourage methodological standards for greater scientific rigor and reproducibility, ultimately, to extend our knowledge of the risks and benefits of cannabinoids for patients and providers. Significance StatementThis work provides a review of prior research related to phytocannabinoids, including therapeutic potential and known risks in the context of drug development within the United States. We also provide study design considerations for future cannabinoid drug development. IV.A.1. Analgesia IV.A.1.a. Δ9-THC IV.A.1.b. Sex differences in the analgesic effects of Δ9-THC IV.A.1.c. Analgesic effects of CBD and minor cannabinoids IV.A.2. Clinical assessment of other therapeutic outcomes IV.A.2.a. Δ9-THC IV.A.2.b. CBD and other minor cannabinoids IV.B. Evidence for adverse effects IV.B.1. Δ9-THC IV.B 2. CBD and other minor cannabinoids V. Clinical study design considerations V.A. Variability in protocol design V.A.1. Drugs and comparators V.A.2. Route and timing of administration V.A.3. Dose and dosing duration V.A.4. Study design V.A.5. Eligibility criteria and sample size V.B. Variability in outcome assessment V.B.1. Assessment of therapeutic outcomes V.B.1.a. Analgesia V.B.1.b. Other therapeutic outcome measures V.B.2. Assessment of adverse effects V.B.2.a. Neurocognitive effects and psychosis V.B.2.b. Abuse liability V.C. Hazard and Risk Management of Cannabinoids VI. Conclusions not been copyedited and formatted. The final version may differ from this version. Pharmrev Fast Forward.