Administration and Dosing of Medical Cannabis

Despite centuries of medical use and several modern studies, 80 years of cannabis (Cannabis sativa, Cannabaceae) prohibition have left clinicians undereducated about its therapeutic uses. A 2017 US study found that 89.5% of surveyed residents and fellows felt unprepared to prescribe cannabis and just 35.5% felt prepared to answer patients’ questions about it. Only 9% of US medical schools include clinical cannabis content in curricula.* While there is a lack of randomized controlled trials (RCTs) in cannabis therapeutics, researchers and caregivers are recognizing RCTs’ limitations in applicability to individual patients, who may be better served by individualized evidence-based practices. Cannabis’ effects vary depending on many factors. It is desirable to find a “sweet spot” of dosing that provides symptom relief without adverse effects (AEs) like unwanted euphoria. The authors combine a review of the literature and their own clinical observations to offer guidance on Good Clinical Practices (GCPs) for cannabis medications. Good Agricultural Practices (GAPs) and Good Manufacturing Practices (GMPs) already developed for herbal medicines should be required for all cannabis medicines, including the use of selective breeding rather than genetic modification. Consumers should be assured of product identity (cannabinoid and terpenoid profiles) and purity (no pesticidal, microbial, and/or heavy metal contamination).

The endocannabinoid system (ECS), found in all chordates, includes cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors and endocannabinoids. The ECS, a homeostatic regulator affecting pain, appetite, digestion, sleep, emotions, and thought processes, was discovered in 1992 but is still not fully understood. Exocannabinoids in cannabis and other molecules bind to ECS receptors. Over 100 cannabinoids occur in and are derived from cannabis. Best known are tetrahydrocannabinol (THC) and cannabidiol (CBD), formed through decarboxylation by heating. Their precursors are tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), respectively. THC is the main psychoactive compound in cannabis. A weak partial agonist of both CB1 and CB2 receptors, THC is used to treat pain, including neuropathic pain; nausea/vomiting; spasticity/spasms; cachexia/wasting syndrome/poor appetite; and anxiety, depression, and posttraumatic stress disorder (PTSD). CBD, lacking and in part countering THC’s intoxicating effects, is a negative allosteric modulator of CB1 receptor, affecting other receptors, including TRPV1 (transient receptor potential cation channel vanilloid subfamily receptor 1), 5-HT1A (5-hydroxytryptamine 1A), adenosine A2A, and nonreceptor mechanisms. It is known to be analgesic, anti-inflammatory, anxiolytic, an antipsychotic. THCA and CBDA have had much less research attention, but the former is noted for anti-inflammatory activity, antagonizing tumor necrosis factor-α, working as an antiemetic, and being an agonist of the PPAR-γ (peroxisome proliferator-activated receptor gamma) nuclear receptor with neuroprotective effects. CBDA also shows antiemetic and anxiolytic effects. Both are anecdotally said to benefit skin and other tumors. Thousands of chemovars vary in concentrations of cannabinoids; monoterpenes like myrcene, limonene, and pinene, all with known pharmacological effects; and the sesquiterpene β-caryophyllene. The latter, a selective full agonist at the CB2 receptor, has anti-inflammatory and analgesic effects. Chemovars are presently classified as THC predominant (Type I), CBD predominant (Type II), or mixed THC-CBD (Type III).

Absorption, distribution, and metabolization determine onset and duration of cannabis’ effects and differ by a form of administration. Smoking (combustion) in the form of cigarettes, sometimes mixed with tobacco (Nicotiana tabacum, Solanaceae) or other plant material, is the most common means of intake, although 30-50% of the product is lost to sidestream smoke, and smoking presents the greatest risk of AEs.** Smoking should be avoided by patients with chronic obstructive pulmonary disease (COPD) or other lung disorders.† Vaporization produces significantly fewer harmful byproducts than smoking, but cannabis efficacy can vary with vaporizer specifications. Uncharacterized forms, such as “dabs,” “shatter,” and “incense,” should not be used medically. For oral (edible product) and topical use, lipophilic cannabinoids are best combined with fats or oils. The oromucosal route has proven efficacious in proprietary metered-dose cannabis medicines. Cannabis is also used vaginally, with absorption by vaginal mucosa, for menstrual pain.

The authors’ dosing strategy, especially for cannabis-naïve patients, is “start low, go slow, and stay low.” Most patients use 1-3 g herbal cannabis daily; fewer than 5% utilize >5 g/d. While tolerance to euphoria develops rapidly, tolerance to benefits does not. Over time, dose escalation is rare unless new needs develop. Sample dosing for night and daytime use are provided. Cannabis has a superior safety profile but is generally contraindicated during pregnancy and lactation and, except for CBD-predominant products, psychosis. It should be used with caution in unstable cardiac conditions. Use in children and adolescents, and as an aid in addiction treatment, remain controversial. AEs, almost all related to THC, are dose-dependent and self-limiting. Clinically significant drug interactions are rare; “there is no drug that cannot be used with cannabis … .” When using high-dose CBD with clobazam, however, the drug dosage must be reduced.

The authors discuss cannabis treatment in epilepsy, cancer, pain, and Parkinson’s disease; in elderly and pediatric populations; in patients using opioid analgesics, and in terms of driving and other safety concerns. Standards of care advocated by the authors are the same as for other medical specialties—examination of prior records when available, thorough history and physical examination, discussion of the pros and cons of treatment, appropriate follow-up, documentation, and communication with other caregivers.

The benefits of medical cannabis remain promising, and while more clinical research is still warranted, medical practitioners should increase their knowledge and utilization of cannabis where appropriate.

* It would be interesting to know how many include information on the endocannabinoid system (ECS).

** No mention is made of any differences between smoking cannabis cigarettes and use of water pipes, commonly held to reduce the harms of smoking, if only by cooling the smoke.

† The authors name asthma as a contraindication, contradicting a large body of anecdotal testimony to cannabis’ benefits in that condition. 

Resource:

MacCallum CA, Russo EB. Practical considerations in medical cannabis administration and dosing. Eur J Intern Med. March 2018;49:12-19.

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