Marijuana (Cannabis sativa) is legalized for personal or recreational use in 29 states and the District of Columbia. The legalization of marijuana is on the 2018 ballot for five additional states: Vermont, New Mexico, Michigan, Rhode Island, and Maryland. Known on the street by more than 200 names, marijuana is a schedule 1 drug under the Controlled Substances Act and is the most commonly abused illicit drug. Regulations related to cultivation and possession of marijuana are enforced by the Drug Enforcement Administration.
A food containing marijuana is technically considered adulterated as defined under U.S. food regulations (21 CFR 342). Despite these regulatory dynamics, food products that contain marijuana with its vast array of psychoactive and nonpsychoactive substances represent approximately 10% of the total U.S. cannabis market, which is valued at nearly $5 billion.
Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive constituent of cannabis. Although marijuana is predominantly smoked, oral administration occurs during illicit use and licit pharmacotherapy (Jacobus and Tapert 2014).
Oral synthetic THC (dronabinol) is approved by the U.S. Food and Drug Administration for treating nausea, vomiting, and anorexia associated with cancer chemotherapy, and there appears to be growing interest in treatment with whole plant extracts and food preparations containing THC and cannabidiol, one of the cannabinoids found in cannabis. Of course, this is not approved for food applications.
Early in 2016, the state of Colorado invoked new regulations that impacted the packaging, labeling, and potency of edible marijuana products (House Bill 14-1366). Specifically, the state required child-resistant packaging and individually packaged products must indicate activated THC in increments of 10 or fewer mg and follow the packaging guidelines stipulated in the Poison Prevention Packaging Act of 1970. The product label must indicate that it is unlawful in commerce outside the state of Colorado and state that, “The intoxicating effects of this product may be delayed by two or more hours.” In addition, Colorado’s Marijuana Enforcement Division was authorized to provide incentives to manufacturers to provide responsible products. Safety through education was strongly supported. Perhaps most noteworthy is that manufacturers must assure products indicate the appropriate potency between 10 mg and 100 mg of THC.
It should be noted that the pharmacokinetics of the various cannabinoids, such as THC, differ based on their route of administration, such as inhalation or oral (Grotenhermen 2003). For example, inhalation of THC may produce psychotropic effects within seconds to a few minutes, whereas those effects are typically delayed by 60 to 90 minutes after oral ingestion.
The resurgence of cannabis edibles has raised a number of public health concerns, especially with respect to children (Wang et al. 2013). Nearly 800 children (under 12 years of age) were evaluated in the emergency department at a children’s hospital as a result of suspected unintentional ingestion of marijuana edibles or intentional use of medical marijuana. Toxicology assessments confirmed marijuana exposure. These young people exhibited lethargy, ataxia, respiratory insufficiency, and dizziness. Half of them required hospitalization.
When cannabis is smoked or vaporized, its delta-9-THC is absorbed through capillary beds in the lungs and rapidly reaches the brain. When cannabis edibles are ingested, the constituent delta-9-THC undergoes a transformation via Phase II metabolism within the liver into 11-hydroxy-THC and further to 11-Nor-9-carboxy-THC. This metabolite is, in effect, a different drug with apparently increased potency and greater duration of action compared with the faster-acting inhaled delta-9-THC. There is evidence that 11-hydroxy-THC diffuses into the brain more readily than THC, and that THC remains bound to proteins in blood longer (Huestis 2005, Huestis 2007). It is critical to understand that pharmacokinetic data demonstrate that 11-hydroxy THC and 11-Nor-9-carboxy-THC accumulation may be explained by more rapid THC oxidation than metabolite excretion (Schwilke et al. 2009).
Cannabis yields over 770 chemical compounds, many of which are less than well-characterized and for which there are no safety data. It is conventional wisdom that the bioactive compounds in cannabis are THC, cannabidiol, and cannabigerol. Only THC is psychoactive, but both cannabidiol and cannabigerol possess pharmacologic activity and appear to modify the effects of THC.
Other biological effects of cannabis are produced by terpenes. Terpenes can be absorbed via the aero digestive tract mucosa but do not survive gastric digestion. Myrcene, one of these terpenes, is thought to interact with THC and produce the sedative effect through smoked or vaporized cannabis varieties. Other terpenes such as beta-caryophyllene and pinene may contribute to the stimulating sativa effect of other cannabis varieties when inhaled.
High THC-potency cannabis is a relatively recent entity. For most of our history with cannabis, cultivated cannabis drug varieties produced only 2% or 3% THC. The Thai Stick variety of cannabis contained around 8%. In contrast, cannabis resin often exceeds 50%, and cannabis oils can top 70% THC (Jacobus and Tapert 2014).
It is important to emphasize that, like alcohol, cannabinoids are commonly detected in impaired and fatally injured drivers (Walsh et al. 2004). Smoked cannabis (Ramaekers et al. 2006, Drummer et al. 2004) and oral THC (Menetrey et al. 2005) markedly affect cognitive and psychomotor skills. Even more concerning are the recent findings from a variety of academic centers that address impaired adolescent brain development with marijuana exposure; persistent marijuana use has been linked to a decline in IQ, even after investigators controlled for educational differences (Meier et al. 2012).
It also must be noted that marijuana shows promise for treating medical conditions including chronic pain, muscle spasms, seizure disorders, and nausea from cancer chemotherapy. At least some of those benefits are thought to come from cannabidiol, which is not thought to produce mind-altering effects.
Despite the putative benefits of marijuana and its component cannabinoids, we desperately need to better understand how exposure via various routes of administration, including oral through marijuana edibles and especially during the developmental teen years, influences brain development and brain injury. The legalization of marijuana may prove to be of significant political and social benefit, but the medical impact of readily available and potent edible forms of this plant must be better understood and approached with utmost care and caution.
Roger Clemens, DrPH, CFS,
Univ. of Southern California’s School of Pharmacy,
Los Angeles, Calif.