Edible Cannabis Products: It Is Time for FDA Oversight

The legalization of cannabis (marijuana) for medical and recreational purposes in states throughout the United States has greatly increased its availability and use by adults and teens. Much of the earlier research on cannabis focused on its administration by smoking. Very little recent research has been conducted on the administration of cannabis by the oral route, the presumption apparently being that the 2 routes of administration are equivalent in terms of both their psychoactive effects and their toxicity. As the use of cannabis-laced “edibles” continues to increase, it is becoming clear that this presumption may not be correct. Several reports of severe cannabis-induced toxicity have appeared in both the lay press1 and in the medical literature.2 One man, a 19-year-old college student, ate a cannabis-laced cookie (approximately 6.5 “servings,” although the product was not tested for potency or content uniformity) and shortly thereafter began rambling incoherently and subsequently jumped to his death from the balcony of a Denver, Colorado, hotel. The Denver coroner listed cannabis intoxication as a significant factor in his death.2 A second man developed hallucinations and rambling speech after eating cannabis-containing candy and concomitant ingestion of an unidentified prescription medication, and in the midst of an apparent psychotic break, fatally shot his wife while she was calling 911 for help.1 In early September 2014, five high school students in the San Francisco, California, area, aged 14–16, became ill after eating brownies that had been laced with cannabis.3 Three of the students developed nausea and vomiting, and 2 became unconscious and were hospitalized. The brownies were sold to the students by a classmate. There are no toxicology results indicating if the brownies contained other drugs or if they contained only cannabis. What was the common denominator in these cases? In every instance, those affected consumed the cannabis orally, rather than by smoking. Although nausea, vomiting, lightheadedness, and occasional adverse psychiatric or paranoid reactions have been associated with smoking cannabis since the 1960s, reports of severe alterations in consciousness requiring hospitalization have been quite rare. If the brownies contained only cannabis (tetrahydrocannbinol, THC), aside from overdosage, what caused such severe reactions (psychosis, unconsciousness)? The answer may reside in the differences in metabolism between orally ingested and smoked cannabis. Smoked cannabis is absorbed into the pulmonary circulation and returned to the heart through the pulmonary vein. From the heart, it is distributed systemically, without passing through the liver. However, orally ingested THC is subject to both transmural absorption and metabolism in the gastrointestinal tract and “firstpass” hepatic metabolism as it passes through the liver. As a result, THC is metabolized more extensively by the oral route, leading to the synthesis of a much larger amount of 11-OH-THC than is generally formed following smoking. The 11-OH-THC metabolite is psychopharmacologically active and can combine its psychotropic effects with those of THC to produce a more robust psychotropic effect in the CNS.4,5 The magnitude of the effect of the combined 11-OH-THC and THC most likely was the cause of the psychotic reactions and loss of consciousness described in the cases reported above. As far back as 1973, Lemberger et al6 demonstrated the psychotropic effects of the 11-OH-THC metabolite when he administered tritiated intravenous doses of THC, 11-OH-THC (formulated in ethanol) or ethanol alone under blinded conditions, to 9 casual cannabis users. Following the administration of 1mg of 11-OH-THC, a marked tachycardia and euphoric “high” occurred in 3–5 minutes, and the psychologic