The leaves and flowers of the cannabis plant contain tetrahydrocannabinol (THC), the compound in marijuana that produces a “high” when smoked. In addition to the natural THC found in marijuana, synthetic cannabinoid (SC) compounds also produce a high when consumed. SCs and cannabis leaves and extracts also can be mixed into foods and beverages (edibles). Cannabis extracts are enriched in THC, and SCs can be much more potent than THC itself. These edibles can deliver extremely large amounts of THC and SCs to the body through overconsumption. THC and SCs act in the brain by binding to the cannabinoid receptor. In acute cannabinoid overdose, excessive THC/SCs can cause anxiety, paranoia, visual and auditory hallucinations, and nausea. In some cases, these symptoms are severe enough to require emergency medical attention. Drinabant binds to the same brain receptor as THC/SCs and can be administered to block their activity during an acute overdose. The goal of this project is to develop the preclinical data and clinical materials necessary to enable clinical trials to treat acute cannabinoid overdose.
Acute cannabinoid overdose (ACO) results from the consumption of large quantities of cannabinoid compounds. These include delta-9-THC, the naturally occurring psychoactive compound in cannabis plants, as well as other SC compounds. Although SCs are chemically distinct from THC, THC and SCs elicit psychoactive effects through the binding and activation of cannabinoid (CB) receptors in the brain, principally the CB-1 receptor. Initially developed as research tools to study CB receptors, SCs are reported to be more potent and efficacious than THC at activating CB-1 receptors. A critical issue with edibles is that absorption of the THC/SC through the gut is delayed compared to smoking. The subsequent delay in the onset of a high leads some to overconsume these edibles. Because it can be difficult to gauge how much THC/SC is contained in an individual edible, this overconsumption can quickly result in an overdose. Symptoms of ACO have been reported to last anywhere from several hours to days, leading some individuals to require emergency medical attention or even hospitalization. Individuals using SCs are about 30 times more likely to require emergency medical care than those smoking marijuana.
The therapeutic hypothesis is that a CB-1 antagonist can reverse the clinical manifestations of ACO by replacing the agonist (THC or SC) bound to CB-1 receptors. Prior clinical studies have demonstrated that oral administration of CB-1 antagonists (drinabant, surinabant) can block the pharmacodynamic effects of inhaled THC. Orally administered drinabant has a slow onset, making it impractical to administer in the acute overdose setting. To improve the pharmacokinetics, the lead collaborators have proposed a parenteral route of administration (intravenous or intramuscular injection) that would be more amenable to treating ACO in the emergency medical setting.
Opiant Pharmaceuticals, Santa Monica, CA
Phil Skolnick, Ph.D., D.Sc. (hon.)
Public Health Impact
The risks of ACO are increased by the consumption of synthetics and edibles, because it is difficult to know how much THC or other SC is present in foods and beverages. If symptoms drive a patient to seek medical care, no FDA-approved medications exist to treat ACO. Emergency medicine departments can only manage symptoms, which in the severest cases could require longer hospitalization.
BrIDGs scientists have initiated a preclinical development campaign to advance drinabant to clinical evaluation. Planned activities include development of an injectable formulation and the pharmacokinetic and toxicology studies needed to support an Investigational New Drug application.