The endocannabinoid (eCB) system is one of the most widespread systems in the central nervous system

(Figure). It consists of receptors, endogenous transmitters or eCBs, and enzymes that synthesize and degrade eCBs. The 2 main receptors are the G-protein–coupled receptors, cannabinoid-1 receptor (CB1R) and cannabinoid-2 receptor (CB2R), but in addition, some cannabinoids also engage transient receptor potential channels, and peroxisome proliferator–activated receptors. The 2 most well-studied eCBs include the lipid ligands anandamide and 2-arachidonoylglycerol. The enzymes involved in the biosynthesis and degradation of anandamide are N-acylphosphatidylethanolamine-selective phospholipase D and fatty acid amide hydrolase, respectively, while the enzymes involved in the biosynthesis and degradation of 2-arachidonoylglycerol are diacylglycerol lipase, monoacylglycerol lipase and 2-arachidonoylglycerol hydrolase.

In contrast to other neurotransmitters, for example, dopamine, that are synthesized ahead of time and stored in vesicles for release, anandamide and 2-arachidonoylglycerol are synthesized on demand from their precursors present in lipid membranes, prompted by activation of G-protein–coupled receptors or by depolarization. After synthesis, eCBs are rapidly released into the extracellular space, where they bind to and activate presynaptic or postsynaptic CB1R or CB2Rs, inhibiting the further release of neurotransmitters.

CB1Rs, densely expressed in the brain, are critical to mediating the psychoactive effects of cannabis, as they are the targets of THC, a partial agonist at this receptor. CB2Rs, in contrast, are mostly expressed peripherally (immune, gastrointestinal, and peripheral nervous systems).

In contrast to eCBs, exogenous cannabinoids, such as THC, are metabolized over several hours before being excreted. Thus, the duration of effects of THC and eCBs are rather different, with eCBs having brief effects and THC having prolonged effects. The important role of the eCB in neurodevelopment may explain why adolescence is a critical period wherein individuals are particularly susceptible to the effects of exogenous cannabinoids, potentially resulting in the disruption of eCB-mediated processes.

As reviewed elsewhere, a wealth of preclinical literature supports the notion that activation of CB1-R by exogenous cannabinoids during adolescence leads to persistent and enduring changes in brain function.

Clinical evidence also supports that young age is a risk factor for conversion to psychiatric disorders with prolonged cannabis exposure, including serious mental illnesses.

The increasing use of cannabinoids, combined with the availability of more potent products, warrants an appropriate understanding of their psychiatric consequences. In this narrative review, which spans the breadth both preclinical and clinical literature, the psychiatric adverse consequences of cannabinoids are summarized, distinguishing their acute effects from effects associated with their persistent use, in order to inform clinicians. As few randomized controlled trials have specifically assessed the safety of herbal cannabis, most of the data on safety are derived from randomized controlled trials with cannabinoids (eg, dronabinol and nabilone) or from data on cannabis use. Clinical implications are discussed subsequently.

The onset of cannabinoid effects depends on the route of administration, with effects emerging within a few minutes with the inhaled route, but taking much longer (60–90 minutes) after oral consumption.

The duration of these effects are highly variable, but typically last for 2 (inhaled) to 4 hours (oral).

The acute psychiatric effects of cannabinoids have greater likelihood of occurrence and severity with higher doses and higher THC/CBD ratio and full agonists, such as SCs. Why some healthy individuals are more vulnerable than others to acute psychiatric effects of cannabinoids is not entirely clear. Individuals with pre-existing psychiatric disorders may be more prone to experience acute psychiatric effects of cannabinoids. Individuals who use cannabinoids regularly may show blunted responses to some of the acute effects of cannabinoids, which may be related to development of tolerance.