Cannabis Use Disorder

The Cannabis Family

There are over 700 different types of plants within the Cannabis family; the two main subspecies are Cannabis indica and Cannabis sativa . Cannabis sativa has a higher ratio of THC to CBD, whereas Cannabis indica has a higher ratio of CBD to THC. Different cannabis plants are engineered to have different properties; “hemp” plants, for instance, are legal in a number of US states and are cannabis plants with high concentrations of CBD and negligible THC. The concentration of THC and CBD varies throughout different parts of the cannabis plant and is highest in female plants’ flowering tops. These areas produce high numbers of trichomes , fine glandular outgrowths that produce THC, CBD, and other cannabinoids.

Cannabis potency is considered high if it contains greater than 10% of THC by dry weight. The average potency of cannabis has steadily increased over time as cannabis plants have been selectively bred for higher THC content.

A note on terminology: There is no such thing as the “marijuana plant,” all forms of plant-based cannabis are subsumed under the cannabis family. Although marijuana and cannabis are commonly used interchangeably, “marijuana” is a term created during the Great Depression to mark cannabis as a drug mainly used by Mexicans.

Cannabinoids

Cannabinoids refer to the family of molecules which share the 21-carbon structure of THC and include plant-based, endogenous, and synthetic cannabinoids. See Fig. 8.1 for a side-by-side comparison of their molecular structures.

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  Plant-based cannabinoids: More than 100 plant-based cannabinoids have been identified, but the main cannabinoids to know are THC and CBD . Both molecules have long aliphatic chains responsible for their hydrophobic, lipophilic properties and perfusion into adipose tissue ( Fig. 8.1 ).

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  Endogenous cannabinoids: Anandamide and 2-arachidonoylglycerol are the main endogenous cannabinoids to know and are the key ligands for endocannabinoid receptors (CB1 and CB2) expressed widely in the central nervous system (primarily CB1) and the periphery (primarily CB2).

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  Synthetic cannabinoids: These are a heterogeneous family of ever-evolving, laboratory-produced cannabinoids that share structural homology with THC, although they are misleadingly marketed for their “natural” high and at times for their “legal” high. The prototypical synthetic cannabinoid is HU-210 (for Hebrew University, where the first synthetic cannabinoid was created). Synthetic cannabinoids are known and sold by many names, including K2 and spice.

Standard urine drug screens (UDSs) cannot detect synthetic cannabinoids for THC because of its inexact homology with THC. This property can be exploited by individuals who want to evade urine drug screens.

Dronabinol is synthetically produced delta-9-THC and will cause a positive urine drug screen for THC because it is structurally identical. Nabilone is a synthetic analog of THC, and it has minimal euphoric effects.

Cannabinoids: Pharmacology and Mechanism of Action

For the board examination, it is important to know the differing receptor properties and mechanisms of action for THC, CBD, and synthetic cannabinoids.

THC:

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  Partial agonist at CB1 and CB2 (CB1>CB2)

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  Modulates beta-2-adrenergic receptors

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  Modulates mu- and delta-opioid receptors

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  Metabolized by CYP3A4, inhibits CYP2C9, induces CYP1A2

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  Rapidly metabolized to 11-hydroxy-THC (psychoactive), then to THC-carboxylase (not psychoactive)

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  Elimination half-life ranges from 25 to 36 hours and is longer for regular cannabis users (in part due to storage in fat reserves)

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  Predominantly eliminated via feces (>65%) and urine (20%)

CBD:

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  Low affinity for CB1 and CB2

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  Modulates mu- and delta-opioid receptors

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  5-HT1A partial agonism

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  Modulates psychotomimetic effects of THC

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  Suggested to have anticonvulsant, antipsychotic, antianxiety properties

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  Does not have euphoric, intoxicant effects

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  Metabolized by CYP3A4, it inhibits CYP2D6 and CYP2C9

Synthetic Cannabinoids (e.g., K2, Spice, HU-2010):

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  Full agonists at CB1

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  Have much higher receptor affinity (approximately 100×) for CB1 compared with THC

Synthetic cannabinoids have greater psychotomimetic properties compared to plant-based THC because it has greater receptor affinity and is a full agonist at CB1, in addition to lacking any CBD.

Rimonabant is a CB1 receptor antagonist and has been studied to treat cannabis use disorder and weight loss.

The Endocannabinoid System

THC was first isolated in 1965. Subsequent decades of research and interest in the effects of THC led to the discovery of the endocannabinoid system. Here we review the structure and function of the endocannabinoid system as well as cannabinoid receptors.

The endocannabinoid system regulates a wide variety of physiological properties, including pain, appetite, mood, immune system modulation, gastrointestinal tract function, the cardiovascular system, and stress regulation. For the board examination, the two key receptors of the endocannabinoid system to know are cannabinoid receptors 1 and 2 (CB1 and CB2), although there are others under investigation. Both CB1 and CB2 are G-protein receptors, and CB1 is the most abundant G-protein receptor expressed in the CNS. CB1 is widely expressed in various brain regions as well as in most tissues and organs in the periphery. Centrally, the highest concentrations can be found in the hippocampus and the basal ganglia. CB2 receptors, however, are largely expressed in immune cells but are also expressed in the CNS. Endogenous ligands for CB1 and CB2 include anandamide and 2-arachidonyl glycerol, both lipid-based retrograde neurotransmitters.

An important property of CB1 is that it co-localizes and dimerizes with a number of other receptor types in the CNS and the periphery. These include the mu-, kappa- and delta-opioid receptors, orexin-1 receptors, A2A adenosine receptors, and the beta-2-adrenergic receptors.

CB1 receptors co-localize with beta-2-adrenergic receptors, which is postulated to cause its adrenergic-like effects (e.g., tachycardia or panic attacks in cannabis intoxication).

The combination of cannabinoids with anticholinergic drugs can lead to marked tachycardia.

Cannabis Intoxication

The signs and symptoms of cannabis intoxication are summarized in Table 8.1 . Recall that CB1 receptors co-localize with beta-2-adrenergic receptors and therefore can cause a number of adrenergic-like effects, including tachycardia, blood pressure variability, and tachypnea. The cognitive effects of cannabis intoxication include short-term memory, judgment, concentration, and motor impairment; the latter effect becomes important for cannabis-related traffic accidents. The psychotomimetic effects of THC can lead to psychiatric effects, including anxiety, hypervigilance, and psychosis.

Cannabis hyperemesis syndrome (CHS) is a consequence of heavy cannabis use and is characterized by nausea, abdominal pain, and severe cyclic vomiting. Individuals who present with CHS are predominantly young, male, heavy and/or daily cannabis users who frequently report relief of symptoms with very hot showers. The pathophysiology is unclear, but the most effective treatments to date include cessation of cannabis use, oral dopamine antagonists (e.g., haloperidol), or topical capsaicin (applied to the abdomen). The hypothesized pathophysiology of CHS involves dysregulation of the endocannabinoid system and CB1 receptors in the hypothalamus and gastrointestinal tract.

Cannabis intoxication is not a common chief complaint for individuals who come for medical attention compared with other intoxication syndromes; among those who do present in emergency settings, it is most often for anxiety, panic, psychosis, or CHS. At doses of THC above 7.5 mg/m ² (approximately 12 g for an average adult woman; 14 g for an average adult man), it can cause delirium, postural hypotension, myoclonic jerking, and panic attacks. For reference, an average joint contains approximately 0.5 to 1 mg of THC.

The time to onset of action, peak, and duration of effects varies greatly depending on the route of administration (oral, sublingual, smoked). Table 8.2 summarizes these differences and common side effects for each route of administration.

Although commonly believed to be toxin-free, cannabis smoke in fact leads to a higher respiratory burden of carbon monoxide and tar than tobacco. This effect is independent of the concentration of THC in the cannabis plant.

Cannabis Withdrawal Syndrome

Cannabis withdrawal is a relatively recently identified syndrome following abrupt cessation of frequent cannabis use. Cannabis withdrawal is not as dangerous as alcohol/sedative-hypnotic withdrawal or as uncomfortable as opioid withdrawal but can lead to distressing symptoms that make it difficult to quit. The symptoms of cannabis withdrawal are fairly nonspecific and include anxiety, difficulty sleeping, decreased appetite, irritability, and restlessness. Most symptoms have onset within 24 to 72 hours, peak within 1 week, and last for approximately 1 to 2 weeks.