Marijuana is a dry, shredded green or brown mixture of flowers, stems, seeds and leaves of the hemp plant Cannabis. Cannabinoids were originally defined as the phytocannabinoids contained in Cannabis. As with opiates, later definitions were more inclusive, defining cannabinoids as “all ligands of the cannabinoid receptor and related compounds including endogenous ligands of the receptors and a large number of synthetic cannabinoid analogs” (Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clinical Pharmacokinetics, 2003, (42), 327–360.).

Preparations of marijuana have a rich history in terms of medical use and myth. The fiber of the plant is used for rope, and the psychoactive varieties of the plant are used for both their medicinal and intoxicating effects. Marijuana contains more than 60 different cannabinoids, but the primary active ingredient is Δ9-THC. Cannabinoids have two accepted medical uses in the United States. Dronabinol (Marinol; the pure isomer of Δ9-THC) and nabilone (Cesamet; a synthetic analog of THC) are approved for use in refractory nausea and vomiting associated with cancer chemotherapy and appetite loss in HIV/AIDS patients with anorexia. Many potential medical uses of cannabis preparations are being considered in the United States, including the amelioration of spasticity caused by spinal cord injury and multiple sclerosis, analgesia treatment for asthma, the treatment of glaucoma, and use in the treatment of movement disorders, including dystonias, dyskinesias, and tardive dyskinesia.

Marijuana is also the most commonly used illicit drug in the United States. It produces intoxicating effects when ingested, usually by inhalation, including euphoria and mood swings characterized by initial feelings of “happiness” or sudden talkativeness, a dreaming or lolling state, and general activation and hyperactivity. Higher doses are associated with psychedelic-like effects, such as an increased sensitivity to sound and a keener appreciation of rhythm and timing. The perception of time is often slowed, with an exaggeration of the sense of time. Perceptions of space may be broadened, and near objects may appear distant. Intoxication is commonly associated with visual “hallucination-like” effects that are mostly illusionary transformations of the outer world.

Following ingestion, Δ9-THC has a peculiar distribution in the body, initially sequestering in vascularized tissue and later in fat-rich tissues. It has a long terminal half-life of approximately 30 h, but its metabolites can be measured in urine for weeks after ingestion. The pathological effects of intoxication or chronic high-dose use include an impaired ability to drive while intoxicated, cardiovascular risks for people with pre-existing cardiac problems, anxiety, panic reactions, impairment in executive function, impairment in the development of executive function, exacerbation of schizophrenic-like symptoms in individuals who are vulnerable to schizophrenia (with some evidence that Δ9-THC can precipitate schizophrenic-like syndromes), and a possible causal role in the vulnerability to schizophrenia. Marijuana smoke may also have the same potential toxicity as cigarette smoke with regard to lung function.

Marijuana produces a substance use disorder (DSM-5 criteria) or Substance Dependence (DSM-IV criteria) with many characteristics similar to other drugs of abuse. Tolerance develops to the intoxicating and physiological effects, and a withdrawal syndrome has been defined in both humans and animals. In humans, the most common symptoms associated with cannabis withdrawal are decreased appetite and weight loss, irritability, nervousness, anxiety, anger, aggression, restlessness, and sleep disturbances. Most of the DSM-IV criteria for Substance Use Disorder were met by individuals diagnosed with Substance Dependence on cannabis. Preoccupation with obtaining and using marijuana is represented by the persistent presence of marijuana in the individual’s daily living and choices of activities. Compulsivity is represented by continued use despite marijuana-related consequences. Relapse or the propensity to relapse is reflected by a return to marijuana use after a period of abstinence and may provide confirmation of the suspected diagnosis.

The behavioral mechanism of action of cannabinoids is hypothesized to include perceptual disinhibition of both external and internal cues or states without motivational disinhibition. This perceptual disinhibition can be pleasant or unpleasant depending on internal and external contexts. The discovery of cannabinoid CB1 and CB2 receptors and high-potency ligands in the brain led to the identification of anandamide and 2-AG. These endocannabinoids act as retrograde neuromodulators in the central nervous system and regulate brain excitability through local actions on presynaptic GABA and glutamate neurons. In animals, Δ9-THC and other cannabinoids have reinforcing properties in models of brain stimulation reward, conditioned place preference, and self-administration. The acute reinforcing effects of cannabinoids involve the mesocorticolimbic dopamine and opioid peptide systems in the ventral tegmental area and basal forebrain. Similarly to alcohol and opioids, the disinhibition of specific GABAergic and glutamatergic systems may facilitate the activation of reward neurotransmitters associated with the acute reinforcing effects of cannabinoids.

Genetic studies have shown that knockout of the CB1 receptor blocks the acute reinforcing and dependence-inducing effects of cannabinoids and blunts some of the effects of opioids, suggesting cross-talk between the opioid and cannabinoid systems. Cannabinoids that act through the CB1 receptor inhibit adenylate cyclase, which in turn inhibits phosphokinase A, leading to the activation of inwardly rectifying potassium channels and inhibition of P/Q-type voltage-dependent calcium channels. This combined inhibition leads to a presynaptic action at all levels of the brain motivational systems.

In the withdrawal/negative affect stage of the addiction cycle, tolerance is observed in animals, and both somatic and motivational withdrawal syndromes have been observed. Decreases in mesocorticolimbic dopamine activity are associated with the motivational effects of cannabinoid withdrawal. Acute withdrawal from cannabinoids is associated with CRF activation in the extended amygdala, similar to other drugs of abuse.

In the preoccupation/anticipation stage, there are limited preclinical data, but cannabinoids can elicit drug-primed reinstatement in relapse models, not only for cannabinoids, but also for other drugs of abuse. This reinstatement can be blocked by CB1 receptor antagonists and opioid receptor antagonists.

The explosion of research in the cannabinoid field will most certainly provide further insights into the neurobiology of cannabinoid addiction and the role of the endogenous cannabinoids in normal adaptive function.

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