Marijuana and the Cannabinoids

Background and History of Cannabis and Marijuana

Basic Pharmacology of Marijuana

• Cannabis sativa, the flowering hemp plant, exudes a resin containing a number of unique compounds known as phytocannabinoids.
• Cannabis can be obtained in several different types of preparations, including marijuana and hashish, both of which may be smoked or taken orally. Dabbing refers to inhalation of the heated vapors of a newer kind of cannabis extract. Hashish and dabs are preferred by some users because of their greater potency compared with marijuana and the resulting increase in subjective “high.”
• The consumption of cannabis for its intoxicating effects is thought to date back thousands of years in Eastern cultures. The practice of marijuana smoking was introduced into the United States in the early 1900s by Mexican and West Indian immigrants.
• An anti-marijuana campaign instituted in the 1930s led to the first federal regulations controlling this substance.
• The most important psychoactive phytocannabinoid is Δ⁹-tetrahydrocannabinol (THC). A non-psychoactive constituent, cannabidiol (CBD), is also of interest because of its emerging potential for treating a variety of neuropsychological and neuropsychiatric disorders.
• Inhaled THC is rapidly absorbed from the lungs into the circulation, where it is almost completely bound to plasma proteins. Oral THC consumption yields slower absorption and a lower plasma peak than occurs following smoking.
• THC is extensively metabolized in the liver, and the metabolites are excreted mainly in the feces and urine. Following a single dose of THC, total clearance of the drug and its metabolites may take days because of sequestration of these compounds in fat tissue.

Mechanisms of Action

• Two cannabinoid receptors, CB₁ and CB₂, have been identified and their genes cloned.
• The CB₁ receptor is the principal cannabinoid receptor in the brain, where it is expressed at a high density in the basal ganglia, cerebellum, hippocampus, and cerebral cortex.
• The CB₂ receptor was first identified in the immune system, but it is also found in a number of other tissues, including the brain, where it is mainly localized in microglial cells.
• Cannabinoid receptors belong to the G protein–coupled receptor superfamily. Receptor activation can inhibit cAMP formation, inhibit voltagesensitive Ca²⁺ channels, and activate K⁺ channels.
• CB₁ receptors are typically located on axon terminals, where they act to inhibit the release of many different neurotransmitters.
• Agonists at the CB₁ receptor include the synthetic full agonists CP-55,940 and WIN 55,212-2 and the partial agonist THC. The first selective CB₁ antagonist was SR 141716A, also known as rimonabant.
• THC administration to mice causes a classical tetrad of CB₁ receptor–mediated effects that consist of reduced locomotor activity, hypothermia, catalepsy, and hypoalgesia.
• CB₁ agonists also impair learning and memory consolidation in several different kinds of tasks. Interference with memory of hippocampaldependent spatial tasks has been linked to inhibition of LTP in the hippocampal CA1 area and a reduction in oscillatory activity within the hippocampal circuitry.
• CB₂ receptor activation in the immune system causes cytokine release and changes in immune cell migration toward an inflammatory site.
• The brain synthesizes several substances, called endocannabinoids, that are neurotransmitter-like agonists at cannabinoid receptors. Anandamide was the first endocannabinoid to be discovered; however, another endocannabinoid called 2-AG is present in the brain at higher levels than anandamide.
• Endocannabinoids are generated on demand from arachidonic acid–containing membrane lipids by a Ca²⁺-dependent mechanism and are released from the cell by a process that does not involve synaptic vesicles. They are believed to be removed from the extracellular space by a carrier protein called the endocannabinoid membrane transporter.
• Anandamide and 2-AG are degraded primarily by FAAH and MAGL, respectively.
• Endocannabinoids usually function as retrograde messengers that are synthesized and released from postsynaptic cells to activate CB₁ receptors on nearby nerve terminals. This process leads to an inhibition of voltage-gated Ca²⁺ channel opening and a consequent reduction in neurotransmitter release from the terminals. However, two other modes of endocannabinoid signaling have been discovered. First, in some cases the endocannabinoid (usually anandamide) remains within the postsynaptic cell where it activates either a cannabinoid receptor or an excitatory ion channel called TRPV1. Second, endocannabinoids can activate cannabinoid receptors on astrocytes, thus causing release of glutamate from those glial cells.
• A well-characterized example of endocannabinoid retrograde signaling involves excitatory glutamatergic synapses in the hippocampus along with some other brain areas. Glutamate release from the nerve terminal activates mGluR5 receptors in dendritic spines, which elevates intracellular Ca²⁺ levels and triggers 2-AG synthesis and release. 2-AG diffuses back to the terminal where it activates CB₁ receptors, resulting in inhibition of voltage-gated Ca²⁺ channels and a reduction in glutamate release. This negative feedback system regulates brain excitability and helps protect the brain against glutamate excitotoxicity.
• The endocannabinoid system plays a complex role in learning and memory of hippocampal-dependent tasks. Some studies indicate that endocannabinoid signaling inhibits learning or memory processes, whereas other study findings are more consistent with an involvement in extinction of an already learned spatial task.
• Enhancing endocannabinoid signaling has anxiolytic effects in both stressed and unstressed laboratory animals, and it also leads to an antidepressant profile in standard rodent tests of depressive-like behavior. In contrast, reduced endocannabinoid levels are associated with increased anxiety- and depressive-like behaviors. In auditory fear conditioning tasks, endocannabinoids facilitate extinction of the CR (freezing) when the CS (tone) is no longer paired with the US (foot shock). This finding is consistent with a theorized role for the endocannabinoid system in alleviating fear.
• In recent years, marijuana has been legalized for medical use in many states despite the lack of well-controlled clinical studies demonstrating its therapeutic efficacy. Oral preparations of synthetic THC or a THC analog are currently licensed for treating nausea and vomiting in cancer chemotherapy patients, as well as the wasting syndrome in patients with AIDS. An oral spray containing both THC and CBD is also approved in many countries (not including the United States) for neuropathic pain and spasticity in patients with multiple sclerosis. The endocannabinoid system is being actively studied as a target in the treatment of many other kinds of disorders, including headaches, visceral pain, neurodegenerative disorders and stroke, and a variety of neuropsychiatric disorders. Finally, a strong initiative is underway to develop CBD-based medications for pediatric epileptic syndromes that are refractory to standard antiseizure drugs.

Acute Behavioral and Physiological Effects of Cannabinoids

• The subjective characteristics of cannabis intoxication include feelings of euphoria, disinhibition, relaxation, altered sensations, and increased appetite. The euphoric effects produced by smoking marijuana appear to be mediated at least partly by CB₁ receptors. Psychopathological reactions can occur, particularly at high doses or in inexperienced users.
• Cannabis acutely causes impairment in episodic verbal memory and working memory, attention, inhibitory control, and psychomotor performance. Some of these effects are reduced in magnitude when participants have been pretreated with CBD.
• Researchers have had difficulty demonstrating reliable IV self-administration of THC in rodents and rhesus monkeys; however, both self-administration and drug-seeking behavior for this compound have been shown in squirrel monkeys. Certain properties of THC may underlie its lack of clear reinforcing properties in rats and mice, as these species more readily self-administer the synthetic cannabinoid WIN 55,212-2, which is a full CB₁ receptor agonist. Rodent studies have additionally demonstrated the ability of WIN 55,212-2 to produce a conditioned place preference and a reduced threshold for electrical self-stimulation of the brain. These effects are all mediated by activation of CB₁ receptors.
• Endocannabinoids are involved in the brain’s reward system. These substances help mediate the rewarding and reinforcing effects of natural rewards like sweetened solutions as well as the effects of various abused drugs such as opiates.
• Cannabinoid reinforcement has been shown to depend on the CB₁ receptor and may also involve DA, since cannabinoids stimulate the firing of DA neurons in the VTA and enhance DA release in the nucleus accumbens. The mechanism underlying cannabinoid enhancement of dopaminergic activity involves activation of CB₁ receptors expressed by inhibitory VTA GABAergic interneurons, thereby resulting in a disinhibition of dopaminergic cell firing.

Cannabis Abuse and the Effects of Chronic Cannabis Exposure

• Marijuana is the most heavily used illicit drug in the United States.
• Early behavioral (e.g., conduct) problems have been associated with an increased likelihood of early marijuana use.
• Initial exposure to marijuana usually occurs during adolescence, after the individual has already had experience with alcohol and/or cigarettes. Some investigators have hypothesized that alcohol and tobacco are “gateway” drugs to marijuana, which then serves as a potential gateway to other illicit drugs. However, it is difficult to determine whether marijuana actually facilitates the progression to these more dangerous substances.
• Other factors such as family issues, poor school performance, and a strong positive response to early marijuana experience are risk factors for the transition to regular use and possibly dependence.
• DSM-5 contains diagnostic criteria for cannabis intoxication, withdrawal, and use disorder. Criteria for cannabis use disorder are the same DSM-5 criteria for any substance use disorder but applied specifically to cannabis. Severity may be mild, moderate, or severe depending on the number of criteria met by the patient. Longitudinal studies indicate that about 20% to 25% of cannabis users will develop a cannabis use disorder at some point in time, but the disorder resolves over time in most individuals.
• Many factors contribute to the risk of developing a cannabis use disorder, including early onset of use, progressing to daily use, experiencing highly positive reactions to cannabis, use of cannabis to cope with negative emotions, concurrent use of tobacco, living alone, experiencing major life stressors, having a comorbid psychiatric disorder, possessing specific SNPs for the CB₁ and FAAH genes, and being male.
• Controlled laboratory studies have demonstrated tolerance to repeated THC exposure in both humans and experimental animals. Such tolerance is related to a desensitization and down-regulation of central CB₁ receptors, including CB₁ receptors in the cerebral cortex of regular marijuana smokers.
• Heavy (e.g., daily) marijuana users are at significant risk for developing dependence on the drug and for undergoing withdrawal symptoms upon becoming abstinent. Withdrawal symptoms include heightened irritability, anxiety, aggressiveness, depressed mood state, sleep disturbances, reduced appetite, craving for marijuana, and a cluster of physical symptoms consisting of abdominal pain, tremors, sweating, fever, chills, and headache.
• Chronic THC exposure in laboratory rodents also causes the development of dependence that can be demonstrated using the procedure of precipitated withdrawal with rimonabant. Neurochemical studies of cannabinoid-dependent animals undergoing withdrawal have found reduced DA cell firing, increased CRF release, and endocannabinoid system changes that could contribute to some of the symptoms of cannabis withdrawal in human users.
• Individuals who have developed cannabis dependence report a number of life problems, which leads some of these individuals to seek treatment. nnSome success has been achieved with various kinds of psychotherapeutic interventions, and there has been additional improvement in outcome from adding a voucher-based incentive program to the standard treatment approach. Nevertheless, most dependent individuals find it difficult to maintain long-term abstinence.
• Pharmacotherapeutic approaches to the treatment of cannabis dependence are now being investigated. Approaches using cannabinoid agonists such as nabiximols spray are also being tested. Although such treatments can reduce withdrawal symptoms in cannabis-dependent patients, they have not yet demonstrated efficacy in improving long-term recovery from the disorder.
• Concerns have been raised over possible adverse consequences of chronic cannabis consumption. There is a negative association between the amount of cannabis use by young people and their educational performance, although it is not yet known whether this association is causal. It is possible that heavy cannabis use can produce persistent cognitive deficits and/or an amotivational syndrome characterized by apathy, loss of achievement motivation, and decreased productivity. Alternatively, early cannabis use may be linked to the adoption of an unconventional lifestyle that devalues educational striving and achievement.
• Testing of long-term cannabis users after (possible) withdrawal symptoms have subsided has revealed deficits in several cognitive domains, including attention, ability to concentrate, executive functions, verbal learning and memory, and psychomotor performance. Some, though not all, of these deficits may persist over a long time period following abstinence.
• Neuroimaging studies of regular cannabis users have reported structural and biochemical changes in certain brain regions, including reduced volume of the hippocampus and parts of the PFC, and deficits in white matter integrity. Chronic use has also been associated with decreased striatal DA synthesis and decreased dopaminergic responses to challenge with psychostimulant drugs. These neurochemical differences were correlated with some of the psychological (cognitive and mood) differences between users and nonusers.
• Rodent studies have investigated the neurobiological and behavioral consequences of repeated cannabinoid exposure during adolescence. This research has shown cannabinoid-mediated changes in several neurotransmitter systems, altered synaptic plasticity, dysregulated emotional and social behaviors, and impaired cognitive function. In addition, abnormal growth of dendritic arbors and spines has been observed in the PFC, hippocampus, and nucleus accumbens.
• Health consequences of heavy marijuana smoking include respiratory problems, increased risk of a myocardial infarction, interference with the reproductive system in both men and women, suppression of immune function, and adverse effects on offspring development when used by pregnant women.
• Synthetic designer cannabinoids marketed as “K2” or “Spice” began to be sold over the internet in 2004. Synthetic cannabinoids are typically highly potent full agonists at both CB₁ and CB₂ receptors. Because of their potency, these substances can produce a severe state of intoxication and have caused a range of adverse health effects including kidney damage, seizures, panic attacks, first-onset psychosis, and even a small number of fatalities. Taken together, these consequences indicate the unusually high degree of toxicity of synthetic cannabinoids, and they highlight the danger of using these substances.