The Chinese emperor Shen Nung is believed to be the first to describe the properties and therapeutic uses of cannabis, which appeared in his compendium of Chinese medicinal herbs written in 2737 B.C.E. Following this, cannabis was cultivated for its fiber, seeds, medicinal use, and recreational consumption, which then spread to India from China [2].

In 1839, William O'Shaughnessy, a British physician and surgeon working in India, was the first individual in Western medicine to discover the use of cannabis as an analgesic, appetite stimulant, antiemetic, muscle relaxant, or anticonvulsant. In 1854, cannabis was listed in the United States Dispensatory; however, after prohibition was repealed, American authorities condemned the use of cannabis, claiming it responsible for insanity, intellectual deterioration, violence, and various crimes. In 1937, the U.S. Government introduced the Marihuana Tax Act. According to this legislation, a tax of $1 per ounce was collected when cannabis was used for medical purposes and $100 per ounce when it was used for unapproved purposes [3]. Cannabis was removed from the U.S. Pharmacopoeia in 1942 [2].

Cannabis use disorder is best described as a chronic relapsing disease characterized by compulsive seeking and use of cannabis, accompanied by functional and molecular changes to the brain [6]. The single most defining aspect of cannabis use disorder is the salience of the relationship with the drug. The stronger the relationship, the more likely the patient will continue problematic use despite internal and external consequences. Individuals who use cannabis often believe it is necessary to get through daily activities, alleviate stress, and cope with problems. Physiologic adaptation, evidenced by tolerance and withdrawal, is often present but may not be sufficient for diagnosis. Cannabis use disorder is diagnosed behaviorally and is evidenced by cravings for cannabis, preoccupation with use of the drug, sneaking and concealing ingestion, loss of the ability to control cannabis use, and continued use despite significant physical, psychological, social, or occupational consequences [6]. The fifth revised edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR) uses 11 behavioral criteria to diagnose cannabis use disorder; it may be further qualified as mild, moderate, or severe based on the number of diagnostic criteria fulfilled (Table 1) [6].

Cannabis withdrawal is a condition that occurs following cessation or substantial reduction in use in previously heavy and chronic users [6]. Withdrawal symptoms (e.g., depression/mood changes, anxiety, sleep difficulties, anorexia, physical symptoms) must result in significant distress and/or affect the patient's social, occupational, or other important areas of functioning.

Identifying patients with a cannabis-related disorder can be difficult, because use disorders and associated problems are typically slow to develop. Patients frequently do not recognize they have a problem or do not want to give up their drug use. They may also be attempting to conceal their drug use from parents, physicians, and other authority figures. Unexplained deterioration in academic or work performance, problems with or changes in social relationships, and changes in recreational activities are signs of a possible problem [7].

Cannabis is the most widely used substance aside from alcohol in the United States. Of the 70.3 million illicit drug users in the United States in 2022, 88% of those individuals had used cannabis at least once in the past year [4,8]. The 2022 National Survey on Drug Use and Health (NSDUH) found that 46.9% of Americans 12 years of age and older had used cannabis at least once in their lifetimes, and 15% were current (past-month) users of cannabis [4,8]. In 2022, adolescent girls (12 to 17 years of age) used cannabis at a rate of 7.6%, compared with 5.3% of adolescent boys in the last 30 days; however, after 18 years of age, men used cannabis more frequently than women in every age group. The demographic with the highest rate of cannabis use is those 18 to 25 years of age, with greater than 26% of individuals reporting current use [4,8]. Among ethnic groups, those of two or more races (24.6%), American Indian/Alaska Native (18%), and Black/African Americans (16.8%) 12 years of age and older are the most likely to currently use cannabis, followed by White (15.6%), non-Hispanic/Latino mixed race (15.3%), Hispanic/Latino (13.5%), and Asian (6.2%) individuals [8].

Cannabis is the most widely used substance aside from alcohol in the United States. Of the 70.3 million illicit drug users in the United States in 2022, 88% of those individuals had used cannabis at least once in the past year [4,8]. The 2022 National Survey on Drug Use and Health (NSDUH) found that 46.9% of Americans 12 years of age and older had used cannabis at least once in their lifetimes, and 15% were current (past-month) users of cannabis [4,8]. In 2022, adolescent girls (12 to 17 years of age) used cannabis at a rate of 7.6%, compared with 5.3% of adolescent boys in the last 30 days; however, after 18 years of age, men used cannabis more frequently than women in every age group. The demographic with the highest rate of cannabis use is those 18 to 25 years of age, with greater than 26% of individuals reporting current use [4,8]. Among ethnic groups, those of two or more races (24.6%), American Indian/Alaska Native (18%), and Black/African Americans (16.8%) 12 years of age and older are the most likely to currently use cannabis, followed by White (15.6%), non-Hispanic/Latino mixed race (15.3%), Hispanic/Latino (13.5%), and Asian (6.2%) individuals [8].

A major risk factor for adolescent substance abuse, including cannabis use, is the presence of conduct problems in childhood. This may be because family conflict, poor parental monitoring, parental substance use, academic problems, and association with peers who use cannabis are all risk factors for both substance abuse and conduct problems. More than half of adolescents with substance abuse problems also exhibit conduct problems [4,14]. Co-occurrence of these problems is a strong predictor of poor outcome following substance abuse treatment. Factors associated with cannabis use disorder include male sex, adolescent aggression/delinquency, childhood abuse (particularly sexual abuse), and evidence of adolescent risk-taking behaviors, such as cigarette smoking, conduct problems, and involvement in a delinquent peer group [4,14]. One study found that externalizing disorders (e.g., antisocial personality disorder) from proximal developmental periods were a significant risk factor for future cannabis use disorders in adolescents and young adults; internalizing disorders were not [22]. Exposure to multiple risk factors is associated with poorer prognosis.

Several factors associated with successful cessation of cannabis use have been identified. These factors include older age, female sex, married marital status, infrequent cannabis use, absence of delinquent behavior, exposure to formal treatment, higher socioeconomic status, high school completion, and non-using friends [26,27].

Cannabis contains more than 500 known chemical compounds, more than 100 of which are grouped under the category of cannabinoids [2,34]. The two main cannabinoids are delta-9-tetrahydrocannabinol (delta-9-THC) and cannabidiol (CBD), with THC the primary psychoactive chemical. Other cannabinoids include delta-8-THC, cannabinol, cannabicyclol, cannabichromene, cannabigerol, terpenes, and flavonoids, all of which are present in smaller quantities and have little proven psychotropic effects compared with THC. The psychotomimetic and anxiogenic effects of THC itself are thought to be attenuated by CBD [2,34]. Cannabinoid receptor type 2 (CB2) activity accounts for some anti-inflammatory and antinociceptive effects, while the anxiolytic effects of CBD result from 5-HT1A (serotonin) receptor agonist activity, among other receptors [2,35]. CBD also exhibits significant anti-inflammatory and analgesic effects [2,34].

Cannabinoids are present in the stalks, leaves, flowers, and seeds of the plant, but they are particularly abundant in the resin secreted by the female plant. THC content varies among the available sources and preparations of cannabis. Advances in cultivation (such as hydroponic farming) and plant-breeding techniques have increased the potency of cannabis products over time. For example, in the 1990s, the average THC content in a marijuana flower was less than 2%; in 2017, the most popular strains contained 17% to 28% THC. Development of concentrated products (e.g., oil, dabbing products, edibles) can contain 95% THC or even greater [2,36].

As little as 2.5 mg of THC is enough to produce measurable psychological and physical effects in the occasional cannabis user. Upon transferring to the bloodstream, cannabinoids are distributed rapidly systemically, first reaching the fatty tissues and organs with the highest blood flow, such as the brain, lungs, and liver [2]. Within the brain, cannabinoids are differentially distributed, reaching high concentrations in the neocortical areas, especially the frontal cortex; the limbic areas, including the hippocampus and amygdala; sensory areas, such as the visual and auditory cortex; motor areas, including the basal ganglia and cerebellum; and the pons [2]. Whether THC accumulates in the brain with long-term use is unknown, due to limits in THC access and accumulation imposed by the blood-brain barrier.

Cannabinoids are highly fat soluble and accumulate in fatty tissues. From these tissues, the compounds are very slowly released into other parts of the body. In occasional users, the plasma elimination half-life of THC is approximately 1 to 3 days; in chronic users it is 5 to 13 days [2].

Cannabinoids are mainly metabolized in the liver, where they produce more than 20 metabolites, some of which are psychoactive and many of which have plasma elimination half-lives of the order of 50 hours. The major metabolite is 11-hydroxy-THC, which may be more potent than the parent compound and be responsible for some of the effects of cannabis. Relative to inhalation, first-pass hepatic metabolism with oral ingestion yields a greater proportion of 11-hydroxy-THC [2].

As with many drugs, cannabis can enhance or attenuate the effects of other medications. A combination of dronabinol (a cannabinoid) and prochlorperazine is more effective in reducing chemotherapy-associated nausea and vomiting than prochlorperazine alone [57]. Cannabis can also augment the sedating effects of other psychotropic substances, such as alcohol and benzodiazepines. A number of synergistic effects may be therapeutically desirable, such as the enhancement of:

Dronabinol, a synthetic THC derivative, is approved for the treatment of refractory nausea and vomiting caused by antineoplastic drugs used for the treatment of cancer and for appetite loss in anorexia and cachexia of patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) [50]. Dronabinol and nabilone, another synthetic derivative, are generally considered safe, effective antiemetics and are recommended by the National Comprehensive Cancer Network for this use [40]. A vast body of anecdotal evidence from the past 150 years as well as preclinical and clinical trial results strongly indicate a valuable role for cannabis in controlling nausea and vomiting caused by cytotoxic drug administration or secondary to another primary medical condition [62]. A meta-analysis of cannabinoid efficacy in chemotherapy-induced nausea and vomiting found superior antiemetic efficacy of dronabinol, nabilone, levonantradol (not approved for use in the United States), and smoked cannabis compared with conventional drugs and placebo [63].

The euphoriant potential of cannabis is probably the single most important characteristic in sustaining its widespread and often chronic recreational use. This effect varies greatly with dose, route of administration, expectation, environment, and personality of the user. However, dysphoric reactions to cannabis are not uncommon. In some cases, use may result in severe anxiety and panic, unpleasant somatic sensations, and paranoia. Anxiety-panic reactions are the most common adverse psychological effects of cannabis use. Flashbacks, whereby the original drug experience (usually dysphoria) is re-experienced weeks or months later, are possible and may represent a psychological reaction similar to that of post-traumatic stress disorder [45].

The changes in perception that result from cannabis and THC affect all sensory modalities. Color and sound perception may be heightened, and musical appreciation may be increased. Temporal and spatial perception is distorted, impairing judgment of distance and time. Even after small doses, persons under the influence of cannabis consistently overestimate the passage of time. Persistent visual changes, some lasting for months, have been documented [45].

Cannabis smoke contains many of the same constituents as tobacco smoke (minus the nicotine), including bronchial irritants, tumor initiators (mutagens), tumor promoters, and carcinogens. The tar from cannabis smoke also contains higher concentrations of the carcinogens benzanthracenes and benzopyrenes than tobacco smoke tar. Smoking a cannabis cigarette results in inhalation of three times the amount of tar of a tobacco cigarette, and respiratory tract retention is greater than smoking a tobacco cigarette. As a result, cannabis use may result in impairment of lung function, leading to airflow obstruction and hyperinflation [41,45].

There is not sufficient evidence of significant immunologic damage in humans from cannabis [45]. However, it is important to note that cannabis may be contaminated with micro-organisms, such as Aspergillus and Salmonella, as well as fecal matter. Therefore, a potentially serious adverse effect of cannabis is the risk of infection. In addition, chronic cannabis use may lead to impaired pulmonary defense against infection. The risk of infection is of particular concern in patients with HIV/AIDS due to their increased susceptibility to infection from fungal and bacterial contaminants and epithelial damage from the smoke [7].

Neurochemical causes of cannabinoid withdrawal include reduced dopaminergic activity along the ventral tegmental area-nucleus accumbens pathway, and upregulated expression and release of corticotropin-releasing hormone (CRH) in the central nucleus of the amygdala [3].

Until fairly recently, cannabis was not considered a drug with a liability of dependence and addiction. In the limited research, withdrawal did not appear to lead to any obvious physical symptoms, and animals failed to self-administer the drug, a behavior usually associated with drugs of addiction [86]. Few studies had focused on the treatment of cannabis abuse or dependence. However, it is now known that individuals can develop a chronic use pattern associated with dependence symptoms and recurrent psychosocial problems [124]. Two factors have contributed to the historical lack of research: the common beliefs that cannabis abuse rarely occurred as a primary problem and that cannabis use did not produce a true dependence syndrome. Data contrary to these assumptions first appeared in the late 1980s, and treatment development and efficacy studies specific to cannabis dependence first began to appear in the scientific literature during the 1990s [135]. As medicinal use of the drug has accelerated into the mainstream, and bolstered by the discovery of the human endocannabinoid system, a large amount of research into many facets of cannabis and cannabis use has emerged.