Cannabis is one of the most commonly used drugs in the United States. More than 48.2 million people in the US aged 12 years and older (17.5%) have used cannabis in the last year.1 Although evidence suggest that some medical conditions may benefit from cannabis use, there is a lack of high-quality randomized controlled trials examining the potential therapeutic uses of cannabis and a lack of prospective studies looking at associated adverse effects.

The risks and benefits of any cannabinoid-­containing compound need to be carefully weighed for each patient. This includes consideration of potential effects on comorbidities and drug-drug interactions. The increasingly widespread use of cannabis legit online dispensary shipping worldwide makes screening and counseling patients about the potential risks vs benefits a priority.

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Pharmacology
Cannabis sativa and Cannabis indica are the 2 most commonly used strains of cannabis, a plant containing approximately 540 chemical compounds, of which more than 100 are classified as cannabinoids.2 The compound generally responsible for producing intoxication (high) is delta-9-tetrahydrocannabinol (THC); cannabidiol (CBD) does not produce this effect but may have therapeutic effects.3

Cannabis can be found in natural and synthetic formulations that contain psychoactive and inactive compounds. Cannabis concentrates can be inhaled or vaporized. Products for oral ingestion include pills, teas, edibles, tinctures, and gummies. Lozenges, lollipops, and dissolvable strips can be taken sublingually. Topical products include oils, lotions, and bath salts.4

The potency of THC content in samples of recreational cannabis has increased dramatically, from less than 4% in the early 1990s to more than 15% in 2018; some current variants and cannabis concentrates can have much higher THC levels.4 In the last 2 decades, the percentage of nonpsychoactive components has steadily decreased, resulting in an increase in the psychoactive to nonpsychoactive component ratio from 14 times in 2001 to 80 times in 2017.5 The result is that some currently available products may have a greater ability to produce a high.

Psychoactive Drug Components
The absorption and distribution of THC is highly variable depending on the route of administration and individual patient characteristics. When consumed via inhalation (smoking or vaping), the onset of action is typically within 10 minutes; systemic bioavailability is 11% to 45%.6 When THC is consumed orally there is a greater variability in onset and effects due to first-pass metabolism through the liver and significant degradation by gastric acid. Peak THC levels have been reported at 1 to 6 hours after oral ingestion; systemic bioavailability is 4% to 20%.6

The metabolism of cannabis occurs via 2 hepatic cytochrome oxidases, CYP2C9 and CYP3A4. Its plasma half-life ranges from 1 to 3 days in occasional users to up to 13 days in chronic users, and it is eliminated through feces (65%) and urine (20%).6 The elimination half-life can be substantially longer in regular cannabis users because cannabis is highly lipophilic. With regular use, cannabis accumulates in adipose tissues over time, resulting in a slow release when blood levels are low and accounting for a positive urine drug screening for up to 6 weeks after last consumption vs 4 weeks in occasional users.7

Receptors and Reward Pathways
Endogenous cannabinoid receptors are found in the brain, spine, and peripheral nervous system, with components of cannabis acting as a partial agonist at both cannabinoid receptor type 1 (CB1) and type 2 (CB2) sites.8 Within the central nervous system, THC strongly binds to CB1 receptors accounting for its psychoactive properties; CBD does not.8 Cannabis impacts the release of several neurotransmitters such as acetylcholine, norepinephrine, γ-aminobutyric acid, and serotonin within multiple regions of the brain. Areas impacted include the frontal cortex, basal ganglia, cerebellum, hippocampus, and cerebral cortex, accounting for some of the drug’s clinical effects.6,8,9

Binding within the peripheral tissues occurs at CB2 receptors, primarily located within cells in the immune system (B lymphocytes and splenic macrophages), peripheral nerve terminals, and the vas deferens.8 The mechanism of action in the periphery is less clear, but cannabinoids may play a role in the regulation of immune and/or inflammatory reactions.8 Both CB1 and CB2 cells are found in the cardiovascular system.6

Like alcohol and other psychoactive substances, cannabis is processed through the mesolimbic dopamine pathway, the same circuitry involved in the regulation of reinforcement and reward.9 This pathway is associated with reinforcement of adaptive behaviors and the natural high associated with joy or accomplishment. Cannabis binding bypasses the brain’s neurotransmitters and directly stimulates the release of dopamine within the reward pathway, triggering an artificial high. Long-term cannabis use eventually causes changes in this reward circuit. Over time, this results in an increase in impulsiveness to use the substance, which provides a reward, and a decrease in the pleasure or gratification associated with it, accounting for clinical symptoms related to tolerance.9

Physiologic Effects of Cannabis Use
Acute Intoxication
Physiologic effects of acute intoxication may include euphoria, tachycardia, hypertension, conjunctival injection, dry mouth, increased appetite, impaired judgment, and paranoid delusions.10 Acute neuropsychiatric effects can be highly variable in presentation and appear to be dose dependent. At low doses, mood is described as euphoric, with decreased depression, anxiety, and tension; conversely, at higher doses there is increased anxiety, dysphoria, and panic.10 Other neurologic or psychiatric effects may include10-12:

Slowed reaction times and impaired motor coordination
Impaired attention, concentration, short-term memory, and risk assessment
Distortions in time and spatial perception
Increased intensity of visual/auditory perception
Depersonalization, hallucination, grandiosity, paranoia, and/or other signs of psychosis
These effects are additive when combined with other central nervous system (CNS) depressants. Mood-altering effects typically resolve within hours, but residual effects of a dose of cannabis might last for 24 hours. In laboratory studies of cognitive and behavioral effects, evidence suggests that the effects of cannabis increase as the dose consumed or level of THC in blood increases. Evidence also suggests that effects of cannabis on driving simulator performance and collision risk increase as dose consumed and levels in the body increase.