____________________________________________________ Medical Marijuana and Other Cannabinoids
These factors appear in the results of a 20-year longitudinal study of pulmonary health in 5,115 participants who smoked cannabis [142]. The authors stated that pulmonary risks from cannabis smoking had been overstated and found that, unlike tobacco smoking, cannabis smoking had no effect on measures of pulmonary function. Medicinal use of smoked cannabis was also found to be very unlikely to produce adverse effects on pulmonary function [142]. In 878 Canadians 40 years of age and older, history of tobacco smoking or tobacco and mari- juana smoking, but not marijuana-only smoking, significantly elevated the risk of respiratory problems or chronic obstructive pulmonary disease (COPD) relative to non-smokers [143]. In a 2022 study comparing 56 cannabis smokers and 33 tobacco- only smokers, the cannabis smokers showed higher rates of emphysema and airway inflammation than nonsmokers or tobacco-only smokers [144]. However, the researchers were careful to point out that high rates of concomitant tobacco smoking in the cannabis group made drawing firm conclu- sions difficult. Vaporizing systems have been developed to further minimize pulmonary risks from smoked cannabis. These involve heating the plant material short of combustion and then inhaling the mist (instead of smoke). Vaporization may produce smaller quantities of the toxic smoking byproducts carbon monoxide, polycyclic aromatic hydrocarbons and tar, and compared with smoked cannabis, vaporization was found to significantly reduce carbon monoxide levels [115; 116]. One study evalu- ated the subjective and physiologic effects and expired carbon monoxide in frequent and occasional cannabis users following placebo, smoked, vaporized, and oral cannabis [145]. Partici- pants’ subjective ratings were significantly elevated compared with placebo after smoking and vaporization; only occasional smokers’ ratings were significantly elevated compared with placebo following oral dosing. Smoking produced significantly increased expired carbon monoxide concentrations post-dose compared with vaporization [145]. Immunosuppression Concern was raised in the 1990s over the potential negative effects of cannabinoids on immune function in immunosup- pressed patients, particularly those with HIV. Data from several studies have alleviated these concerns. In HIV patients randomized to placebo, dronabinol, or smoked cannabis for 21 days, both cannabinoid groups failed to show increased viral load or reductions in protease inhibitor levels or CD4 or CD8 cell counts. Both cannabinoid groups showed statistically significant weight increases, and the smoked cannabis group showed significantly increased CD4 and CD8 counts [146]. Supportive data include a study of primates injected daily with THC before and after infection with simian immunodeficiency virus (SIV). Contrary to expectations, chronic cannabinoid exposure did not increase viral load or diminish immune function. Instead, the primates given THC showed significantly decreased rates of early mortality from SIV infection, associ-
ated with attenuation of plasma and cerebrospinal fluid viral load and retention of body mass [147]. Other conformational findings include a 10-year follow study of HIV patients, which found that regular cannabis smoking had no effect on viral load or CD4 and CD8 cell percentages [148]. An exception comes from preclinical trial results suggesting that increased CB2 activity may impose risks in immunocompromised patients with specific infection, such as Legionella [59]. Further, results of a 2022 study found that THC, used for the treatment of chemotherapy-induced nausea, reduced the therapeutic effect of PD-1 blockade that impeded antitumor immunity, indicat- ing an immunosuppressive role of the ECS [149]. Neurocognitive Impairment There is abundant evidence from studies in adult subjects that smoking cannabis has an acute effect on motor coordination and impairs verbal and working memory for several hours after ingestion, an effect mitigated by several factors, including the degree of previous exposure to cannabis, the dose of THC, the ratio of THC to CBD, and genetic susceptibility [150]. These effects on cognition, mediated by THC, appear to resolve within hours to days after cessation of cannabis exposure. The long-term effects of chronic cannabis use are more subtle and complex and involve multiple domains of cognitive func- tion, as evidenced by psychologic testing and brain imaging studies. A growing body of evidence indicates that while significant neuropsychologic deficits may develop following chronic cannabis use, these deficits are largely reversible if chronic use did not commence until after one achieves adulthood (i.e., after full anatomic maturation of the brain). Early-onset (in adolescence) and long-term use of cannabis causes the greatest morphologic and functional impairments in the still-developing brain, and these deficits may not resolve completely after cessation of usage [150; 151]. Results from the 2012 Dunedin study provide the most defini- tive data on neurocognitive effects from cannabis use [152]. This prospective study followed 1,037 individuals from birth in 1972/1973, assessed their cannabis use at ages 18, 21, 26, 32, and 38 years. Neuropsychologic testing was administered at 13 years of age, before cannabis use was initiated, and at 38 years of age, after persistent cannabis use patterns were established. Family member informants provided corroborating input. Among adolescent-onset, heavy cannabis users, there was an average decline in IQ of 8 points from 13 years of age to 38 years of age (impairment that was global and detectable across five domains of neuropsychologic functioning) and attention and memory problems observable by informants. Following cessation or infrequent use (median past-year use: 14 days) for one year, the IQ decline remained significant. In contrast, adult-onset heavy cannabis users did not exhibit IQ decline as a function of persistent cannabis use. The authors concluded that these findings suggest a neurotoxic effect of cannabis on the developing adolescent brain [152].
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