Adverse effects of heavy cannabis use: even plants can harm the brain

Abstract

1. Introduction The spread of laws legalising cannabis for medicinal or recreational use has been accompanied by more relaxed attitudes towards cannabis. Data from the United States show that in states that have legalised cannabis, prevalence of daily, weekly, and monthly cannabis use was 11.3%, 18.3%, and 25.0% respectively, whereas in countries where it is still illegal, it was lower (7.4%, 11.6%, and 16.8% respectively).46 Evidence indicates a trend of increase among adolescents,58 a particular vulnerable category for the initiation of substance use.114 In parallel, we have seen the concentration of THC (Δ-9-tetrahydrocannabinol) in the cannabis sold both in the United States and in Europe rising and those types of cannabis with high THC,35 and a corresponding decrease of cannabidiol (CBD) content,17,35,95 becoming more widely available. Most commonly, cannabis is used for its enjoyable effects, the “high” feeling.69 In addition, in those countries where its use has been legalised, many people smoke cannabis for medical use, anxiety, depression, and pain relief,71 with those suffering from chronic pain being at higher risk of developing cannabis use disorder (CUD).57 This review aims to challenge the widespread view that cannabis being a “plant” does not carry adverse effects, and review the evidence concerning the effects of cannabis use on mental health and cognition. 2. Understanding cannabis The plant Cannabis sativa contains more than 100 different psychoactive ingredients,33,53,74 but the most widely studied are THC (Δ-9-tetrahydrocannabinol) and CBD (cannabidiol),36,74,84 synthesised from the same precursor, cannabigerol. Therefore, types of cannabis with high concentrations of THC produce low CBD and vice versa.23 THC is a partial agonist at both the cannabinoid receptors (CB) CB2 R and CB1 R, the latter highly abundant in the brain.64, 83, 97 THC is responsible for most of the enjoyable and adverse effects that commonly arise after acute and regular cannabis use.8,24,116 Conversely, CBD is a negative allosteric modulator at the CB1R,76 whose effects are distinct and, in many cases, opposite of those observed with THC. CBD does not induce euphoria but may exert anxiolytic, antiepileptic, anti-inflammatory, and analgesic properties Figure 1.9,10,22,91,99,100,108Figure 1.: This diagram graphically illustrated first, the differential and in fact opposite psychiatric and cognitive effects of THC and of CBD, and second, how both compounds derive from the same precursor. Therefore if, for instance, a Cannabis sativa plant is genetically driven to the production of high quantity of THC, it will only be capable to synthesise small quantities of CBD.103. Cannabis intoxication and dependence 3.1. Acute adverse effects Cannabis use can lead to intoxication, defined as a series of “clinically significant problematic behavioural or psychological changes (eg, impaired motor coordination, euphoria, anxiety, sensation of slowed time, impaired judgment, and social withdrawal) that develop during, or shortly after, cannabis use.”2 The experience of feeling “high” after cannabis use is variable and subjective,48 depending on the dose, the environment, and previous experience and expectations of the drug user.101 The most common acute adverse effects are panic attacks and other forms of anxiety, mostly reported by naive users.50,51 Because cannabis impairs psychomotor skills, reaction time, and motor coordination, its use leads to increased risk of motor vehicle accidents.6,98 Current cannabis users have higher rates of hospitalization for injury from all causes than former cannabis users or nonusers.41 3.2. Cannabis use disorders DSM-5 CUDs is now a single diagnostic entity including abuse and dependence3; it is prevalent (2.54% 12-month prevalence among U.S. adults), associated with comorbidity and disability, and largely untreated.56 Moreover, CUD often presents comorbidly with psychotic disorders.59 Preclinical studies support the evidence that exposure to THC leads to dependence.1,16,19 Cannabis can induce tolerance in humans60,65 and dependence.16 Because cannabis is eliminated slowly from the body, withdrawal symptoms are generally mild. Nevertheless, discontinuation of long-term frequent cannabis use can induce anger, decreased appetite, irritability, nervousness, restlessness, and sleep difficulties,13,79 suggesting that the alleviation of abstinence symptoms contributes to the maintenance of daily cannabis use.52 Recent evidence, from the Netherlands, has shown an association between changes over time in average THC content in the type of cannabis available and rates of admission to specialist cannabis treatment units.37 4. Cannabis and psychosis 4.1. Epidemiological evidence Cross-sectional and prospective studies demonstrate a causal link between cannabis use and psychotic disorder, with greater risk for cannabis users, compared to nonusers.73,85,88,89 The most recent meta-analysis reported a pooled odds