Cannabis has been an illicit substance in countries that signed the UN Single Convention for more than 50 years. Nevertheless, cannabis is the most commonly used illicit substance globally. In 2020, the United Nations estimated that 209 million or 4% of persons of the global adult population had used cannabis in the previous year (1). The last-year prevalence of the European adult population is 22.2 million or 7.7% (2). Switzerland has one of the highest national prevalence rates of cannabis use in Europe. Whereas the lifetime prevalence for European adult population is 27.3%, the lifetime prevalence for the Swiss adult population is 34% (3). Approximately 4% of the Swiss population used cannabis in the past-month (3).

These prevalence rates suggest that cannabis prohibition has not been able to sustainably reduce cannabis use. In contrast, prohibition is associated with high health and social costs due to unsafe product quality, stigmatization and criminalization of users as well as access barriers to harm reduction, prevention, and treatment (4, 5). Furthermore, cannabis causes less societal and individual harm compared to illicit opioids and stimulants (6) or legal drugs such as alcohol and tobacco (7, 8). The comparatively high number of users, the modest harms of cannabis use, as well as the high costs of its prohibition have led to increased public discourse reconsidering prohibition and prompting alternative cannabis regulation models.

Besides strict prohibition, the opposite pole of the legislative spectrum—free commercial market—is equally associated with increased public health costs, because industry is interested in promoting cannabis use (9). In contrast, the middle-ground regulation may minimize the adverse effects of both extremes. This could be achieved by implementing policies to improve public health and safety, to protect minors, as well as to reduce crime (9, 10). These policies may include, e.g., pricing according to product potency, a governmental monopoly on production and sales, restriction of advertisement, minimum age, health education on safer use, prevention programs, and treatment-referrals (11).

Various states have introduced legal cannabis laws for recreational use and further countries propose to legalize cannabis in the near future. The implemented regulatory models vary widely. In particular, since 2012 over a dozen US states have implemented a commercial cannabis model similar to the alcohol and tobacco regulations (12). Canada followed suit in 2018 with a focus on public health (13), while in Uruguay cannabis is strictly regulated and controlled by the government since 2013 (14). Given the general shift in cannabis legislation—away from prohibition toward regulation—knowing the effects of these policies on cannabis use patterns as well as on mental and physical health is paramount for clinicians and policymakers alike. However, evidence for public health from available observational studies is inconclusive.

Recreational cannabis legalization in US states has been associated with an increased frequency of cannabis use among adults (15, 16). Among adolescents and young adults (< 21 years), there was no association between cannabis legalization and cannabis use (15, 17–19). In Uruguay, the legalization of recreational cannabis was not associated with past-month- and past-year-prevalence among young adults (18–21 years); however, it was associated with a transitory increase in risky and more frequent use in young adults that decreased thereafter (20). The cannabis regulation in Canada was associated with an increased 3-month prevalence among adults (> 25 years), but not related with increased frequency of use (21, 22). Additionally, a shift in mode of administration toward lower-risk methods has been observed. Specifically, cannabis users reported less cannabis smoking, increased vaporizing, and consumption of edibles following cannabis legalization (21).

To assess the public health impacts of recreational cannabis regulation, previous studies predominantly evaluated the prevalence and frequency of cannabis use (23). However, these outcomes are of limited clinical significance since the majority of cannabis users are low-risk users and do not suffer from adverse health outcomes related to their use (24). Nonetheless, between 10 and 30% of those, who use cannabis, do fulfill the criteria for a cannabis use disorder (25–28). As cannabis use disorders substantially contribute to the global disease burden (29), investigating the impact of legalization on cannabis use disorder may be of greater concern for public health.

Additionally, not only cannabis use, but also comorbid mental and physical health indicators are of major interest for public health and drug policy reforms (23). Cannabis use disorder has been associated with comorbid psychiatric disorders (30, 31), in particular with an increased risk of use disorders of other substances, psychosis (32, 33), anxiety (34), and depression (35, 36). Whereas extensive evidence has shown that frequent use of potent cannabis is related to an increased risk of psychosis, the evidence for depression and anxiety is less clear (37–39). However, a causal relation was not established in these studies. Thus, it remains unclear whether the increased risk of mental disorders is attributable to cannabis use or other confounding factors. Furthermore, the relation between cannabis use and physical health is also uncertain. Chronic bronchitis is the most consistently found adverse effect of cannabis smoking (40, 41). In contrast to the adverse health effects of cannabis use, there is additional growing evidence evaluating the beneficial health effects of medical cannabis. Medical cannabis has been associated with improvements of symptoms of mental disorders, including anxiety, schizophrenia, and sleep (42, 43). Further, low-to-moderate evidence supports the treatment of a range of physical conditions, including chronic pain, nausea, and vomiting caused by chemotherapy, and some treatment resistant epilepsies (44, 45). However, evidence on the impact of recreational cannabis legalization on comorbid mental and physical health outcomes in cannabis users is rare. One epidemiological study has shown that cannabis laws for medical use in the US are associated with reduced mental health problems (46). Research on the impacts of recreational cannabis laws on mental and physical health indicators in cannabis users is yet lacking.

To our knowledge, there is no randomized controlled study evaluating the effects of recreational cannabis legalization compared to the illicit market on relevant health outcomes. Available evidence is based on observational studies, including pre-post-legalization comparisons or comparisons between states with recreational cannabis regulation and states without. However, these study designs are not able to distinguish between secular trends and changes due to cannabis regulation and thus, causality remains unclear (47). The aim of the present randomized controlled study is to investigate the effects of cannabis regulation for recreational purposes compared to the illicit market on problematic cannabis use, mental disorders, and physical health. Although cannabis for recreational use is prohibited in Switzerland, scientific studies on recreational cannabis are allowed since 2021 (48). Hence, Switzerland offers a unique opportunity to gain scientific knowledge about alternative cannabis regulation approaches. We hypothesize that regulated cannabis access in pharmacies will reduce problematic cannabis use as within a regulated approach several conditions are available to facilitate lower-risk use and treatment. Furthermore, we hypothesize that regulated cannabis access will improve mental and physical health outcomes.

Moreover, the effects of chronic cannabis use on epigenetic DNA-expression regulation are not yet fully understood. Its mechanisms may provide explanations for the development of cannabis use disorder and cannabis withdrawal syndrome, as well as emotion-regulating effects of cannabis use. To date, an association between cannabis use and the expression of neurotrophic growth factors (49, 50) as well as changes in the hypothalamic–pituitary–adrenal (HPA) axis (51) have been observed. The Pro-opiomelanocortin (POMC) and NR3C1 genes play an important role in the regulation of the HPA axis, through which the release of stress hormones like adrenocorticotropin (ACTH) and cortisol occurs. The NR3C1 gene encodes the glucocorticoid receptor to which glucocorticoids such as dexamethasone bind and is essential for further signal transduction (52). POMC is a hormone precursor of interest, as it is susceptible to epigenetic regulation through DNA methylation as well (53). In patients with alcohol and opioid dependence, epigenetic gene express regulation mechanisms are associated with craving symptoms (54, 55). A pilot study showed a significant increase in POMC methylation in opioid-dependent patients following heroin injection (52). The neurotrophic growth factor brain-derived neurotrophic factor (BDNF) is associated with central dopamine release. Hence, an alteration in BDNF expression may be related to the reward effects and dependence potential of psychotropic substances (56). In the context of neurocognitive performance, as well as the development of substance-related dependence disorders, nerve growth factor (NGF), vascular endothelial growth factor-A (VEGF-A), and glial cell line-derived neurotrophic factor (GDNF) have been investigated in addition to BDNF (52, 57–59). However, in connection with cannabis use, the epigenetic regulation of these genes has so far been insufficiently studied and research on non-clinical populations of cannabis users is scarce.