Early Consumption of Cannabinoids : From Adult Neurogenesis to Behavior, Citlalli Netzahualcoyotzi et al., 2021

Early Consumption of Cannabinoids : From Adult Neurogenesis to Behavior

Citlalli Netzahualcoyotzi, Luis Miguel Rodríguez-Serrano, María Elena Chávez-Hernández and Mario Humberto Buenrostro-Jáuregui

International Journal of Molecular Sciences, 2021, 22, 7450.

doi : 10.3390/ijms22147450



The endocannabinoid system (ECS) is a crucial modulatory system in which interest has been increasing, particularly regarding the regulation of behavior and neuroplasticity. The adolescent–young adulthood phase of development comprises a critical period in the maturation of the nervous system and the ECS. Neurogenesis occurs in discrete regions of the adult brain, and this process is linked to the modulation of some behaviors. Since marijuana (cannabis) is the most consumed illegal drug globally and the highest consumption rate is observed during adolescence, it is of particular importance to understand the effects of ECS modulation in these early stages of adulthood. Thus, in this article, we sought to summarize recent evidence demonstrating the role of the ECS and exogenous cannabinoid consumption in the adolescent–young adulthood period; elucidate the effects of exogenous cannabinoid consumption on adult neurogenesis; and describe some essential and adaptive behaviors, such as stress, anxiety, learning, and memory. The data summarized in this work highlight the relevance of maintaining balance in the endocannabinoid modulatory system in the early and adult stages of life. Any ECS disturbance may induce significant modifications in the genesis of new neurons and may consequently modify behavioral outcomes.

Keywords : cannabinoids; endocannabinoid system; adult neurogenesis; behavior; memory; learning;
stress; anxiety


1. A Worldwide View of Cannabinoid Consumption

Drug use worldwide is an important public health issue since the number of people that use legal and illegal drugs has been increasing. As an example, alcohol remains the most widely used substance of abuse in the world. In the global status report on alcohol and health, 2018 edition, theWorld Health Organization (WHO) stated that 43% of the world population aged 15 years or over have consumed alcohol in the past 12 months (2016), indicating that 2.3 billion people are current drinkers [1]. Regarding tobacco consumption, the United Nations Organization reported that 23.2% of adults globally were recurrent smokers [2]. Additionally, marijuana (Cannabis sp.) is still the most commonly used illegal drug. Worldwide, the number of cannabis users in 2018 was estimated to be 192 million, corresponding to a prevalence of 3.86%. North America has the highest consumption rate at 14.56%, followed by Australia and New Zealand (10.6%) and West and Central Africa (9.3%) [3]. In the United States of America (USA), marijuana use has been consistently increasing since 2007, particularly among young adults from 18–25 years old, but also in adults older than 25 years [3]. A meta-analysis using wastewater-based epidemiology (an alternative for human biomonitoring and a promising tool with which to estimate drug consumption in the population) recently reported that cannabis had the highest consumption rate (7417.9 mg/day/1000 people), followed by illicit drugs such as cocaine, morphine, methamphetamine, codeine, methadone, ecstasy, amphetamine, and methadone [4]. Table 1 summarizes the key statistics regarding drug abuse consumption in users aged 15 years old and above.

Table 1. Consumption of the main drugs of abuse (% of the 15-year-old and above population).

Substance Worldwide Americas Oceania Africa Asia Europe
Alcohol [1] 43.00 54.10 53.80 32.20 33.10 59.90
Tobacco [2] 23.40 15.00 33.50 17.30 43.70 31.20
Cannabis [3] 3.80 8.80 10.57 6.32 1.86 5.39
Amphetamines [3] 0.55 1.30 1.35 0.41 0.42 0.47
Opioids [3] 1.16 1.86 2.47 1.04 1.11 0.68
MDMA (Ecstasy) [3] 0.41 0.53 1.67 0.26 0.37 0.61
Cocaine [3] 0.38 1.49 1.56 0.27 0.06 0.89

Although other countries, such as the USA, legalized the medicinal and controlled consumption of some derivatives of cannabis in the 1990s, in the 2000s, the approval of its recreational use began. In recent years, several countries in the Americas, including Uruguay (2013), Canada (2018), and up to 17 states (such as Oregon, Washington, and California), two territories, and the District of Columbia in the USA [5], have legalized the recreational use of marijuana. It is essential to understand the effect that this legalization has had on the use of cannabis in the general population, and young people in particular.

In December 2013, Uruguay became the first country in the world to legalize the sale, cultivation, and distribution of recreational cannabis [6]. A survey conducted in 2018 reported that 8.9% of the population aged 15–65 years used marijuana in the month before the survey. However, cannabis use prevalence in young people aged 19–25 years increased up to 20.8%, followed by a prevalence of up to 16.4% among those aged 26–35 years [7]. A recent study by Laqueur et al. (2020) estimated the impact of this legalization on adolescents, perceived availability, and perceived risk of marijuana use. Researchers have found no evidence of a legalization effect on cannabis use or the perceived risk of use compared with prelegalization data. Nevertheless, an increase in student perception of marijuana availability (58% observed vs. 51% synthetic control) following legalization was reported. The authors conclude that the noncommercial model of national cannabis legalization may not lead to an increase in adolescent marijuana use in the short term [8].

Rotermann (2019) reported that in Canada, from 2004 to 2017, cannabis use decreased among 15- to 17-year-olds, remained stable in people 18 to 24 years old, and increased among adults aged 25 to 64 years. The Canadian federal government legalized nonmedical cannabis use by adults in October 2018. From 2018 to 2019, an increase from 14% to 18% was observed in the rates of marijuana use; mainly, the rate of marijuana use in males increased from 16% to 22%. However, marijuana use rates for females (13%) and seniors (4%) remained mostly stable. The same study reported that in 2019, approximately 60%
of regular consumers reported using at least one cannabis product. On average, 27.5 g of dried marijuana was consumed by each user over three months [9].


5. Conclusions

As demonstrated in the present review, the ECS is a crucial modulatory system for the development of the nervous system, with the adolescent–young adulthood stage being a particularly sensitive time period. Exposure to cannabinoids during this period can have long-term consequences, such as adult neurogenesis and behavior, through to adulthood. Furthermore, exposure to cannabinoids interferes with the optimal performance of the ECS and provokes defects in the neurogenic process; these outcomes have been associated with psychiatric diseases and cognitive alterations. Thus, ECS equilibrium is necessary to maintain optimal adult neurogenesis. The present review has provided multiple lines of evidence showing that there are several behavioral effects of cannabinoid exposure during adolescence, demonstrating the effect that adolescent exposure to cannabinoids has in adulthood, and indicating that the magnitude of the effects depends on important factors such as age of consumption onset, dose and length of exposure, as summarized in the tables.

Although marijuana (cannabis) is the most consumed illegal drug in the world, it is becoming legalized in an increasing number of countries. Additionally, its highest consumption rate is observed during adolescence, so it is of particular importance to understand its effects in the early stages of life (adolescence and young adulthood), particularly the alterations it can provoke in brain functionality, along with its impact on adult neurogenesis and the optimal performance of adaptive behaviors (e.g., the stress response, learning and memory, and anxiety). The legalization of marijuana implies not only changing its status from illegal to legal, but studies have shown that there is an immediate impact on its consumption, as well as on its perceived availability and risk of use. It is therefore important to continue research on the association between cannabinoid use and all its possible beneficial or detrimental effects, including adult neurogenesis and adaptive behaviors. This research will also help improve the present understanding of the consequences that the legalization and use of marijuana and cannabinoids can have on the world population. Some issues to investigate in-depth in future studies are: the mechanisms by which adolescent cannabinoid consumption induces sex-specific plastic differences; the role of noncannabinoid receptors, such as TRPV1, GPR55 and PPAR, in the modulation of adult neurogenesis mediated by cannabinoids; and the specific mechanisms and intracellular pathways involved in cannabinoid-induced neuroplastic regulation. Additionally, whether the facilitation of neuronal proliferation, differentiation, migration, maturation, and neuronal survival mediated by the ECS can be effective under pathological conditions warrants further investigation. We know that the scientific community focused on studying adult neurogenesis and cannabinoids is striving to address the above and many other issues that remain unresolved. Joint effort in this area will help improve the present understanding of ECS function, cannabinoids, and their neuroplastic and behavioral implications. This research will undoubtedly yield new treatment opportunities for neurodevelopmental, neuropsychiatric, and addiction disorders.