While consisting of more than 400 different active constituents, the cannabinoid Δ9-tetrahydrocannabinol (THC) is the primary psychoactive constituent of the Cannabis sativa plant. THC is believed to be primarily responsible for the addictive potential and cognitive effects of cannabis [41]. Another major cannabinoid in cannabis is cannabidiol (CBD), which is a potent anti-inflammatory agent that causes a variety of other effects [33,42].

The neurobiological mechanism underlying the effects of cannabis is the endogenous cannabinoid system or endocannabinoid system (ECS). The ECS has a regulatory role in neurotransmitter release. The two main receptors of this system are the cannabinoid CB1 and cannabinoid CB2 receptors. The CB1 receptor is a pre-synaptic heteroreceptor that can primarily be found in the central nervous system and is abundant in brain areas associated with emotional responses, motivation, and motor control. The CB2 receptor is primarily located in the peripheral and immune tissues. Both receptors may be activated by either endocannabinoids (naturally generated inside the body) or cannabis and cannabis-related synthetic compounds [42]. The neuronal activity of other transmitter systems, such as the glutamatergic, dopaminergic, and GABAergic system, can be modulated by the ECS. The ECS is a retrograde messenger system that regulates both inhibitory and excitatory neurotransmission according to an on-demand principle [33]. It has been implicated in a wide variety of behavioral functions such as various cognitive functions, the regulation of fear and anxiety-related behavior, and the modulation of the effects of drugs of abuse [30,43]. Moreover, the ECS is considered to play an important role in higher-order brain functions, including executive function, which continue to develop during adolescence [30,44].

THC exhibits partial agonistic activity for both CB1 and CB2 receptors [45]. It has been shown that THC administration can disrupt the endocannabinoid-mediated regulation of synaptic transmission [1]. CBD has low affinity for both CB1 and CB2 receptors and is a negative allosteric modulator that reduces the binding of CB1 agonists. CBD has been shown to have beneficial neuroprotective, anxiolytic, antipsychotic, and anti-inflammatory properties, though the underlying mechanisms for these effects remain elusive [46]. Many of the psychological effects of cannabis are biphasic, thus depending on the dose level, the THC/CBD ratio, and the user. Due to these biphasic effects, cannabis can either lead to relaxation and euphoria or anxiety and dysphoria. Anxiety due to cannabis use appears to be related to the THC level of the dose as well as the anxiolytic action of CBD. A high dose of CBD combined with THC reduces the intoxicating effects of THC [47].

Importantly, the ECS reaches peak activity and expression during adolescence and is involved in fine-tuning the mesolimbic dopamine pathway, which is involved in regulating reward-associated processes [33]. This makes the ECS a key modulator of adolescent developmental processes involving the mesolimbic reward circuitry and, subsequently, a key modulator in vulnerability to drug addiction. THC leads to elevated dopamine levels in the mesolimbic dopamine system [33]. Therefore, it is possible that the use of cannabis during adolescence can disrupt normal brain development and increase vulnerability to drug addiction [48].

Various effects of cannabis have been reported, some of which are positive and some negative. Research shows that cannabis may have positive effects on symptoms associated with neurological disorders, such as multiple sclerosis (MS) and chronic pain [49]. For example, cannabis-based medication can improve subjective alleviation of MS symptoms and improve appetite and sleep [49,50]. Moreover, research among 274 participants with an average age of 51.2 years with treatment-resistant chronic pain showed that medicinal cannabis improved pain symptom scores, pain severity scores, and pain interference scores. In addition, social and emotional disability scores improved and opioid consumption decreased [51]. Cannabis is also used to treat sleep disorders. However, whereas cannabis improves sleep in patients with pain-related disorders, there is no benefit for healthy participants’ sleep. While participants report subjective improvements in sleep, there are no objective improvements found in sleep patterns [52]. In short, evidence shows that cannabis might be of therapeutic value. 

Besides promising therapeutic effects, adverse effects of cannabis use have been reported. A distinction can be made between adverse effects observed in short-term use versus those observed in long-term or heavy cannabis use. The adverse effects of short-term use include impaired short-term memory and motor coordination [53], altered judgement [54], hallucinations, and paranoia [3,55]. These effects can interfere with learning and retaining information and increase the risk of injuries by interfering with driving abilities [54,56]. Adverse effects of long-term or heavy use include altered brain development, cognitive impairment, poor educational outcomes, increased risk of psychosis [57], and diminished life satisfaction and achievement [3]. Individuals who use cannabis have a one in five risk of developing CUD [58]. Moreover, Blanco et al. (2016) showed that individuals who used cannabis in the last twelve months had a higher chance of developing any mood, anxiety, and/or SU disorder than individuals who did not use cannabis [59].

Importantly, the adverse effects of cannabis are influenced by the age of cannabis use onset, the maximum daily use in terms of dosage, and the conditions of use [25,57]. Most of the effects of long-term/heavy use named above are strongly associated with cannabis use that begins early in adolescence. In addition, early and regular cannabis use is a predictor for increased risk of CUD. Individuals who begin to use cannabis in adolescence are approximately 2–4 times more likely to have symptoms of cannabis dependence within the first two years of use than those who begin use in adulthood [60]. Likewise, altered brain development, cognitive impairment, poor educational outcomes, and diminished life satisfaction and achievement are all related to early initial use [3]. Another factor that plays an important role in the eventual effect of using is the potency of cannabis. For example, the average THC level of Dutch home-grown cannabis (Nederwiet) is significantly higher than that of imported cannabis [26]. Compared with low-potency cannabis, high-potency cannabis appears to be associated with a greater risk of anxiety, depression, psychotic symptoms, and cannabis dependence [27].

In short, besides therapeutic effects, cannabis can have serious adverse effects. Adolescents and young adults need to take special caution when using high (THC)-potency cannabis products and be aware of the additional risks of starting cannabis use at an early age of onset on a regular basis and with a family history of mental health problems.

As the brain continues to develop throughout adolescence, cannabis may influence neuropsychological development and functioning. In view of the increased sensitivity of the cannabinoid system and the ongoing maturation of particularly the frontal regions of the brain during adolescence, exogenous cannabinoids could disrupt normal brain development and have an impact on cognitive function [8]. Indeed, several animal and human studies have provided evidence for the association between cannabis exposure during adolescence and connectivity and morphological changes in brain structures that are densely populated with cannabinoid receptors (e.g., in the hippocampus, cerebellum and prefrontal cortex (PFC)) [61,62]. Weiland et al. (2015), however, found no association between daily cannabis use and morphological changes in brain structures in adolescents [63]. Although research into the relationship between cannabis use and morphological/structural changes is inconclusive, various studies have shown that long-term and heavy cannabis use is associated with impaired neurocognitive functioning in animals and humans [64,65,66]. For example, studies comparing adolescents using cannabis on a regular basis with a control group reported that they performed more poorly on tasks assessing verbal memory [67,68], intelligence [69], attention [67,68], and executive functions [68,69,70] and that they have a reduced processing speed [68,70]. However, these results should be treated with caution as it is not entirely clear how and to what extent cannabis affects mental functions. For example, THC seems to interfere with the encoding of verbal memory without interfering with retrieval, suggesting that cannabis does not influence learned information prior to the use [71]. Moreover, there is no consensus about the way cannabis use and impaired executive functions (EFs) are related. One mechanism by which poorly developed EFs may increase the risk of cannabis use is through more impulsive risk-taking and externalizing behavior, which is associated with substance use. Gustavson et al. (2017) found that impaired EFs were indeed a risk factor for early aspects of (poly)substance use in adolescence. However, non-EF factors, such as genetic factors that influence the subjective effects of substances, play a larger role in the actual progression to substance dependence [72].

Whether or not the neuropsychological effects of cannabis persist after extended periods of abstinence is still debated. Some studies have reported (subtle) lasting neuropsychological deficits in adolescent cannabis users compared to non-users [68,73]. For example, overactive brain regions involved in higher-order cognitive processes [74] and the default mode network—a set of regions in the brain that are active during passive tasks and possibly involved in the capacity to imagine future actions or events [75]—were seen in cannabis users compared to a control group after a period of abstinence [74]. These results indicate a vulnerability of the adolescent brain to residual effects of long-term cannabis use [48]. However, meta-analyses have shown that no residual, non-acute effects of cannabis use on cognitive performance in adolescents and adults were detectable after one month or more of abstinence [76,77]. Factors that affect the impact of cannabis use are the magnitude and frequency of use, medical versus recreational use, and the length of abstinence [78].

An important limitation is that most studies contributing to this debate are retrospective or cross-sectional case–control, without proper assessment of cognitive function prior to the onset of cannabis use. To clarify temporal associations between neurocognitive development and cannabis use and guide prevention efforts, prospective longitudinal studies are needed that include pre- and post-drug use neurocognitive assessments [8].