The use of cannabinoids and its derivatives for chronic pain is increasing. Two most well-known and clinically relevant forms of cannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The main receptor targeted are cannabinoid receptor 1 (CB1) and CB2. Indications for the utilization of THC are multiple sclerosis, cancer-related pain/cancer-related nausea and vomiting (anti-emetic), peripheral neuropathic pain, and HIV-associated weight loss.

‘Cannabis-associated psychosis’ (CAP) refers to a chronic psychotic illness that arises in the context of significant current or past cannabis use. This chapter is an interrogation of the large-scale, multi-centre cross-sectional study of individuals with an established psychotic illness, the bipolar–schizophrenia network on intermediate phenotypes (B-SNIP). B-SNIP used biological characteristics to sub-divide individuals with psychotic illnesses into distinct sub-group,s known as ‘Biotypes’. A subtype associated with adolescent cannabis exposure, Biotype-3, was characterized to have the distinct profile of a significant excess of adolescent cannabis use histories preceding the onset of psychosis, histories of childhood abuse, distinctly preserved cognition, hippocampal morphological and neurochemical abnormalities, normal evoked and resting electrophysiology, more normal MRI grey matter patterns, near-normal saccades and smooth pursuit eye movements, and the lowest schizophrenia polygenic risk scores. Further work is necessary to study CAP in order to find treatments specific for CAP.

Adolescence is a critical window of brain development. The adolescent brain is highly plastic and undergoes developmental and biological changes that are required for proper behavioural and cognitive maturation. However, this dynamic nature of the adolescent brain places it in a state of higher vulnerability to harmful environmental manipulations, such as exposure to drugs such as cannabis. Adolescents may be at a higher risk of suffering from adverse consequences of cannabinoid exposure than the adult population. Animal research supports the hypothesis of the existence of long-term behavioural deficits in adulthood following adolescent cannabinoid exposure depending on the dose of exposure, the age of first exposure and possibly the ratio of THC:CBD.

Abrupt cessation of chronic and frequent cannabis use is associated with cannabis withdrawal. Cannabis withdrawal syndrome is a clinically significant diagnosis and a criterion of cannabis use disorder (CUD) marked by mood and sleep disturbance symptoms, appetite and/or weight loss and restlessness, and physical symptoms such as abdominal pain, shakiness/tremors, sweating, fever, chills and headaches. The goal of this chapter is to fully characterize the clinical significance, time course, neurological mechanisms and treatment of cannabis withdrawal. The chapter synthesizes studies examining individual difference factors (demographics, cannabis use patterns, genetics and heritability and psychiatric comorbidity) that place some people at disproportionally higher risk for cannabis withdrawal or greater severity of symptoms. The cyclical nature of resuming use due to the inability to cope with the distress of cannabis withdrawal is negatively reinforcing and presents major challenges to individuals trying to abstain from problematic cannabis use. Implications for evidence-based strategies that can help mitigate the psychological and physiological symptoms of cannabis withdrawal are discussed.

Human studies have expanded insight about the lasting effects of adolescent cannabis use documenting structural and functional alterations in frontal and limbic regions of the brain, potentially relevant to behavioural vulnerability. Functional neuroimaging indicates that cannabis experience during adolescence is associated with perturbations in regions relevant to cognitive function such as working memory, attention, inhibitory control, and decision-making. Inconsistencies evident in the literature likely relate to variability in amount and frequency of cannabis use, potency, psychiatric comorbidity, and polysubstance use. Translational pre-clinical models help to elucidate how these factors contribute to protracted behavioural vulnerability of adolescent cannabis exposure.

People with psychosis and those at clinical high risk (CHR) for this syndrome have significantly higher prevalence of cannabis use compared to the general population. Furthermore, cannabis use can negatively impact the course and treatment outcomes in psychosis. Understanding the acute subjective and cognitive effects of cannabis and cannabinoids in this population is necessary if we are to disentangle the reasons for the increased prevalence of use; and also to help design interventions. There is little evidence to support the ’self-medication’ hypothesis, in its original form. Among principal phyto-cannabinoids, while THC exacerbates positive and cognitive symptoms of psychosis, cannabidiol lacks these effects and may even improve these symptoms. With the liberalization of cannabis laws in many countries, cannabis and cannabis-based products will be more accessible to both individuals with psychotic disorders and those at risk for psychosis. This chapter summarizes the literature regarding acute effects of cannabis and cannabinoids in people at CHR and with established psychosis.

A plethora of studies in animal models and large epidemiological studies in humans have shown that cannabis consumption during adolescence – a critical neurodevelopmental period for human beings – leads to an increased risk of developing mood disorders in adolescence or in young adulthood. Cannabis interacts with the monoaminergic system and with the endogenous cannabinoid system by altering the mechanism of mood regulation. Recent meta-analyses have also pointed out an increased risk for major depression in young adulthood after cannabis consumption in adolescence, even in the absence of pre-existing depression. Moreover, cannabis is also a risk factor for suicidal behaviours and suicide attempts. In summary, clinical studies suggest that cannabis is consumed by young people with depression largely for self-medication; however, its use, even in the absence of pre-morbid conditions, may also increase the risk of developing a mood disorder and can drive impulsive and suicidal behaviours.

Cannabis and cannabinoids are widely used, both as recreational substances with potential for addiction, and as treatments for a number of disorders. A large body of literature has investigated the harmful and/or beneficial effects of cannabis and/or cannabinoids employing observational and interventional methodologies. These individual studies have been pooled in many meta-analyses. Further, Mendelian Randomization (MR) studies have reported on a causal association between cannabis use and certain outcomes. This chapter reviews existing meta-analyses that pooled observational and interventional studies, and MR studies reporting on health outcomes after exposure to cannabis and/or cannabinoids in the general population, and selected clinical populations. We show that evidence from observational, interventional, and MR studies point towards an association between cannabis and psychosis. Several additional detrimental effects of cannabis emerged, including other psychiatric symptoms, cognitive impairment, and risk of motor vehicle accident (MVA). In terms of therapeutic benefits, cannabidiol seems to be effective for certain types of epilepsy, notably in children. Also, cannabis-based medicines can be effective in improving muscle spasticity in multiple sclerosis, ameliorating chronic pain syndromes, and reducing nausea/vomiting in palliative care settings. Risk–benefit ratios should be discussed with individual patients.

The question of how cannabis potency has changed over time is crucial for estimating the public health effects of cannabis, and for evaluating the impact of drug policies on the safety of cannabis products. This chapter addresses the following questions: What is cannabis potency and why does it matter? How has cannabis potency changed over time? How have cannabis products changed and diversified in new legal markets? What are the methodological limitations of research on cannabis potency, and how can they be overcome? Meta-analytical evidence provides strong evidence for increases in cannabis potency internationally. There is robust evidence for increases in the potency of herbal cannabis and cannabis resin since the 1970s. This increase has been two-fold greater in cannabis resin than for herbal cannabis. Increases in cannabis potency have been particularly marked in new legal markets such as Washington State, where highly potent cannabis extracts and edibles have also risen in prevalence.

Chronic marijuana use impacts an individual’s mind beyond the period of acute intoxication. Persistent downregulation of cannabinoid receptors in the amygdala, the brain’s reward circuitry and frontal cortex alters mental function in a variety of ways, including emotions, motivation and risk of psychotic illness such as schizophrenia. Gruber used a masked faces protocol to demonstrate chronic marijuana users have decreased activity in the amygdala in response to subliminal affective stimuli. She concluded that heavy marijuana users do not process emotional stimuli in the same way as non-users and this is true even when stimuli are below the level of conscious awareness. The complaints by significant others of their marijuana using partner’s emotional absence is consistent with Gruber’s findings. Individuals prone to aggression exhibit more relationship aggression during irritability caused by withdrawal. Decreased motivation over years of marijuana use is evidenced by diminished activity in the nucleus accumbens reward circuitry in response to non-marijuana stimuli. Acute psychotic episodes occur most frequently with high THC products in edible forms. Epidemiologists repeatedly find higher rates of schizophrenia in marijuana users than non-users, and higher rates of marijuana use in schizophrenics than in healthy populations.

The future of marijuana is best seen away from the noise passing for debate that engulfs us and with a thorough understanding of the role our endocannabinoid system plays in brain function. Because the endocannabinoid system is hardwired into reward mechanisms, cannabinoid experiences, whether from THC or endogenous sources, are inherently enjoyable. The question to be explored is what natural behaviors activate our endocannabinoids. Cannabinoid based experience will be valued and sought in the future just as endorphin experiences are today and exercise, meditation and other behaviors will be developed and encouraged both for pleasure and homeostatic balancing of brain chemistry. Science will see marijuana as the provenance of vital neurophysiological discoveries. Without marijuana research we might still have no knowledge of our endocannabinoid system. The future will see the development of an array of valuable new medications that stimulate, block and alter our endocannabinoid function. These medications will provide more effective and more narrowly targeted benefits, with fewer side effects, than what marijuana itself can offer. One facet of our relationship to marijuana will not change at all in the future. Experience seekers, especially the young, will continue seeking the intriguing high marijuana produces, and an unfortunate minority will experience addiction.