by Rachel Little, MA, and Dale D’Mello, MD

Ms. Little is a science writer in Lansing, Michigan. Dr. D’Mello is Associate Professor Emeritus with the Department of Psychiatry at Michigan State University in East Lansing, Michigan.

Funding: No funding was provided for this article.

Disclosures: The authors have no conflicts of interest relevant to the content of this article.

Innov Clin Neurosci. 2022;19(7–9):38–43.

Abstract

Background: Observations regarding psychostimulant and psychedelic drug-induced psychotic states led to the dopamine, serotonin, and glutamate hypotheses of schizophrenia. Expanding knowledge about the endocannabinoid system and the impact of exogenous cannabinoids on the brain and behavior have elucidated several putative pathways to cannabis-induced psychosis.

Objective: The purpose of the present article was to describe these pathways and propose a cannabinoid hypothesis of schizophrenia.

Main points: The endocannabinoid system was reviewed. Evidence regarding the effect of delta 9-tetrahydrocannabinol (THC) on the brain was described. A connection between cannabis use and first-episode psychosis was elucidated.

Conclusion: Understanding the putative pathways to cannabis-induced psychosis might lead to targeted therapeutic interventions and prevention of schizophrenia in susceptible individuals. 

Keywords: Cannabis, THC, psychosis, schizophrenia, CBD, mainstream

According to the United Nations (UN) Office on Drugs and Crime’s 2020 World Drug Report,1 cannabis remains the most commonly used drug in the world. In 2018, it was estimated that 192 million people (3.9% of the global population) between the ages of 15 and 64 years had used cannabis within the last year.2 In the United States (US), efforts to legalize marijuana have intensified, and according to a 2019 Pew Research Center Survey,3 two-thirds of Americans support the legalization of marijuana, which might increase its accessibility to adolescents. 

High-dose psychostimulants (e.g., amphetamines),4 psychedelic compounds (e.g., lysergic acid diethylamide [LSD], mescaline),5 and dissociative anesthetics (e.g., ketamine, phencyclidine [PCP]) have been shown to induce symptoms of psychosis, similar to those observed in people with schizophrenia;6 however, frequent, long-term use of cannabis has been associated with an increased risk of first-episode psychotic disorders.7,8 

While research into the underlying neurobiological substrate of cannabis-induced psychosis is ongoing, it is important to showcase a snapshot of the current research, with the hope of understanding the potential ramifications of cannabis use in vulnerable populations, such as adolescents. Here, we attempt to elucidate the potential psychotogenic effects of cannabis and propose a cannabinoid hypothesis of schizophrenia.

The Endocannabinoid System

The endocannabinoid system helps regulate a broad spectrum of neurophysiological processes, such as neuroplasticity and neurodevelopment, pain, perception, motivation, and immune and gastrointestinal function.9 The endogenous cannabinoids anandamide and 2-arachidonoylglycerol (2-AG) are retrograde transmitters.10 Released from postsynaptic neurons, these endogenous cannabinoids target presynaptic cannabinoid-1 (CB-1) receptors, modulating neuronal activity. CB-1 receptors have been likened to “communication traffic cops.”11 They influence the release of excitatory and inhibitory neurotransmitters. Suppressing the release of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) enhances phasic burst-firing of dopamine in the ventral tegmental area.9 Conversely, enhancing the activity of N-methyl-D-aspartate (NMDA) receptors increases release of the excitatory neurotransmitter glutamate in the hippocampus.9 Endogenous cannabinoids are released on-demand to suppress unwanted (e.g., trauma) or unnecessary (e.g., where you parked your car yesterday) memories.10,11 These neurophysiological processes help maintain proper brain function, memory, and the perception of a person’s self and the environment.10,11

Delta 9-Tetrahydrocannabinol (THC)

THC and the brain. THC and cannabidiol (CBD) are the two best characterized phytocannabinoids (derived from plants) present in marijuana. CBD does not produce any of the psychoactive responses associated with cannabis use. THC, on the other hand, is the primary psychoactive ingredient and is responsible for marijuana’s intoxicating effects.12,13 The psychoactive properties of THC are achieved by binding to CB-1 receptors, which are located in the prefrontal cortex, hippocampus, and cerebellum.14 THC, a partial agonist of CB-1 receptors, alters mood, impairs memory function, learning, and judgment, and induces psychosis in vulnerable individuals.9 

THC stimulates the release of dopamine.15 Research has shown that prolonged use of cannabis can result in tolerance to its effects, particularly within the cognitive function domain, as well as addiction and symptoms of withdrawal upon cessation.16 According to a literature review by Budney et al,17 which examined the validity and clinical significance of cannabis withdrawal syndrome, the severity of withdrawal symptoms associated with prolonged cannabis use were similar to those of other withdrawal syndromes, with emotional and behavioral symptoms most often reported, though the authors of the review noted that physical symptoms were frequently reported as well.17 

Rising potency of cannabis. The THC content in cannabis has been steadily increasing over the past few decades. According to the National Institute on Drug Abuse, the average THC content of marijuana in the 1990s was less than four percent, but in 2018, it was more than 15 percent.12 The increasing potency of marijuana, combined with the availability of high THC concentrates, raises concerns that the consequences of marijuana use today might be worse than in the past, particularly among those who are new to marijuana use and in young people, whose brains are still developing.18 

Hypotheses of Schizophrenia and Effects of Substance Use

The search for causality in substance-induced psychosis is not a new one. The dopamine hypothesis of schizophrenia first emerged in the 1950s with Carlsson’s discovery of dopamine as a neurotransmitter in the brain after observing the effects of chlorpromazine and haloperidol in the brains of mice.19 Researchers later found that high doses of psychostimulants, such as amphetamines, induced positive symptoms of psychosis (e.g., hallucinations, delusions, disorganized thinking), which were thought to be related to enhanced dopamine turnover in the mesolimbic pathway.4 

The serotonin hypothesis of schizophrenia also began emerging in the 1950s. This hypothesis was based on the belief that schizophrenia might be caused, at least in part, by a dysfunction of the 5-hydroxytryptamine (5-HT) system after researchers observed similarities between LSD-induced psychosis and positive symptoms of psychosis in schizophrenia.20,21  

In the 1990s, the glutamate hypothesis emerged, when researchers observed that PCP (or “angel dust”) induced a wider spectrum of psychotic symptoms, both positive and negative, similar to those observed in schizophrenia.1 It was theorized that hypoactive glutamate NMDA receptors, which reside on cortical GABA interneurons, accelerated downstream dopaminergic mesolimbic activity, inducing positive symptoms (e.g., hallucinations, delusions), while these receptors simultaneously decelerated downstream dopaminergic mesocortical activity, inducing negative symptoms (e.g., cognitive dysfunction, blunted affect).6

Cannabis-induced Psychosis

Lasting at least 48 hours, cannabis-induced psychosis can occur during intoxication or withdrawal.22 While the exact causes of cannabis-induced psychosis are still being debated, at least seven potential pathways have been elucidated.9

Disturbed sense of agency. Agency is “the ability to recognize oneself as the agent of one’s thoughts and actions,” including “the recognition of one’s own body and body parts.”9 Disruptions of agency from cannabis use can cause the individual to believe that their actions are being planned and executed by an external force. Patients who experience auditory hallucinations display similar source monitoring deficits. They have difficulty determining whether sounds or voices originate from within themselves or external sources. Similarly, patients who display persecutory delusions commonly use externalizing, rather than internalizing, defenses (e.g., attributing life’s misfortunes to others rather than themselves).23  

Executive function deficits. THC has an effect on the prefrontal cortex, where CB-1 disruptions can negatively affect the regulation of human behaviors, such as attentional processing, goal selection, salience processing, and working memory. The inability of the brain to filter out irrelevant stimuli, as well as an overactive focus on other stimuli that is difficult to redirect, might explain the occurrence of delusional thoughts in some individuals who use cannabis.24 

Memory dysfunction. There is a compelling body of evidence that THC can produce acute and long-term memory dysfunction.24 This suggests that cannabis use might negatively affect an individual’s ability to carry out day-to-day activities that require the ability to remember and perform simple tasks (e.g., remembering to take medication, keep an appointment, or recall specific details of a conversation). 

Neurophysiological aberration. Patients with schizophrenia display a spectrum of neurophysiological aberrations, or biological markers, which reflect impaired information processing. These include measures of inhibitory failure (e,g., nonsuppression of P50 auditory evoked potential).9,25 Sensory gating is the ability to filter out extraneous, irrelevant sensory stimuli. Patients with schizophrenia have impaired sensory gating. Nonsuppression of the P50 auditory-evoked potential, wherein a test auditory signal is preceded by a warning signal, is considered a valid biological marker of sensory gating.26 Cigarette smoking transiently alleviates this sensory gating deficit in patients with schizophrenia, whereas smoking cannabis aggravates it.27,28

Hippocampal dysfunction. Alterations in hippocampal anatomy, perfusion, and activation have been reported in patients with schizophrenia.29 Habitual use of high potency marijuana is associated with gray matter loss in the hippocampus, especially in individuals with early psychosis, which can culminate in the formation of false memories.30,31 By parsing multiple stimuli, the hippocampus helps an individual separate illusion from reality.9 This process can be hindered in an individual under the influence of cannabis, which can result in difficulty parsing stimuli into rational thought and discerning reality.29 The hippocampus is particularly susceptible to the effects of THC, compared to other brain regions.32 While the downregulation of CB-1 receptors is restored to normal after 28 days of abstinence from cannabis in all other brain locations, downregulation persists in the hippocampus.32

Impaired neuroplasticity. The brains of adolescents undergo rapid development.33 The endocannabinoid system, which undergoes significant changes during adolescence, is critically involved in synaptic reprogramming. Endocannabinoids acting on CB-1 receptors finely calibrate neuroplasticity in the adolescent brain, pruning unnecessary synapses to strengthen the growth of others.34 This pruning ensures a smooth transition to the architecture of the mature adult brain, with well-preserved cognitive functions.33 THC exposure during adolescence modifies the developmental profile of the endocannabinoid system. Anandamide levels, which are typically elevated in the prefrontal cortex during late adolescence, are reduced by escalating high dose THC. Flooding the system with THC can disrupt this delicate process and might induce lasting effects on impulse control, as well as cognitive and executive functions.33–35 

The IMAGEN study examined the effects of cannabis use on brain development in 799 adolescent subjects. At the five-year follow-up, cannabis use was negatively associated with thickness of the left and right prefrontal cortices. There was a dose-dependent effect on cortical thickness.35 

Altered neural circuitry. Studies have found an association between escalating pattern of cannabis use during adolescence and functional dysconnectivity between the nucleus accumbens and the medial prefrontal cortex.36

Nonadherence to antipsychotic medication. Long-term cannabis use in patients with first-episode schizophrenia has been associated with nonadherence to prescribed antipsychotic medications, resulting in subsequent psychotic relapse and psychiatric rehospitalization.37 Relapse occurs twice as often among those who continue to smoke marijuana, compared to those who stop smoking. It is estimated that 30 percent of adverse outcomes associated with cannabis use in schizophrenia are related to nonadherence with recommended treatment.37 

Microsomal enzyme induction or inhibition: modifying antipsychotic pharmacokinetics. Aromatic hydrocarbons present in smoked marijuana induce the cytochrome P450 (CYP450) 1A2 hepatic metabolic pathway, much like hydrocarbons in cigarette smoke. Enzyme induction accelerates the breakdown of antipsychotic drugs, particularly olanzapine and clozapine, which are primarily metabolized through the P450 1A2 pathway, thereby lowering serum levels, making the drugs less effective, and contributing to psychotic relapse.4,38 Conversely, CBD, which is an inhibitor of the CYP450 2C19 and 3A4 metabolic pathways, inhibits metabolism of antipsychotic drugs, such as lurasidone, quetiapine, cariprazine, and brexpiprazole, and anti-anxiety drugs, such as clonazepam and diazepam, which are primarily metabolized through these pathways.38,39 Enzyme inhibition slows metabolic breakdown, increasing serum levels and adverse effects. This can lead to nonadherence to medications and subsequent psychotic relapse.39,40 

Summary. These converging pathways suggest that sustained cannabis use might cause memory problems, a disturbed sense of self, poor impulse control, and nonadherence to recommended treatment. Additionally, similarities between cannabis-induced neurophysiological aberrations and those observed in schizophrenia lend support to the cannabinoid hypothesis.

Link to Schizophrenia and the Cannabinoid Hypothesis Defined

Almost 50 percent of individuals who experience an initial episode of cannabis-induced psychosis are diagnosed with schizophrenia 2 to 4 years after their first psychosis experience.22,41 The age of onset of schizophrenia is 10 years earlier in individuals that use cannabis habitually, compared to those who are nonusers.41 This apparent link between cannabis use and onset of schizophrenia is an extension of previously published research on cannabis-induced psychosis.7,22,41

Current research7,8 has led the United Kingdom (UK) Schizophrenia Commission to declare that cannabis consumption is the “single most preventable risk factor in the development of a psychotic disorder.”7 However, many of those who experience an episode of psychosis continue cannabis abuse.37 While the long-term recreational use of cannabis might be attributed to addictive behavior, the worldwide shift to cultural acceptance of cannabis use might also contribute to its increase in use and, subsequently, to a potential increase in cases of cannabis-induced psychosis.42,43 

Therapeutic Benefits of Cannabis

Cannabis has been approved for medicinal use by several states in the US for a variety of health conditions, such as chronic pain, glaucoma, weight loss/nausea/vomiting, anorexia, certain neurological disorders, and posttraumatic stress disorder (PTSD).44 This might contribute to the apparent shift in public perception of cannabis from illicit substance to medicine. Three cannabinoid compounds are now approved by the Food and Drug Administration (FDA) in the US: dronabinol, nabilone, and CBD. 

Dronabinol and nabilone are approved for the treatment of weight loss in patients receiving chemotherapy, acquired immunodeficiency syndrome (AIDS), and anorexia. CBD is approved for treating seizures associated with Dravet or Lennox-Gastaut syndromes. In the UK, nabiximols has been approved for treating spasticity related to multiple sclerosis (MS). Research on potential therapeutic benefits of THC on “fear suppression” by targeting and encouraging the endocannabinoid system to suppress specific unwanted memories in patients with PTSD symptoms is ongoing.44 

Cannabis has also become mainstream in the forms of CBD oils, marketed to help with pain relief. These medicinal reliefs can be found for purchase in major grocery stores and on the internet. This might potentially contribute to public perception that cannabis use is safe and acceptable for everyone.34,43 However, this obscures important differences between cannabis (the plant) and its chemical components, THC (a psychotogenic alkaloid) and CBD (a relatively innocuous therapeutic compound).

THC vs. CBD

THC and CBD, two of the best characterized phytocannabinoids derived from the marijuana plant, have vastly different properties. In a group of healthy volunteers, THC and CBD had opposing effects on brain function.45 When viewing fearful faces, THC enhanced, whereas CBD attenuated, activation in the amygdala (the brain’s fear center). Similar opposing effects were observed in the superior temporal gyrus (the center for auditory perception) when listening to spoken speech.45 

Several placebo-controlled trials have suggested that CBD has modest antipsychotic properties.46–48 Nevertheless, some experts conclude that the evidence for recommending CBD in individuals with psychosis is currently insufficient.49

Patients with psychotic disorders might seek medicinal cannabis to treat insomnia. In one study, 69 percent of patients with psychosis acknowledged using marijuana to improve sleep.50 As is true with other hypnotic compounds, cannabis improves subjective sleep quality.51,52 However, as tolerance develops for its sleep-promoting capacity, patients might seek higher potency preparations without direct medical supervision or approval.51 Attempts at cessation might lead to rebound insomnia, which, in turn, might lead to perpetuation of use and potential addiction.16 Cannabis withdrawal has been associated with impaired sleep efficiency, decreased time spent in Stage 1 and Stage 2 sleep, and diminished rapid eye movement (REM) latency.51 

Implications of Normalizing Cannabis Consumption

The widespread legalization of medical and recreational cannabis, amplified by its promotion in the mainstream media, has potentially led to normalizing the drug experience.43 Epidemiologic studies suggest that the escalating rates of overall marijuana consumption in the US between 2011 and 2014 were influenced by reduced risk perception.43 Additionally, reduced risk perception might contribute to the escalation of recreational cannabis use among children and adolescents.53 As of 2016, 44.5 percent of high school seniors acknowledged consuming cannabis.53 If early cannabis use impedes neuroplasticity, then a generation of users might inadvertently diminish their cognitive and executive capacity.34 Youths ranging in age from 16 to 25 years are at the highest risk of developing a drug-induced psychosis that might later be diagnosed as schizophrenia.22 Escalating use of cannabis in younger individuals has been associated with an increased risk of first-episode psychosis, particularly in geographic locations where recreational cannabis has been legalized.42,43 

Treatment Options and Concerns for Relapse in Patients with Schizophrenia

The rising tide of cannabis use has propelled a parallel exponential growth in studies that explore therapeutic approaches, such as strategies for managing cannabis use disorder in the general population54 and patients with concurrent psychosis.55 Traditional practices, such as motivational enhancement therapy, contingency management, and cognitive behavioral therapy (CBT), used as individual modalities, have modest benefits in cannabis use disorder.54,55 

In randomized, controlled trials (RCTs) of drugs for cannabis dependence, the cannabinoid receptor agonist dronabinol,56 the opioid υ receptor antagonist naltrexone,57 gabapentin,58 and N-acetylcysteine59 have demonstrated modest effects on curbing the use of cannabis.60

Bosanac et al55 have previewed the management of cannabis use in patients with psychotic disorders. Understanding a patient’s reasons for using cannabis can enhance engagement. Integrated treatment approaches that simultaneously address cannabis use and psychotic disorders in the same treatment setting are more effective than sequential or parallel treatment. Integrated treatment incorporates CBT, motivational enhancement therapy, case management, family support, and psychoeducation.55 

Overall, in patients with psychosis and concurrent cannabis use disorder, maintenance on antipsychotics is associated with lower rates of cannabis use. Among antipsychotics, second generation compounds as a group, particularly clozapine, have demonstrated superior results, compared to first-generation antipsychotics, in decreasing cannabis use in patients with schizophrenia and concurrent cannabis use disorder.61 In one study, 31 patients with schizophrenia and concurrent cannabis use disorder were randomly assigned to switch to clozapine or stay on their current antipsychotic. Patients assigned to clozapine used significantly less marijuana than those on other antipsychotics during the 12-week study period.61 However, nonadherence with antipsychotic medication has long been recognized as an antecedent of relapse in patients with psychosis and cannabis use disorder.7,37

As highlighted earlier, some patients with schizophrenia might use cannabis with the belief that marijuana can help with their symptoms, and thus utilize self-medication rather than prescription antipsychotic medications.50 A combination of motivational interviewing and CBT appear to be more effective than standard treatment through the practice of psychosocial interventions.55 Long-acting injectable antipsychotics are superior to oral equivalents in preventing relapse in dually diagnosed patients with psychosis and comorbid substance use disorder.62 Starr et al62 compared the efficacy of long-acting injectable paliperidone palmitate (PP1M) versus oral paliperidone in 269 subjects with schizophrenia and concurrent substance abuse with a history of recent incarceration. PP1M was superior to the oral formulation in delaying time to treatment failure.62 Rozin et al63 examined the effect of long-acting antipsychotics versus oral antipsychotics in patients with early psychosis. The cohort included 24 cannabis users and 27 cannabis nonusers. Cannabis users were substantially more likely to report dissatisfaction with antipsychotic medications and more likely to experience rehospitalization. Those maintained on long-acting formulations were less likely to be hospitalized than those maintained on oral formulations.63

Conclusion

High potency cannabis products, which are increasingly accessible to children and adolescents worldwide, produce a diversity of deleterious effects on the developing brain. States that have medicalized, decriminalized, and legalized cannabis have observed softened attitudes, increased acceptance, expanded indiscriminate use, and increased rates of hospitalization for first-episode psychosis.42,43 Understanding the putative pathways for cannabis-induced psychosis might lead to targeted therapeutic interventions. Disseminating scientific information concerning the broad spectrum of cannabis-induced cognitive deficits and risks of enduring serious mental illness might prevent the onset of schizophrenia in susceptible individuals. 

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