UW ADAI - Symposium - 2024 - Reviewing the Evidence
(September 19, 2024) - Deepak Cyril D'Souza

A Yale University cannabis researcher who examined the interplay between cannabis and psychosis delved into his studies and findings before responding to attendee questions.

Here are some observations from the Thursday September 19th University of Washington Addictions, Drug, and Alcohol Institute (UW ADAI) Symposium titled, “Cannabis, Schizophrenia, and Other Psychotic Disorders: Moving Away from Reefer Madness Toward Science."

My top 3 takeaways:

• UW ADAI Cannabis Education and Research Program (CERP) Research Scientist Sharon Garrett introduced the final speaker of the morning session, Yale University School of Medicine Psychiatry Professor Deepak Cyril D’Souza (audio - 1m, video - UW ADAI).
  • Garrett mentioned D’Souza’s work as “a staff psychiatrist at [Veterans Affairs] VA Connecticut Healthcare System where he’s worked since 1992, and he’s an active clinician, teacher, and researcher with 30 years of experience.”
    • At time of publication, D’Souza also served as the inaugural Director of the Yale Center for the Science of Cannabis and Cannabinoids, and as a member of Connecticut Medical Marijuana Program Board of Physicians. In 2023, he was the editor of the third edition of Marijuana and Madness, and had been awarded a federal grant to “study genetic risk factors in cannabis use disorder in humans.”
  • Garrett shared that D’Souza was “the Vikram Soti Professor of Psychiatry at the Yale University School of Medicine” and highlighted his international presence as he connected from Portugal. D’Souza’s presentation was pre-recorded, but he participated remotely in the subsequent question and answer session.
  • Additional cannabis research material D’Souza authored or contributed to included:
    • Cannabinoids and Psychosis: Pharmacological Evidence (2004)
    • Cannabinoids and Psychosis (2007)
    • Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: A systematic review and meta-analysis (2019)
    • Efficacy and safety of a fatty acid amide hydrolase inhibitor (PF-04457845) in the treatment of cannabis withdrawal and dependence in men: a double-blind, placebo-controlled, parallel group, phase 2a single-site randomised controlled trial (2019)
    • Preliminary in vivo evidence of lower hippocampal synaptic density in cannabis use disorder (2020)
    • Cannabis and Psychosis: Recent Epidemiological Findings Continuing the “Causality Debate” (2022)
    • Cannabis, cannabinoids and psychosis: a balanced view (2023)

• D’Souza titled his presentation "Gone to pot? The complex relationships between cannabis, cannabinoids and psychosis," covering a wide variety of specific symptoms and medical conditions, along with ongoing research on topics like addiction and the human endocannabinoid system (audio - 35m, video - UW ADAI).
  • Terminology - D’Souza began by defining mental conditions, psychosis specifically, as it was “important for us to define these things before we talk about them.” He noted psychosis had several different symptoms which could each vary in severity.
    • Conditions he mentioned included “hallucinations, delusions, paranoia, other perceptual alterations, ideas of reference, disorganized speech and disorganized behavior and also catatonia.” These “psychotic symptoms,” might “occur in isolation,” he noted. The other “domains of symptoms” included “negative symptoms, which include blunted affect, amotivation, social withdrawal, [and] anhedonia.” The last domain D’Souza mentioned was “cognitive symptoms” which involved “impairments and attention, memory, executive function, processing, speed, social cognition and abstract reasoning.”
    • D’Souza said, “these three domains of symptoms constitute a psychotic disorder, which the prototypical psychotic disorder that we speak about is schizophrenia.” Although experts “don't really know the cause of schizophrenia…We think genetic factors may play a role, and environmental factors may play a role,” he believed that “cannabis schizophrenia costs a lot to society, both in terms of direct costs and indirect costs, and the treatments that we have for it, while good in many cases, are not so good for many patients.”
    • D’Souza historically situated academic thinking around schizophrenia in terms of another medical problem: “More than 100 years ago, we thought of pneumonias as if people had symptoms such as cough, fever, fatigue, sweating and so on…We thought of pneumonias as just one entity, [but] we realized that there were pneumonias that were caused by chemicals, viruses, fungi, and there were bacterial pneumonias.” He felt “we’re probably at the same place…as we were with pneumonias 50 years ago,” speculating schizophrenia would eventually be understood as “many distinct syndromes…one might be related to substances.”
  • Cannabis and Psychosis - D’Souza acknowledged that while delta-9-tetrahydrocannabinol (THC) was well known, he had been getting more interested in “delta-8-THC, which shares many similarities with it,” as well as with synthetic cannabinoids. He provided some context around how the relationship between cannabis and psychosis was perceived by researchers.
    • He explained that “back in 2008 there were a number of products that emerged on the market here in the US that were were under the umbrella term ‘spice’ and ‘K-2.’” He stated the products caused intoxication, and “were not detectable…at the time in, in the urine. But what these products contained were highly potent synthetic cannabinoids.” D’Souza reported such compounds could be “between 10 and 200 times more potent than” delta-9-THC, and researchers “saw pockets of cases across the states of people becoming acutely psychotic after consuming these drugs.” He considered there to be “data emerging from synthetic cannabinoids that also support this idea of this relationship between cannabis and psychosis,” adding, “fortunately…synthetic cannabinoids, are not being used as much as they were being used previously, in part because cannabis [wa]s being increasingly legalized.”
    • Considering natural cannabinoids and psychosis, D’Souza said, “I would argue that this relationship was recognized almost 200 years ago,” citing a French psychologist who authored a book titled Hashish and mental alienation in 1845 which outlined many symptoms of cannabis-induced psychosis and argued individuals’ “reaction was dose related.”
      • An english translation of the book was published in 1973 under the title Hashish and Mental Illness.
    • “Closer to home, I'm originally from India,” D’Souza acknowledged, mentioning the Indian Hemp Drugs Commission which issued an 1894 report on cannabis use in what was then-British India. While he indicated their report found “moderate use of these drugs produced no mental injury. It is otherwise with excessive use.” D’Souza saw this as more historic evidence that there was a link between dosage and psychotic symptomology, not just amount, but “potency of the product.” He clarified his use of the term dosage, stating he wasn’t “just referring to the amount, but I'm also referring to the potency of the product,” or the amount of a substance needed to provoke a particular response.
      • Historic studies of cannabis in North America include the LaGuardia Committee report from 1944, and the federal Shafer Commission report published in 1972.
  • Temporal Relationship - D’Souza argued there were “three distinct relationships between cannabis, cannabinoids, and psychosis outcomes [which he’d arranged] based on the temporal relationship between exposure to these compounds and the development of psychosis outcomes.”
    • In one relationship, “is the idea of psychosis that emerges immediately following exposure but resolves by the time intoxication is over.” D’Souza told the group that symptoms of psychosis which dissipated with intoxication were considered “acute, transient psychosis.”
    • In the middle “is the onset of psychosis following exposure, but in this case, the psychosis lasts for a period longer than intoxication.” He shared that this was regarded as “an acute, persistent psychosis, where the psychosis lasts well beyond the period of intoxication,” but some designated this “cannabis induced psychosis.”
    • Most concerning, “the idea of exposure to cannabis in adolescents followed months and sometimes years later by a chronic, persistent, recurrent psychotic disorder, which in our current nosology we call schizophrenia.” This relationship was termed “chronic recurrent psychosis that begins days or months or years after exposure.”
    • D’Souza shared some of his research on the topic, which went back almost 20 years, “where we invited healthy individuals with no known risk for psychosis, and…administered different doses of THC to them, versus placebo…we found here that THC induced a range of psychosis-like effects in healthy individuals.” He outlined a variety of effects participants reported, stating they were “compelling symptoms that we would associate with psychosis.” D’Souza argued other studies of cannabis had made similar conclusions, “it's a fairly large effect size that we are seeing with the administration of THC versus placebo [and there were] many other studies that have been done…to just summarize that in laboratory studies, we…and others have shown that THC can induce the positive symptoms” as well as “negative symptoms and a range of cognitive deficits, which are also core features of schizophrenia.”
  • Academic Studies - Starting with a 2021 study out of Denmark, D’Souza noted the comprehensiveness of that country’s health records and remarked that the authors had found increasing “rates of cannabis induced psychosis…increased by almost threefold, and this increase…seemed to parallel the increased availability and potency of cannabis in Denmark.”
    • He reported that this study, and others in Scandinavia “showed that individuals who had been hospitalized for cannabis induced psychosis…depending on what definition used, 50% of them were re-diagnosed with schizophrenia.” D’Souza interpreted this as an individual who had a psychotic episode following cannabis use “and you're seen in an emergency room, then it's very likely that…may be a sign of the later development of a chronic psychotic disorder.” He called cannabis a possible “harbinger…of a later chronic psychotic disorder.”
    • D’Souza lauded the keynote presentation of King’s College London Professor Marta Di Forti, stressing some of her points, “whether you're looking at just psychotic symptoms or the diagnosis of a psychotic disorder, i.e., schizophrenia. If you put all these studies together, and there have been a number of studies that have been done over the last 40 years or so in different countries, it seems like the risk for schizophrenia or psychosis is about four to six fold higher.” Furthermore, he argued this body of work showcased “the highest risk for developing schizophrenia was in those people who were daily users of cannabis and who used high potency cannabis,” as well as “the longer the duration of exposure, the earlier the exposure so if you are exposed in early adolescence, your risk is greater.” For those initiating cannabis use “as a young adult, we think that childhood trauma and a family history of having a psychotic disorder or some other serious mental illness [conferred] a greater risk of development of, of psychosis or schizophrenia,” said D’Souza.
    • However, he recognized “not everyone who smokes cannabis or uses cannabis develops psychosis, and not everyone with a psychotic disorder was exposed to cannabis.” He compared this to cigarette and cancer risk: “Not everyone who smokes cigarettes develop lung cancer, and not everyone who has lung cancer has smoked cigarettes, but we would all agree that smoking cigarettes is, is an important and preventable cause of lung cancer.” Additionally, D’Souza indicated there “may be genetic factors that interact with cannabis exposure, conferring a higher risk for a psychotic disorder” that weren’t yet understood. He emphasized the importance of taking “into account the fact that even if we consider [cannabis use] a component cause, if we can minimize the risk of the development of any new cases of psychosis by even ten or 20% that would…have a significant impact on the mental health of our society and citizens, and also reduce costs substantially, both to society, to families, and individuals.”
      • Other factors which have been found to increase risks of schizophrenia include childhood attention deficit hyperactivity disorder (ADHD), growing up in impoverished, stressful, or urban environments, or structural changes in the brain.
    • D’Souza next considered “effects of cannabis in people with an established psychotic disorder,” having conducted “important experimental studies, double blind, randomized, placebo controlled studies, where we invited people with schizophrenia to participate in a safe laboratory study where they received different doses of THC versus placebo.” There hadn’t been much data at the time, he continued, only an anecdotal “self-medication hypothesis, according to which people with schizophrenia were using cannabis to medicate their symptoms.” D’Souza said researchers looked into the possibility and “what we found is that the two different doses of THC…did not decrease - increased positive and negative symptoms of psychosis…and this occurred in individuals who were taking antipsychotic medications that therefore antipsychotic medications are not protective of this.” He added that several subsequent studies had similar findings, leading him to “say with…confidence, that there's no data to support the self medication hypothesis.”
    • When considering people who didn’t have a schizophrenia diagnosis, D’Souza said some people “identified as, as having some greater risk” such as a family history of schizophrenia, were less researched. He referred to a Columbia University study “where they invited young, healthy controls to smoke a joint, and they looked at measures of paranoia, anxiety and euphoria or high, and they compared that to individuals who were at risk for developing schizophrenia.” The resulting scans of individuals’ brains showed those “who are clinically high risk for developing schizophrenia had greater responses to THC on measures of paranoia and anxiety,” he stated.
  • Addiction - Separate from schizophrenia, D’Souza acknowledged cannabis was “associated with addiction,” and that addiction had been on the rise as cannabis accessibility increased following legalization in states across the U.S.
    • Cannabis use and addictive behavior played a role in “acute cognitive deficits, and has been associated with long term cognitive deficits. There's some debate of whether those cognitive deficits resolve completely or not,” he stated. Also troubling were patterns observed in adolescent cannabis use and increased risks for future depression or suicidal ideation. 
    • If you or someone you know has contemplated suicide, please reach out to the National Suicide Prevention Lifeline by calling 988, or find additional suicide prevention tools from the Washington State Department of Health (DOH).
  • Endocannabinoid System -  D’Souza established that “all animals and humans have an endocannabinoid system,” and this system included two types of receptors and “involves endogenous compounds that bind to these receptors.”
    • Endocannabinoid systems “seem to support homeostatic mechanisms…they serve a role in balancing the effects of other neurotransmitter systems. We think that the endocannabinoid system is important in circadian rhythm, sleep, and appetite.” He observed “muchies” and sleepiness had long been associated with cannabis. 
    • D’Souza further said, “especially during adolescence, the endocannabinoid system may regulate stress and anxiety, and…perhaps most relevant to the development of schizophrenia, we think that the endocannabinoid system may be involved in neurodevelopmental processes.” He mentioned “pruning,” a process in adolescent brain development where “connections that are not necessary are removed and connections that are necessary are strengthened. So this pruning process basically pulls away…unnecessary connections, and [was] under the control of the endocannabinoid system.” D’Souza warned that when the endocannabinoid system was “perturbed by someone smoking cannabis, one could imagine how this pruning process could be messed up, and…brain development could be, could be disrupted, and that could lead to long term implications.”
  • Wrapping up his remarks, D’Souza reiterated three points:
    • “First is that I've shown you fairly convincing data that cannabis can induce an acute, transient psychosis. This has been shown in fairly well controlled experimental studies. I can say with confidence that this relationship is causal, given that a person is fine one minute, not fine after they get THC, and then recover.”
    • “People with psychosis seem to be more vulnerable to the effects of cannabis and cannabinoids, and…there's mounting evidence that exposure to cannabis and cannabinoids might contribute to the development of a chronic, recurrent psychosis, or psychotic disorder, which we currently call schizophrenia.”
    • “The age of exposure and dose of exposure are important, and cannabis may precipitate or hasten psychosis in those individuals with the high risk for psychosis, and while some are more vulnerable than others is not clear and would be a subject of further study.”
  • D’Souza argued regulated sale of high THC products meant the items were increasingly common and “we shouldn't be surprised that we may see greater number of cases of new onset psychosis and also greater exacerbations of psychosis in those individuals who already have an established psychotic disorder.”
    • He advocated for policies to “delay the age of first exposure” such as education, but also by limiting dosage with potency caps on some products “particularly concentrates, and strengthen measures to limit access by minors.” If high-risk groups could get specialized education that would also be beneficial, argued D’Souza. 
    • While not yet ready for “prime time, it looks like we are beginning to identify genes that might…confer a greater risk for the development of psychosis,” D’Souza said.
    • He concluded with a plug for the research text he’d edited, Marijuana and Madness.

• Several questions were posed to D’Souza by attendees, including whether cannabidiol (CBD) increased psychotic symptoms, concerns about pesticides or solvents, and policy options to improve outcomes.
  • The moderator of the wider panel, Washington State Liquor and Cannabis Board (WSLCB) Research Manager Sarah Okey, asked if there was any evidence that CBD could cause or worsen psychotic symptoms, D’Souza replied that he was not aware of any evidence to that effect. “CBD, on its own, as an isolate does not appear to be associated with psychosis,” and he noted some research supported “that CBD may have, in fact, antipsychotic-like effects” (audio - 3m, video - UW ADAI).
  • Okey shared a question about the potential for pesticides and solvents to remain in cannabis products after processing, and the possible impact it could have on risks. “This is also related to how, within the legal market, there are hopes to create safer cannabis products,” she stated, asking for “any research around that” (audio - 1m, video - UW ADAI).
    • D’Souza responded that he didn’t know much “about the issue of pesticides and fungicides in…cannabis, but if we are talking about this in the context of psychosis, it would seem to me the, the single biggest driver of psychosis in cannabis is THC.”
  • Okey relayed that attendees wanted to know what specific policy recommendations could reduce risks for those most susceptible to cannabis-related harms. She asked for “effective policy changes or interventions, either clinical or…larger scale of, of how to find individuals who are at higher risk, or use policy to reduce harms” (audio - 12m, video - UW ADAI).
    • Several panelists offered common ideas including age restrictions around purchase and use, taxation, restricting advertising, education campaigns, or capping THC content by product type.
    • D’Souza agreed that a “multi-pronged” approach was needed:
      • He emphasized brain development continued until 25, and advised initiation of cannabis use to be as late as possible.
      • “I'm not as pessimistic about education, given that we were quite successful in convincing young people to stop smoking cigarettes, and we can take what we learned from that and apply it towards cannabis,” he observed.
      • He was less critical of cannabis legalization than he was of cannabis commercialization, commenting if there was “a lot of money to be made, it's going to be a…real challenge in, in implementing strategies.”
      • D’Souza’s final point was “continue to…support scientific research in identifying” groups at greatest risk “to develop serious mental illness from cannabis exposure.” He hoped to see more “tailored medicine,” but only if there was support of “research to identify those who are vulnerable.”

Information Set