CATR: What is substance-induced psychosis (SIP) and how common is it?

Dr. Beckmann: It’s a good question and one that is relatively poorly understood. We don’t know if some people are just vulnerable to developing psychosis when using substances or if they are prone to psychosis in general and substance use pushes them over the edge. In terms of prevalence, the incidence of SIP in the general population is about 6.5 per 100,000 per year. To put that into context, the prevalence of comorbid SUD and psychosis in the general population is 9.7 per 100,000, and the prevalence of primary psychotic disorders without SUD is 24.1 per 100,000 (Weibell MA et al, BMC Psychiatry 2013;13:319). So, it’s not especially common, but given the questions I raised before, it’s challenging to know what the actual incidence is.

CATR: What substances are most commonly associated with SIP?

Dr. Beckmann: Cannabis is the most common, followed by stimulants, and then the so-called “club drugs.” We don’t see those as often, but they have a high risk of causing SIP.

CATR: There’s some controversy around how cannabis relates to psychosis.

Dr. Beckmann: The controversy is to what extent the link is causal. We still don’t know entirely, but our knowledge has evolved recently given liberalization of cannabis laws, particularly in Europe. We now have large epidemiological studies that are clear: As cannabis availability increases and as cannabis potency increases, the incidence of psychosis increases. That’s especially true in young people and with high-potency cannabis. A large 2019 study found that youth who used high-potency cannabis daily had a risk of developing psychosis double that of the general population. High-potency cannabis, defined as THC >10%, increased the risk by four-fold (Di Forti M et al, Lancet Psychiatry 2019;6(5):427–436). Many, perhaps all, of those people probably had an underlying genetic predisposition toward psychosis, but the population-level increase is striking. What we understand much less is what happens over time. Will the psychosis persist long term even in the absence of substance use? How many will go on to be diagnosed with a primary psychotic disorder?

CATR: The study made the distinction between high- and low-potency cannabis at 10% THC. That’s not very high.

Dr. Beckmann: True. In 1995, the average THC potency of plants seized by the DEA was 4%. In 2014, it was 12%. In Washington state, where cannabis is legal recreationally, the largest market share of whole-plant cannabis is 20% THC and up. And that’s just talking about whole-plant cannabis. THC concentrates with at least 60% are popular, especially among young people, again who are particularly vulnerable. Some waxes, dabs, and edibles can get close to 100% THC (Editor’s note: For more on cannabis products, see CATR Sept/Oct 2022).

CATR: And what about stimulants?

Dr. Beckmann: Stimulants are the other big category of drugs that cause SIP. That includes prescription stimulant medications, cocaine, and methamphetamines. As you might expect, the risk of SIP is dose dependent, meaning SIP risk increases as stimulant exposure increases. For reasons we don’t entirely understand, methamphetamines seem to be particularly prone to causing SIP, with rates as high as 20%–25% of people who use methamphetamines developing some symptoms of SIP.

CATR: And prescription stimulants?

Dr. Beckmann: Stimulants we prescribe, typically to treat ADHD, carry some risk as well, but SIP from these substances is almost always in the context of misuse. Healthy controls will only begin to experience psychotic symptoms at doses much higher than we typically prescribe: 100–300 mg for amphetamines and even higher for methylphenidates. But prescription stimulants in adolescents are associated with a small increase in the subsequent development of psychosis. A 2019 study looked at claims data from over 220,000 adolescents and young adults prescribed stimulants for ADHD. The rate of psychosis was 0.21% for patients taking amphetamine products and 0.1% for patients taking methylphenidates (Moran LV et al, N Engl J Med 2019;380(12):1128–1138). Both of these numbers are extremely small—and may represent an “unmasking” of symptoms that would have emerged anyway—but it’s a reason to consider starting with a methylphenidate product instead of an amphetamine, given the overall comparable efficacy between the two classes. That’s in addition to strategies to prevent misuse when appropriate, such as using long-acting formulations and dispensing limited quantities.

CATR: And then we have club drugs as well?

Dr. Beckmann: The term “club drugs” can refer to compounds in a number of classes. There are the synthetic cathinones, like bath salts, and psychedelics including tryptamines. The cathinones are sympathomimetic compounds and have effects similar to stimulants. The tryptamines, like psilocybin and dimethyltryptamine (or “DMT”), have their action as serotonin agonists. There is much less research on these, and there are many different compounds, each of which confer varying levels of risk. It’s hard to generalize, but overall, these drugs are thought of as being particularly high risk for SIP, but not necessarily with the same level of literature behind the conclusion (Editor’s note: For more on designer drugs, see CATR Sept/Oct 2021).

CATR: Can you speak about the relationship between SIP and primary psychotic disorders? Can a single episode of SIP cause schizophrenia?

Dr. Beckmann: That’s the big question. We do know that a SIP episode raises the risk of developing a psychotic disorder later on, but it’s again difficult to talk about causality. We know that people with psychotic disorders—including people who are in the early, or prodromal, period—are more likely to use substances than others in the population. And it’s almost certainly the case that people with high genetic loading and other risk factors for developing a psychotic disorder are more likely to develop symptoms of psychosis when they do use substances. But does the substance use accelerate the development of psychosis? Are there people who develop SIP and go on to develop schizophrenia who would not have in the absence of substance use? These questions are much harder to answer. And at the end of the day, we don’t know what a given patient’s individual susceptibilities are ahead of time and which ones are more important than others. In broad strokes, the more risk factors a patient has for psychosis, the more likely that substance use could lead to SIP.

CATR: What are some key clinical features of SIP?

Dr. Beckmann: There are no pathognomonic findings, but there are a few clues to look for. In terms of history, I look for anything demographically unusual: someone with no family history of psychosis or bipolar disorder, or a first episode of psychosis older than we would expect. In terms of presentation, SIP tends to have fewer or less severe negative symptoms compared to primary psychotic disorders. People with SIP can sometimes have better insight than those with primary psychotic disorder; a patient with schizophrenia might say “Voices are talking to me,” whereas someone with SIP is more likely to say “I hear voices that aren’t there.” A feature that is a little less consistently reported is that SIP not only has fewer negative symptoms, but also more positive symptoms: more hallucinations, more delusions. Of course, it can be diagnostically helpful if someone can achieve a period of abstinence.

CATR: What about rates of agitation?

Dr. Beckmann: Higher incidence of agitation can be seen, particularly with stimulants and cathinones, though it can be hard to differentiate SIP from stimulant or cathinone intoxication, where there also tends to be a fair amount of agitation.

CATR: Let’s talk about treatment. What are some general approaches to keep in mind?

Dr. Beckmann: The first thing to keep in mind is that any patient with an SUD should get addiction treatment. Once you have a diagnosis to the best of your ability, treatment is ideally a combination of medication and psychosocial interventions. The medication is symptom driven, so we are primarily talking about antipsychotics. We don’t know if medications will necessarily bend the trajectory of someone’s disease progression, or their prognosis, but the goal here is symptom relief.

CATR: Are there specific agents that are more effective than others?

Dr. Beckmann: Not really. There’s a suggestion that olanzapine might be more effective, but you could say the same thing about psychosis in general (Srisurapanont M et al, Drug Alcohol Depend 2021;219:108467). I keep clozapine in the back of my mind if other antipsychotics aren’t helping much. In addition to being our most effective antipsychotic overall, it actually might decrease substance use among patients with psychosis (Lahteenvuo M, et al, Br J Psychiatry 2022;221(6):758–765). I recognize the practical challenges to prescribing clozapine, but I also see that as a problem in our field: It’s a lifesaving medication that doesn’t get used often enough.

CATR: How long should antipsychotics be continued?

Dr. Beckmann: The quick answer is the same as in schizophrenia: until they’re no longer necessary, or their benefits no longer outweigh the risks. My approach is if the patient’s psychotic symptoms are minimal, if their life circumstances are reasonably stable, and if they are no longer using substances or have cut their use down markedly, then a slow and careful antipsychotic taper is reasonable. And before starting, discuss with the patient that the plan would be to go back on the antipsychotic if symptoms become concerning again.

CATR: What about non-medication treatments?

Dr. Beckmann: There is a broad umbrella of psychosocial interventions that are known to be helpful for both primary psychotic disorders and SUDs separately. Psychotherapy has evidence, of course, as well as interventions that involve a person’s community, whether that’s family, friends, or peers. Motivational interviewing is an invaluable skill set when working with any patient who is resistant to change. And involving peers with lived experience can also play a very important role. Ideally, different modalities of treatment should be integrated with one another. Even if the SUD and psychosis providers are not the same individual, their interventions should be parallel rather than sequential.

CATR: How do you counsel patients after an episode of SIP?

Dr. Beckmann: Like all psychiatric diagnoses, we want to provide honest, nonjudgmental psychoeducation. They should understand that each episode of SIP puts them at higher risk of future episodes. The research arm of the clinic I used to work in, Mass General’s Recovery Research Institute, has a general addiction resource webpage that I like (www.recoveryanswers.org). The Schizophrenia Society of Canada has a website that can serve as a good educational resource as well (www.cannabisandpsychosis.ca). The Cannabis Research Report from the National Institute for Drug Abuse is a resource for patients with lots of information about cannabis risks, including a page on psychosis (www.tinyurl.com/bddamveu).

CATR: And other than just abstaining from substance use, how might a patient lower their risk of a subsequent psychotic episode?

Dr. Beckmann: Keep harm reduction principles in mind. In general, SIP risk is dose dependent. So for stimulants, having patients decrease their overall use might be helpful. For cannabis, I ask: “What do you get out of using cannabis?” “What do you like about it?” “What don’t you like about it?” Depending on their answer, perhaps they would be willing to use lower-potency products. Given the possible opposing actions of CBD and THC, it is also helpful if a patient switches to a product with a higher CBD:THC ratio.

CATR: Thank you for your time, Dr. Beckmann.