CHPR: Many patients we see on the inpatient psych unit have both a psychiatric and a substance use diagnosis, and it can be tricky to figure out whether their psychotic symptoms reflect the drug use versus the underlying psychiatric disorder. How do you distinguish between these diagnoses?

Dr. Athanasiou: I start by looking at the type of symptoms the patient is experiencing. We typically see predominantly positive symptoms—hallucinations and delusions—with substance-induced psychosis (SIP), whereas primary psychotic illnesses, such as schizophrenia, are more likely to also present with negative symptoms, like blunted affect and lack of motivation. Next, I look at the onset of symptoms in relation to the timing of potential substance use. The presence of psychotic symptoms prior to initiation of substance use indicates the presenceof a primary psychotic disorder, while the onset of psychotic symptoms shortly after substance use increases the likelihood of SIP. 

CHPR: What are some ways we can determine onset accurately?

Dr. Athanasiou: You can look at the results of urine drug tests, family history of substance use or psychotic disorders, collateral information about recent drug use or prodromal symptoms, and even physical exam findings, like constricted pupils, that may indicate recent drug use. But it can still be difficult to differentiate between them, especially considering that substance use is widespread in individuals with psychotic disorders. Also, SIP can persist for a period beyond the expected substance intoxication or withdrawal. When this occurs, it can make it particularly difficult to differentiate. The DSM qualifies this dilemma by stating that a primary psychotic illness should be considered when the symptoms persist for longer than about one month after substance use. 

CHPR: But might symptoms of SIP sometimes persist beyond a month?

Dr. Athanasiou: Yes, and this is an important question that we are still trying to understand better. There’s evidence that, for some individuals who use methamphetamines, the symptoms of psychosis can persist beyond a month (Fiorentini A et al, Front Psychiatry 2021;12:694863). 

CHPR: Does that mean the DSM’s one-month duration might be too restrictive?

Dr. Athanasiou: For time-limited symptoms resulting from the direct effects of a particular substance, such as methamphetamine-induced transitory psychotic symptoms, it’s still helpful to use the one-month duration as a practical means to differentiate from individuals with a primary psychotic illness. But the persistent symptoms of psychosis that occur with repeated episodes of SIP can extend beyond the one-month mark, so that timeframe does seem too restrictive. 

CHPR: Individuals who use methamphetamine and other stimulants are more likely to subsequently be diagnosed with a primary psychotic illness, even if they’ve been abstinent for several months, compared to individuals who have never used these substances, right?

Dr. Athanasiou: Correct, and we refer to this as conversion or transition rates. Several studies have shown that about 25% of individuals diagnosed with SIP will subsequently transition to a primary psychotic illness (Murrie B et al, Schizophr Bull 2020;46(3):505–516). The rates of these conversions vary for different substances, with rates being highest for cannabis, followed by stimulants.

CHPR: How likely is it that someone can return to their premorbid functioning if they are able to remain abstinent for a lengthy period?

Dr. Athanasiou: This is an important question. For someone diagnosed with SIP, studies have shown that abstaining from substance use significantly lowers their risk of converting to a primary psychotic disorder and improves their level of functioning (Murrie et al, 2020). But several factors affect a person’s likelihood of returning to their premorbid functioning, like the type of substance used, severity of symptoms, age of onset, and family history. 

CHPR: Please elaborate on these risk factors.

Dr. Athanasiou: They shift depending on the substance, but there are some commonalities. In general, the dose or potency of the substance, and the frequency or length of time that the individual has been using, all increase the risk of converting to a primary psychotic disorder. So, for example, if you consider somebody who occasionally uses cannabis versus somebody who meets criteria for cannabis use disorder (CUD), the individual with CUD is at higher risk of subsequently developing a psychotic disorder. Also, several studies have shown that there are different risks based on the substances used—cannabis shows the highest rate of conversion to schizophrenia, followed by methamphetamines and then hallucinogens (Starzer MSK et al, Am J Psychiatry 2018;175(4):343–350). 

CHPR: And age of use is another risk factor.

Dr. Athanasiou: Yes, that’s an important concern. The earlier that someone starts using substances like methamphetamines or cannabis, the higher the likelihood that they’ll develop a primary psychotic disorder later in life. But the prodromal phase of primary psychotic disorders like schizophrenia often begins before adulthood—which is around the same time when cannabis use might first start—so individuals may be more likely to use cannabis during a prodromal phase. Are we seeing people who already have an underlying predisposition to psychotic illness, and then the cannabis use precipitates the onset? Or is there a shared genetic vulnerability to both CUD as well as psychotic illness? What we are likely seeing is not a causal link, bur rather a strong ­association between cannabis and onset of a primary psychotic illness (D’Souza DC et al, World Psychiatry 2023;22(2):231–232). 

CHPR: If cannabis use does precipitate the onset of schizophrenia, it would be good if there were better public health messaging about this possible risk. 

Dr. Athanasiou: Right, especially since the general population does not appreciate the significance of the relationship between cannabis and psychosis. But it’s difficult to distill the scientific evidence into a clear and concise message that resonates with our patients or the public. The evidence tells us that most people who use cannabis will not experience cannabis-induced psychosis, but for a subset of the population, cannabis can be quite risky. I make a point of talking to patients about the risk of cannabis use. For those with a primary psychotic disorder, I tell them that cannabis is likely worsening their symptoms and making it harder for their antipsychotic medications to work. For young patients at risk for a psychotic disorder—for example, patients who have a first-degree relative with schizophrenia—I emphasize that cannabis poses the most significant risk, above any other substance, for triggering a psychotic illness. 

CHPR: It would be great if pediatricians provided psychoeducation on this point to their adolescent patients.

Dr. Athanasiou: I agree. Many pediatricians do, and this topic is becoming a greater public health concern now that cannabis is being legalized throughout the country and globally, because at the same time it seems that the perception of its harms may be decreasing. People are more willing now to initiate cannabis use, to use it more frequently, and to use it in higher potencies. In addition, the concentration of THC in cannabis products has been increasing in recent years. In the early 2000s the potency was less than 9%, but many of the current cannabis flower products have a potency over 20% (www.tinyurl.com/29mcf4fe). Newer formulations such as vape pens or concentrates can have even higher concentrations, upwards of 80% THC (www.tinyurl.com/ycmjbv2c). 

CHPR: Unlike cannabis and methamphetamine, the likelihood of psychosis from opioids is low, right? 

Dr. Athanasiou: Right, but a concern now is that we are seeing many more people use both opioids and psychostimulants, especially methamphetamines. Many experts see this combination as the next phase—some people call it a “fourth wave”—of the opioid crisis.

CHPR: Can you say more about this next phase? What specific concerns do you have about it?

Dr. Athanasiou: There are several concerns about this next phase. One major issue is the potential for inadvertent exposure to hazardous opioids such as illicitly produced fentanyl. This drug poses an elevated risk of overdose fatalities due to its considerably higher potency. Also, opioids and methamphetamines each have their own set of health risks, and when they’re combined, they elevate patients’ risks of harmful outcomes, like heart attacks, strokes, seizures, and respiratory depression. While there are approved pharmacotherapies for opioid use disorders, like buprenorphine, methadone, and naltrexone, there are no approved medications for stimulant use disorders (StUD), and the behavioral therapies that have shown efficacy for StUD are not always easy to access.

CHPR: Do antipsychotic medications work as well for SIP as for primary psychotic illnesses?

Dr. Athanasiou: Several studies have looked at both first-generation and second-generation antipsychotics and have found they are efficacious in treating hallucinations and delusions related to SIP, with most of the evidence based on methamphetamines (Fluyau D et al, Front Psychiatry 2019;10:740). Although there have not been enough studies to guide us specifically on the treatment of SIP, the consensus is to approach it in the acute phase similarly to treatment approaches for primary psychotic disorders. evidence becomes less clear for psychosis that persists beyond the acute phase, but generally clinicians will utilize treatment approaches similar to primary psychotic disorders. Some guidelines, such as from Australia, recommend using benzodiazepines before antipsychotics for cases of SIP or agitation in acute settings (www.tinyurl.com/57wstbp3). The concern stems from the cardiovascular risks—such as QT prolongation—from drugs like methamphetamine and cocaine, which can be exacerbated by antipsychotics. If benzodiazepines are not effective, then antipsychotics would be the appropriate next treatment. 

CHPR: You referred to behavioral therapies for StUD a few moments ago. Can you say more about treatments for SIP besides antipsychotic meds?

Dr. Athanasiou: This is a great question because it is always important to address the substance use as well as the psychosis. Studies have shown that cessation of substance use significantly reduces the reoccurrence of psychosis, and so an integrative approach that addresses both the psychotic illness and the substance use is important. Several psychosocial treatments appear effective for substance use disorders. Therapies that incorporate cognitive behavioral therapy, such as the Matrix Model, have shown efficacy for methamphetamine use disorder, as has contingency management (Glasner-Edwards S et al, CNS Drugs 2014;28(12):1115–1126). Motivational enhancement therapy can be effective for multiple substances. Clinicians are familiar with 12-step programs from Alcoholics Anonymous, and many people find such groups are helpful. Psychoeducation is important, and we should always talk with our patients about the negative effects that substances can have on psychosis. It may also be a good moment to acknowledge the role of extended-release naltrexone. It is approved for use in opioid and alcohol use disorders, but there is recent evidence of its benefit in combination with bupropion in the treatment of methamphetamine use disorder (Trivedi MH et al, N Engl J Med 2021;384(2):140–153). I use this combination along with an antipsychotic for some of my patients who have both a methamphetamine use and psychotic disorder.

CHPR: How long do you continue treatment for SIP? 

Dr. Athanasiou: I try to be mindful that in individuals whose psychoses have remitted after abstaining from substance use, we have an opportunity to try tapering off antipsychotic medications. Some information that helps in making this decision is the number of prior psychotic episodes, response to antipsychotic medication, and the ability to abstain from further substance use. So if, for example, the patient has had no more than three or four episodes of SIP and can abstain from further substance use without demonstrating symptoms of psychosis, then it is reasonable to trial them off the antipsychotic, while reassessing for re-emergence of symptoms every couple of months or so. 

CHPR: Thank you for your time, Dr. Athanasiou.