M is a 24-year-old male who currently resides in shared accommodation that is rented. He is unemployed and supported by social services. He is brought in to the emergency room due to agitated and threatening behavior downtown. He states that the Hell's Angels are attempting to murder him. He believes he unwittingly insulted a Hell's Angels gang member and now they are tracking him down to kill him. He started screaming and waving a knife at a local restaurant when he believed Hell's Angels gang members had cornered him after using cell phone tracking technology. He could hear them talking about their plans to murder him over the music system, that also was broadcasting his thoughts.
On mental status, he is thin and overtly agitated. He appears to be talking to himself. He has very poor self-care with multiple excoriations over his arms. He is yelling and pawing at the air. His thought form is linear and goal directed, though he is difficult to interview due to his rapid speech and easy proneness to escalation. He is disoriented to time and date, but not place or person. The interview quickly ends due to his level of agitation. Urine drug screen is pending.
The amphetamine-type stimulants, with methamphetamine being the pre-dominant substance, are the most widely used illicit drugs in the world after cannabis (for those countries that have not legalized cannabis). Indeed, seizures of methamphetamine by law enforcement,1 hospitalization rates,2 emergency department utilization,3 and treatment seeking4,5 have all increased for methamphetamine use disorders. Psychiatric presentations represent the most common reasons for hospitalization related to methamphetamine use2 where it has been reported that 36.5% of methamphetamine users experience a methamphetamine-induced psychotic disorder.6 Earlier onset of methamphetamine use with longer duration of use, higher frequency of use, and use of greater amounts of substance are associated with increased likelihood of experiencing psychosis.7,8 Clinical staff need to be able to recognize methamphetamine use and the frequent co-occurrence of psychosis.
Differentiating between a methamphetamine-induced psychosis and a primary psychotic disorder like schizophrenia can be challenging, but important given that treatment of the former will focus on addiction treatment, while the latter will focus on longer term antipsychotic medication and psychiatric follow-up.4,7,9 Compounding matters is that a significant number of individuals who develop psychosis with methamphetamine use will develop a persistent methamphetamine-induced psychosis, often with cognitive deficits indistinguishable from those seen with primary psychotic disorders.10 Those with brief, non-persistent psychoses, have been found to have no significant cognitive differences from methamphetamine users without psychoses and healthy controls,10 suggesting a lack of cognitive symptoms in brief psychotic presentations may help determine if there will be a persistent course of psychosis. Further, 22% to 33% of persons diagnosed with methamphetamine-induced psychosis are later diagnosed with a primary psychotic disorder.4,9,11 Persons experiencing psychotic symptoms are often reluctant to disclose psychotic symptoms and may be overly willing to attribute psychotic symptoms to amphetamine use to avoid psychiatric care and antipsychotic medications. They may also be reluctant to disclose the degree or severity of their methamphetamine use to avoid entering addiction treatment.12
Psychotic symptoms that precede substance use, are substantially in excess of what would be expected given the amount of substance used or duration of use, persist despite abstinence (especially for more than a month), and prior psychotic episodes not related to substance use are indicative of a primary psychotic disorder being present according to DSM-5.13 Earlier onset of methamphetamine use, longer duration of use, and use of larger amounts have been associated with the increased likelihood of developing a methamphetamine-induced psychosis.7,8 Recurrence of psychosis after an initial episode however may occur with relatively brief use or with relatively smaller amounts of methamphetamine, potentially reflecting sensitization.8 Reported differences between persons with methamphetamine-induced psychotic disorders compared to primary psychotic disorders include less family history of psychotic disorders, better insight into their illness, fewer negative symptoms, and fewer positive symptoms.9 A positive family history for psychosis, especially in a parent or sibling, should increase clinical suspicion of a primary psychotic disorder. Use coinciding temporally with symptoms suggests a methamphetamine-induced psychosis as would the finding of a positive urine drug screen for methamphetamine. In this regard, if a methamphetamine-induced psychosis is suspected, a urine drug screen should be sought immediately for confirmation, as methamphetamine is rapidly cleared with urine drug screens becoming negative as quickly as 48 hours after use.14
Although there is considerable symptom overlap with studies showing no differences in the severity of Positive and Negative Syndrome Scale scores between methamphetamine-induced psychoses and primary psychoses,15,16 the clinician should suspect a methamphetamine-induced psychosis if there are visual or tactile hallucinations, a high degree of agitation or manic-like presentation, presence of movement disorders typically associated with stimulant use (e.g., stereotypies, choreoathetosis, bruxism),17 signs of sympathomimetic toxicity (e.g., tachycardia, hypertension, diaphoresis),18 stigmata of methamphetamine use is present (e.g., burn marks, scratching from formication, dental erosions), pre-dominantly paranoid delusions, delirium, and if there is an abrupt onset with no prior history (especially in an adult who develops the symptoms later than would be expected, i.e., in 30s or 40s). The clinician should suspect a primary psychotic disorder if there are typical auditory hallucinations (e.g., commenting voices, voices talking among themselves), presence of prominent negative symptoms (e.g., affective flattening, poverty of thought, poor relatability), presence of perplexity, persistent thought disorder, bizarre delusions, or an insidious onset to the psychosis.4
In this case, with the presence of primarily persecutory delusions, high level of agitation, excoriations on his arms, his pawing at the air (potentially due to visual hallucinations), and disorientation should suggest a likely methamphetamine-induced psychosis.
The usual course of a methamphetamine-induced psychosis is that the majority clear within a week with abstinence alone, although a subset can have more prolonged symptoms.4,19 Acute methamphetamine intoxication management tends to focus on de-escalation techniques, limiting stimulation in a secure setting, and short-term management with benzodiazepines for sedation.8,11 When psychosis is present, antipsychotic medications tend to be used first line, even though it takes several weeks for complete therapeutic benefits often to be realized20,21 and there are no head to head trials comparing benzodiazepines to antipsychotics for short-term methamphetamine-induced psychoses. More sedative atypical antipsychotic agents with lower D2 receptor affinity are preferred to avoid dystonic reactions and limit antipsychotic-induced anhedonia that may pre-dispose to relapse to methamphetamine use.8,11 Unfortunately, many persons presenting with a methamphetamine-induced psychosis are discharged once the psychosis has cleared before being engaged in addiction treatment, only to return to methamphetamine use and psychosis re-emerging. If able to be engaged in treatment acutely, treatment outcomes suggest benefits similar to that found for other addictive disorders where longer treatment retention confers better treatment outcomes22 and may also prevent potential conversion in the future to a persistent psychotic disorder.
If persons have persistent psychotic symptoms, then a review of the diagnosis is warranted. Involvement of psychiatric services capable of managing psychotic patients with co-occurring substance use would be the ideal to manage both disorders concurrently.12 Antipsychotic medication is preferred where to date, trials of olanzapine, risperidone, aripiprazole, quetiapine, haloperidol, and clozapine have been found effective in managing the persistent psychotic symptoms of a methamphetamine-induced psychosis or primary psychosis exacerbated by methamphetamine.8,11,19,23–25 Clozapine should be reserved for cases of treatment resistant psychoses that have failed more than 2 adequate trials of antipsychotics and where ongoing methamphetamine use is not the cause of the ongoing symptoms. There is also some concern about haloperidol increasing GABAergic cell death, so the use of atypical antipsychotics with lower D2 blockade may be preferred.8 One study suggested that persons with more positive symptoms of psychosis (e.g., hallucinations, delusions) respond better to risperidone, whereas those with more negative symptoms (e.g., affective flattening, lack of motivation, poverty of thought, cognitive impairments) respond better to aripiprazole.26 However, there is no definitive data to suggest 1 antipsychotic is better than another.12,23,24 Additional considerations of antipsychotic drug choice include possible potentiation of seizures with methamphetamine use and antipsychotic medications known to lower the seizure threshold such as clozapine, chlorpromazine, though this has not been systematically studied.27 There have been no published trials of long-acting injectable antipsychotics in this population. Lower doses may be required.12 It should be recognized too that antipsychotics do not treat methamphetamine use disorder on their own as they do not reliably block the euphoric effects of methamphetamine and have significant side effects, including dysphoria and akathisia, which may worsen substance use disorders by pre-disposing to relapse and cravings.28,29 A meta-analysis of antipsychotic treatment trials for stimulant use disorders without psychosis concluded antipsychotics to have no advantages over placebo regarding abstinence, craving or retention in treatment with higher intolerability-related medication discontinuations.28
For psychotic symptoms that persist beyond 2 to 4 weeks there is currently little guidance as to how long a person should be kept on an antipsychotic medication. Given the potential to convert to an ongoing psychotic disorder, the pragmatic recommendation is to treat in the same way 1 would approach a first episode of psychosis12,20 with an antipsychotic medication for at least 18 months. However, a re-evaluation of the diagnosis should be made at about 6 months25 to limit potential exposure to an antipsychotic medication. If there has been a full resolution of psychotic symptoms with a full functional recovery in the context of there being no family history of psychosis, no prior psychotic episodes, and no signs or negative symptoms, then a gradual tapering off of the antipsychotic may be considered.25
Some have considered whether there is a role for prescription stimulants as a substitution/harm reduction strategy for methamphetamine use disorder. Unfortunately, recent reviews suggest that while there may be brief subjective reports of improvement, trials to date have not found improved abstinence or treatment retention rates.30,31 Prescribed stimulant medication may be particularly risky in patients who have experienced psychosis as they may further worsen active psychosis or cause relapse to psychosis in previously remitted patients,32 although recent literature suggests this risk may be less, especially for well selected persons who have an overt pre-existing attention deficit hyperactivity disorder and are well stabilized on an antipsychotic.33
There are no currently indicated pharmacotherapies for methamphetamine use disorder with or without psychosis. Although some medication trials have demonstrated brief improvements in cravings or decreased use, to date medication trials have not found sustained improvements in abstinence or treatment retention rates. Medication trials have involved, but are not limited to, antipsychotics (as described above), antidepressants (bupropion, mirtazapine, sertraline, paroxetine, and imipramine), anticonvulsants (topiramate, gabapentin), N-acetylcysteine, naltrexone, baclofen, ondansetron, rivastigmine, and selegiline.23–25
Psychosocial interventions remain the mainstay of treatment currently, particularly cognitive behavioural therapy (CBT)/relapse prevention where the Matrix Model seems to have the best evidence.34 It involves motivational strategies to encourage patient engagement, individual and group CBT, psychoeducation for patients and their families, drug monitoring, and self-help involvement. CBT strategies focus on relapse prevention skills early, specifically addressing: drug avoidance, identification of triggers, and drug refusal skills.35 Initial avoidance of people and situations associated with use is preferred to establish abstinence before attempting to challenge urges or cues. One prominent cue associated with use is access to money. Limiting access is critical via use of direct deposit, others caring for funds, getting rid of bank cards/credit cards, and/or withdrawal limits. Involvement of family to optimize structure and support is important as is eliminating immediate access from cues such as disposing of use paraphernalia, drug stashes, and dealer phone numbers, avoiding cues by changing travel routes, changing people of contact, and letting people know of the use problems. Avoiding alcohol and other substances also would be important due to the common relapse scenario where after using another agent they are less likely to refuse methamphetamine or be in a situation where it is readily available. Refusal skills often involve practicing what they would do if in a high-risk situation involving how to refrain from substance use and leave the scenario. However, poor rates of treatment induction and retention remain with psychosocial interventions and the methamphetamine-related cognitive deficits in executive functioning have been hypothesized to limit effectiveness of more cognitive-based interventions.36,37 There is also demonstrated efficacy for contingency management approaches, but these are less readily used or available, and effects may lack durability once contingencies are removed.37 Although motivational interviewing/brief interventions have some evidence, it is substantially less than that for CBT/relapse prevention.38
All patients who present with methamphetamine-induced psychosis should be provided with psychoeducation regarding the risk of recurrent episodes of psychosis with on-going use and the risk of developing a primary psychotic illness.25 It is important to assess the route of methamphetamine administration as a significant proportion (28.2%) of individuals seeking treatment for methamphetamine use reported injection as their usual route of administration.5 If there is a history of injection drug use appropriate investigations should be undertaken for bloodborne illnesses. Even paraphernalia sharing, such as “crack pipes,” should be discouraged, as cracked lips and open sores can be a route of hepatitis C transmission, along with shared filters and spoons. It is important to assess concurrent use of other substances and address these appropriately. In the United States, the concurrent use of opioids and methamphetamine has been increasing, creating additional challenges in this patient population.39
For patients who are not prepared to discontinue their methamphetamine use appropriate harm reduction practices should be employed.40 This may include, but is not limited to, discussion regarding additional precipitants of psychosis (such as sleep deprivation), minimally harmful injection techniques and connection to resources providing clean supplies and safe injection sites where available. All patients using opioids should be offered opioid agonist treatment.41 In addition, all patients should be provided a naloxone kit and training, as there have been increasing reports of fentanyl contaminating methamphetamine.42,43 For patients with persistent methamphetamine use resulting in symptoms of psychosis it may be prudent to consider ongoing treatment with an antipsychotic though this has not been systematically studied and careful consideration should be given to risk/benefit ratio given the side effect profile associated with these medications (see above). Motivational interviewing techniques should be employed to explore the patients desire to continue using and possible alternative areas of intervention, for instance at times patients report using methamphetamine to stimulate wakefulness in order to assure their safety when they do not have access to housing. Connecting these individuals to low-barrier housing may reduce their methamphetamine usage.40
Methamphetamine-induced psychotic disorders occur in 36.5% of methamphetamine users. Most methamphetamine-induced psychotic disorders resolve with abstinence alone in about a week, but a subset have more persistent psychotic symptoms or convert to a primary psychotic disorder. For persistent psychotic symptoms, review the diagnosis, treat with an atypical antipsychotic, and ensure engagement in concurrent addiction and psychosis services. For psychosis that resolves, focus should be on engagement in addiction treatment. In both cases, patients should be provided with psychoeducation, engaged incorporating motivational approaches, and utilize CBT approaches early on that focus on relapse prevention skill development including drug avoidance, identification of triggers, and drug refusal skills.
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