From the Editor

Agitated, excited, violent – when intoxicated. But my patient is also pleasant and engaging when not using substance (crystal methamphetamine).

Amphetamine use seems more and more common. What does the data show? In a new paper for The Canadian Journal of Psychiatry, James A. G. Crispo (of the University of British Columbia) and his co-authors look at amphetamine-related ED visits in Ontario. Drawing on administrative databases, they find a sharp rise over time: a 15-fold increase between 2003 and 2020. They write: “Increasing rates of amphetamine-related ED visits in Ontario are cause for concern.”

In the second selection, Dr. Ishrat Husain (of the University of Toronto) comments on psilocybin and depression in a new Quick Takes podcast. He goes into detail on the new NEJM study – which he co-authored. Dr. Husain discusses the literature and unanswered research questions. “It’s not necessarily all sunshine and rainbows.”

And in the third selection, Dr. Candace Marsters (of the University of Alberta) and her colleagues consider the unusual presentation of young adult with first-episode psychosis in a new paper for CMAJ. With time and diagnostic testing, they conclude that she has anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, and offer observations about that diagnosis and the limitations of testing. “Anti-NMDAR encephalitis is a rare but important differential diagnosis of first-episode psychosis among young adults.”


Selection 1: “Amphetamine-Related Emergency Department Visits in Ontario, Canada, 2003-2020”

James A. G. Crispo, Lisa Liu, Paxton Bach, et al.

The Canadian Journal of Psychiatry, 8 March 2023  Online First

Unregulated amphetamines (including methamphetamine) are a growing concern, particularly since there has been a surge in the use of these drugs in select North American regions. This may be due to factors such as greater availability and ease of access in recent years… In recent years, the drug supply has unintentionally led to stimulant use alongside other unregulated substances. This may have adverse consequences, particularly when amphetamines are used alongside opioids, contributing to opioid-related overdoses.

Amphetamine-related healthcare visits are on the rise. Amphetamine-related hospitalizations have tripled from 55,447 to 206,180 hospitalizations in the United States between 2008 and 2015. In Canada, the number of Manitobans that received first-time care for methamphetamine use increased from 208 in 2013 to 1,454 in 2018. Moreover, amphetamine-related emergency department (ED) visits in Winnipeg increased from 10 to more than 150 visits between 2013 and 2017…

So begins a paper by Crispo et al.

Here’s what they did:

“Using administrative claims and census data, we calculated annual patient- and encounter-based rates of amphetamine-related ED visits from 2003 to 2020 among individuals 18+ years of age. We also performed a retrospective cohort study of individuals with amphetamine-related ED visits between 2019 and 2020 to determine whether select factors were associated with ED revisit within 6 months. Multivariable logistic regression modelling was used to measure associations.”

Here’s what they found:

  • “In 2003, a total of 233 distinct patients had amphetamine-related visits to an ED; this increased to 4,146 in 2020. This represents a nearly 15-fold (1,367.9%) increase in the population-based rate of amphetamine-related ED visits between 2003 (1.9 individuals per 100,000 Ontarians) and 2020 (27.9 individuals per 100,000 Ontarians).” (!)
  • “Sex-stratified trends show that males had more amphetamine-related ED visits than females; the 2020 male ED visit rate was 2.3 times that of the rate for females…”
  • “Seventy-five percent of individuals returned to the ED for any reason within 6 months.” (!)
  • “Psychosis and use of other substances were both independently associated with ED revisit for any reason within 6 months (psychosis: AOR = 1.54… other substances: AOR = 1.84…), whereas having a primary care physician was negatively associated with ED revisit (AOR = 0.77…).”

A few thoughts:

1. This is a good study, offering solid data.

2. To summarize the big finding in a sentence: between 2003 and 2020, there was a 15-fold increase in amphetamine-related ED visits. Wow.

3. Other findings are less surprising, including that patients were likely to be male and younger (that is, under 40) – and often precariously housed.

4. The paper doesn’t consider pandemic data but evidence suggests further increases over the past few years.

5. Why the rise in presentations? “[P]otential increases in the availability and affordability of amphetamines in Ontario may have contributed to the dramatic climb in amphetamine-related ED care observed in our study.”

6. The authors note several limitations, including: “While our analyses are generalizable to the majority of Ontarians, they may be less applicable to individuals with publicly funded insurance other than OHIP, including First Nations People and members of the Canadian Forces.”

7. Amphetamine use has been considered in past Readings, including a podcast interview with Dr. David Castle (of the University of Toronto) that focused on crystal methamphetamine. “It’s highly prevalent, highly available, highly pure and highly destructive.” You can find it here:

The full CJP paper can be found here:

Selection 2: “Psilocybin in the treatment of depression”

Ishrat Husain

Quick Takes, March 2023

In this interview, I speak with Dr. Husain, a Tier 2 Canada Research Chair and the lead of the Mood Disorder Service at CAMH, and we delve deeper into this headline-grabbing research on psilocybin for depression. In our podcast, we discuss the NEJM study results and the challenges of conducting such research. We also touch on micro-dosing, the pragmatic concerns of large-scale accessibility to psilocybin, and if you should be buying your neighbour’s mushrooms.

We highlight from the discussion:

On talking to patients

“[I] tell patients that psilocybin is still very much an experimental treatment.

“There’s been so much interest from patients and the public that I, together with colleagues at CANMAT, published a consensus statement in The Canadian Journal of Psychiatry summarizing essentially what I tell patients day-to-day: psilocybin, although it has encouraging data on its safety and efficacy for depression, is still an experimental treatment that really should be exclusively accessed through clinical trials or in very rare special circumstances through the Health Canada Special Access Programme.”

On media reports

“The media reports are in danger of putting the cart before the horse. I think creating such hype and excitement means that the public is eager for access to this new treatment approach, so much so that they may begin to start looking into ways that they can access it themselves without medical oversight or supervision.”

On the big study

“It’s a three-arm study. They used a one-milligram dose of psilocybin as, effectively, an active control. I was a part of the team that led the study (the Canadian site). We randomized patients to receive either 25 milligrams of psilocybin which is in almost 100% of cases likely to induce a psychedelic experience that lasts up to 6 to 8 hours; the second arm was a medium dose of psilocybin, 10 milligrams, which would cause milder psychoactive or psychedelic effects in most individuals; and then, as I mentioned, the one-milligram active placebo. The results were encouraging in that it showed that the psychedelic dose – the 25-milligram dose – was superior to smaller doses in reducing symptoms of depression. The results also showed that 40% almost of people in the 25-milligram dose arm had an antidepressant response.”

On micro-dosing

“If you look at published literature, micro-dosing psychedelics like psilocybin or LSD is not superior to micro-dosing a placebo in terms of emotional, psychological or cognitive benefits. A large part of it may be the placebo effect. But if you look at the data, we can’t confidently say that micro-dosing is a healthy habit that that people should do to enhance their mental well-being.”

For those interested in reading more, Dr. Husain is the co-author of a letter to the editor just published in The American Journal of Psychiatry wondering about the antidepressant effects of psilocybin in the absence of psychedelic effects:

The Quick Takes podcast can be found here, and is just over 18 minutes long:

Selection 3: “A young adult with first-episode psychosis: when to consider anti–N-methyl-D-aspartate receptor encephalitis”

Candace Marsters, Svetlana Iskhakova, Laura Powe and Adrian Budhram

CMAJ, 6 March 2023  Online First

A 22-year-old woman presented to the emergency department after her roommate reported behaviour that included throwing kitchen items, urinating on the floor and threatening suicide. The patient reported having used alcohol, cannabis and psilocybin that evening. Her medical history was remarkable for a suspected mature cystic ovarian teratoma, which was being monitored by ultrasound, and for possible depression, for which she had reportedly been prescribed fluoxetine several months previously. However, it was unclear whether she had ever taken the fluoxetine, and she was taking no prescription medications at the time of her presentation.

We monitored her on the psychiatric unit and treated her for possible substance-induced psychosis with olanzapine.”

So begins a paper by Marsters et al.

It notes that the patient improved with antipsychotic medications. Unfortunately, after release from hospital, she was admitted a short time later. Various tests were ordered. Significantly – “Computed tomography of her abdomen and pelvis showed a fat-containing, rounded left ovarian lesion measuring 2.1 cm, in keeping with a mature cystic teratoma.” She improves (again) on olanzapine, was discharged and then was lost to follow up, only to re-present 10 months later.

The authors make comments on distinguishing anti-NMDAR encephalitis from more common causes of psychosis, drawing on the literature: “A multicentre observational study of 577 patients with anti-NMDAR encephalitis found that almost all developed neurologic features within 4 weeks, such as cognitive impairment, speech disorders, seizures, movement disorders, autonomic dysfunction or central hypoventilation, and only 1% of patients remained monosymptomatic after 1 month.”

The paper outlines diagnostic criteria.

Probable anti-NMDAR encephalitis

Diagnosis can be made when all 3 of the following criteria have been met:

  • Rapid onset (< 3 mo) of at least 4 of the 6 following major groups of symptoms: abnormal (psychiatric) behaviour or cognitive dysfunction, speech dysfunction (pressured speech, verbal reduction, mutism), seizures, movement disorder, dyskinesias or rigidity or abnormal postures, decreased level of consciousness, autonomic dysfunction or central hypoventilation
  • At least 1 of the following laboratory study results: abnormal EEG (focal or diffuse slow or disorganized activity, epileptic activity or extreme delta brush), CSF with pleocytosis or oligoclonal bands
  • Reasonable exclusion of other disorders

Diagnosis can also be made in the presence of 3 of the above groups of symptoms, accompanied by a systemic teratoma.

Definite anti-NMDAR encephalitis

Diagnosis can be made in the presence of 1 or more of the 6 major groups of symptoms and immunoglobulin G antibodies against the GluN1 subunit, after reasonable exclusion of other disorders.

They make comments about testing:

  • Electroencephalography. “A multicentre observational study found that EEG was abnormal in 90% of patients with anti-NMDAR encephalitis.”
  • Cerebrospinal fluid testing. “A multicentre observational study found that CSF evaluation showed abnormalities compatible with inflammation in 80% of patients with anti-NMDAR encephalitis.”
  • Testing for anti-NMDAR. “Testing for anti-NMDAR can be performed using serum and CSF samples.” Serum testing is not specific or sensitive – and they note the need for CSF samples after a positive serum test.

They add: “Consensus guidelines on when to order tests such as MRI, EEG and CSF do not exist, and clinicians must use their judgment. Neurologic symptoms and abnormalities on EEG and CSF evaluation increase the likelihood of anti-NMDAR encephalitis considerably. Without these factors, the yield from anti-NMDAR testing is low; we ordered the test in our patient because of the association between ovarian teratoma and anti-NMDAR encephalitis.”

A few thoughts:

1. This is a clear, concise paper.

2. The limitations of testing are clearly problematic. Repeating an important point: “clinicians must use their judgment.”

3. Many families wonder about this diagnosis, in part because of the popularity of Brain on Fire, the memoir that was turned into a popular film starring Chloë Grace Moretz. Perspective: “Psychotic disorders are commonly diagnosed among young adults in Canada, with an incidence of 54.9 per 100 000 person-years in Ontario. Anti-NMDAR encephalitis is… a rare disease with an estimated incidence of 0.17 per 100 000 person-years.”

4. Many thanks to Dr. Torfason for bringing this paper to my attention.

The full CMAJ paper can be found here:

Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.