The 5-Fold Psychosis, Mania Risk on High Dose Amphetamine with Lauren Moran, MD

Patients on high-dose amphetamine (≥ 30 mg) have a 5-fold increased risk of developing psychosis or mania, a new study found.^1,2 The study particularly examined dextroamphetamine, and 30 mg of this equals 40 mg of Adderall.

As of now stimulant medications do not have an upper dose limit on their labels, but this case-control study highlights the risk that comes along with high doses of amphetamines. The study included patients aged 16 – 35 years who were hospitalized at McLean Hospital for incident psychosis or mania between 2005 and 2019.

The study ultimately found patients on past-month amphetamine had increased odds of psychosis and mania, compared to controls (adjusted odds ratio [aOR], 2.68; 95% confidence interval [CI], 1.90 – 3.77), with a risk of nearly 63%. A secondary analysis showed past-month methylphenidate use was not linked to increased odds of psychosis or mania compared with controls (aOR, 0.91; 95% CI, 0.51 – 1.55).

In an interview with HCPLive, lead investigator Lauren Moran, MD, a pharmacoepidemiology researcher at McLean Hospital, shared how the findings may inform clinical practice on safe amphetamine dosing.

HCPLive: What would you highlight as the largest takeaway from the study?

Moran: The most important point of the study is that high doses of prescription amphetamines like Adderall are associated with a more than 5-fold increase in the risk of new-onset psychosis or mania.

HCPLive: How do the findings of your study contribute to the current understanding of the psychiatric risk associated with prescription amphetamine, particularly in the latest increasing amphetamine prescribing trends?

Moran: Yes, as you mentioned, there has been an acceleration in the prescribing of events. The risk of psychosis or mania is a known side effect of stimulants. There really is no research on dose. The purpose of the study was to really look to see if there were certain doses that are associated with a greater risk, which is what we found. This is useful because it can provide dosing guidelines for people who prescribe stimulants, you know, who may want to avoid using doses above this 30-milligram dextroamphetamine, which is like basically the equivalent of 40 milligrams of Adderall.

Or if the patient really needs these high doses, just be kind of careful and make sure that you're monitoring for possible symptoms of psychosis or mania. But it is a rare side effect. We don't want to cause alarm, but it's just something that people should take into consideration.

HCPLive: Did this study find a recommended dose?

Moran: We found that there really isn't much of an increase across all of the evidence. There really isn't much increase with the low dose levels, and that's 15 milligrams or below of the dextroamphetamine equivalents. The recommended dose to prescribe is 20 milligrams. But then once you get into between 20 and 30, which is the equivalent of 40 milligrams of Adderall, the dose goes up. But it's most pronounced when you go above 40 milligrams of Adderall.

HCPLive: What specific guidance would you offer clinicians regarding dose limits to minimize the risk of psychosis or mania?

Moran: I would say it really [is] on a case-by-case basis, but they may want to minimize [the] use of doses above the 30-milligram dextroamphetamine equivalent level, which is like 40 milligrams of Adderall. If you’re going to do that, just be careful. I would say make sure that you're monitoring patients frequently, and you're screening for these symptoms of psychosis or mania.

HCPLive: The study found individuals older than 22 years old had a greater risk of psychosis or mania with the drug compared to younger individuals. What might explain this age-related difference?

Moran: Yeah, I actually was curious about that as well. I looked at other characteristics of the older age group to see, did they differ in some other ways? What I found was that they actually were just on higher doses.

So, if you look at the average dose in the older age group, they were on higher doses than younger groups. I think it all kind of boils down to probably being related to the dose.

HCPLive: The study found females had a greater risk of psychosis and mania. Can you explain the sex-related differences?

Moran: In the main analysis, we did not find the effect with age. We found that in one of the sensitivity analyses where…we compared hospitalized control to hospitalized people with mania, and then we did a sensitivity analysis where we compared them to outpatients getting routine care. Because the finding wasn't consistent across 2 analyzes, I'm [not] as convinced by that. [If] we found it in both settings, it would be more robust.

HCPLive: What more research will need to be done to assess these sex-related differences?

Moran: We're actually doing this now. I'd like to replicate these findings using a different study design and a different data source. So, we're doing a study using a cohort design where we follow people who are started on stimulants and then look at their risk after they kind of enter these dose levels.

HCPLive: What additional research is needed to assess the long-term effects of high doses of amphetamine use on psychosis?

Moran: When someone is on high doses, you generally discontinue…the stimulant, and then they may or may not need treatment with an antipsychotic as well. In my clinical experience, the people generally get better and the symptoms resolve. I have seen people developing subsequent episodes of psychosis if they start taking stimulants again or use another substance that can increase your risk of psychosis, like cannabis. That's just my critical experience, not research.

In the United States, it's difficult to do these long-term studies. If you do research in Denmark…or a country with national health insurance, you can follow people throughout their lifetimes, and their insurance doesn't change. [In the US] people may stop getting their care into Mass General freedom…so we can't really follow long-term all the patients. And then other data sources that we use for this type of research, like insurance claims…people change their insurances. It's really hard to do a study to look at the long-term effects, but clinically, I would say that if [patients] stop taking the stimulants…we usually put them on antipsychotic medications for a few months, they usually the symptoms resolve. They do get better, and eventually they can be taken off antipsychotic under the guidance of a psychiatrist.

HCPLive: What specific monitoring strategies would you recommend for clinicians prescribing an amphetamine, particularly at higher doses, to detect and manage symptoms of psychosis?

Moran: Just like screening for a patient experiencing auditory hallucinations, [ask] if they [are] having any strange experiences. One thing that I personally find is helpful is to have patients sign a release for a close family member. Sometimes people don't have insight into their symptoms of psychosis or mania, and so if you see anything that kind of raises an eyebrow, you can ask a family member, have you noticed anything? Or it allows a family member to contact you as a physician, to express any concerns about new behaviors that might be consistent with psychosis or mania. Maybe you see people talking really fast and they're jumping from topic to topic. There's a lot of things that people can kind of pick up just from doing an interview.

HCPLive: Is there anything else you would like to say about this topic before we wrap up?

Moran: One of the findings was that we did not see an increased risk [with] methylphenidate. So, [it] seems like methylphenidate might be a safer alternative if you have concerns that a patient might have risk factors for psychosis or mania.

References

1. ^{Moran, LV et al. “Risk of Incident Psychosis and Mania with Prescription Amphetamines,” American Journal of Psychiatry. DOI: 10.1176/appi.ajp.20230329}
2. ^{Derman, C. Patients on High Dose Amphetamine Face Over 5-Fold Psychosis, Mania Risk. HCPLive. September 12, 2024. https://www.hcplive.com/view/patients-on-high-dose-amphetamine-face-over-5-fold-psychosis-mania-risk. Accessed September 12, 2024.}