Psychedelics in research, much like the flower child, was common in the 1960s. After a decline, in part driven by stricter legislation (Bird, 2019), the last twenty years has seen a resurgence of research in the field (Bird, 2019), as well as recreational use of psychedelics (Livne et al. 2022). Along with other recreational drugs like ketamine (Jiang, 2021), psychedelics are being increasingly examined for their potential therapeutic value (Rucker et al., 2016). Evidence suggests that in such environments, the risk to participants has been minimal (Schlag et al., 2022). In clinical trials, some groups of people are often excluded due to safety concerns, and this often includes individuals with a genetic risk for psychosis or bipolar disorder (Johnson et al., 2008).

However, a controlled trial with safety protocols, ethics review boards, and healthcare providers, is very different from recreational use. Despite this, there is a growing interest in young people in the idea of “micro-dosing”. Micro-dosing is the administration of sub-hallucinogenic doses of psychedelic drugs to self-treat mental disorders (Cameron et al., 2020) or simply to improve daily functioning (mood, cognition, focus, creativity etc).

In this context, a more comprehensive understanding of the consequences of psychedelic uses in such naturalistic settings is important. This is what Simonsson et al., (2024) set out to examine. Using twin data, they explored the association between psychedelic use and psychotic or manic symptoms. They also conducted a co-twin study comparing monozygotic twins’ use of psychedelics and psychotic/manic symptoms. This design allows researchers to remove familial confounding. Finally, they examined the interaction between genetic risk for psychotic/bipolar disorder and psychedelics, on rates of reported psychotic/manic symptoms.

Methods

The Child and Adolescent Twin Study in Sweden (CATSS), is a robust longitudinal dataset, with data on 17,220 twins at baseline (Anckarsäter et al., 2011). 16,255 twins were used for this study, and all measures were collected at one-time point, making this a cross-sectional study.

Self-reported psychedelic drug use, specifically lysergic acid diethylamide (LSD) or psilocybin, was assessed as a binary score (i.e., yes/no previous lifetime use). Other self-reported drug use was recorded for alcohol, tobacco, cannabis, stimulants, sedatives, opioids, inhalants, and performance enhancers. Psychotic and manic symptoms were assessed using continuous self-report measures, the Adolescent Psychotic-like Symptom Screener (APSS) (Kelleher et al., 2011), and the Child Mania Rating Scale Brief Version (Henry et al., 2008). Genetic risk was calculated using polygenic risk scores (you can read more about polygenic risk scores in other Mental Elf blogs including Hagenberg 2024, Aruldass 2024, Donnelly 2024).

All analysis used linear regression models. Two levels of adjustment were conducted. First, models were adjusted for sex only. The second adjustment included sex and other drug use.

Drug use was examined using two definitions:

• Substance-specific drug use: Adjusting the model for each individual substance used.
• Substance-aggregate drug use: Aggregate scores of drug use, including one for tobacco/alcohol, and a second scale for cannabis, stimulants, opioids or inhalants.

Results

Of the 16,255 participants, 541 reported previous psychedelic use. Of these 541, only 6 reported no past use of other drugs. This itself is an interesting finding about the high frequency (99.45%) of polysubstance use in those who use psychedelic substances, in this sample.

In examining the association between psychedelic use and psychotic or manic symptoms, psychedelic use was found to be associated with both a higher number of psychotic symptoms and a higher number of manic symptoms, when the use of other substances was not taken into account. However, when analyses were adjusted for other drug use, the opposite effect was found, showing those who used psychedelics had fewer self-reported psychotic or manic symptoms. This was found in both the substance-specific adjustment and substance-aggregated adjustment.

Only a subsample of monozygotic twins (where one twin had, and the other hadn’t, used psychedelic drugs in their lifetime) were included for co-twin analysis (n=105). The size of this sample is quite small for so many covariates to be used in the adjusted model, and the results should be interpreted cautiously. No significant effect on psychotic symptoms was found in the unadjusted model, but a similar inverted pattern was observed in the adjusted model. Manic symptoms were more frequent in those who used psychedelics in the unadjusted model but less frequent in those who used psychedelics. This was observed in the substance-specific adjusted model but not the substance-aggregate.

The subsample of those who had polygenic risk scores was larger (n=8797) than the twin study. The interaction between polygenic risk score (schizophrenia or bipolar) and psychedelic use was not associated with reported psychotic symptoms. This was true for both unadjusted, and adjusted models. For manic symptoms, there was a significant interaction; Individuals with a higher genetic risk for schizophrenia reported higher number of manic symptoms if they had previously used psychedelics, although the effect is only marginally significant, and with wide confidence intervals i.e. there is wide range in the overall sample. Considering genetic risk for bipolar disorder, the effect is still marginally significant, but also indicates those with a higher genetic risk who use psychedelics report more manic symptoms. As with the psychosis measure, the confidence intervals were very wide.

Conclusions

This study found evidence suggesting that, when the past use of other substances is considered, previous psychedelic use is associated with lower self-reported manic and psychotic symptoms. However, as noted by the authors themselves, this finding should be interpreted with extreme caution, given the cross-sectional nature of the study.

For a more detailed discussion about this, have a listen to the following JAMA podcast episode with first author, Otto Simonsson:

https://edhub.ama-assn.org/jn-learning/audio-player/18862944.

This study also examined genetic risk and found some evidence to suggest that while genetic risk for schizophrenia or bipolar disorder did increase one’s risk of manic symptoms, no effect was found for psychotic symptoms.

Strengths and limitations

The study has several key strengths: First, it had a very large sample, particularly for the examination of the association between psychedelic drugs and psychotic or manic symptoms. This is very valuable when attempting to examine psychedelic use in naturalistic environments. Second, reporting on polysubstance use and adjusting for this means the study can elucidate the specific association between psychedelics and psychotic/manic symptoms, while accounting for the possible influence of other, related factors like the use of other drugs. Finally, the novel use of co-twin monozygotic twins allowed for a consideration of familial confounding, which is not normally possible. This is useful, as substance use can be effected by family circumstances e.g., parental substance use, neglect, maternal psychological health, poor supervision (Nawi et al., 2021). With this study design, the assumption is that these confounding factors will have less of an impact on the study results.

However, there is a very big caveat to this study, which the authors themselves explicitly acknowledge:

The nature of the phenotypic data (cross-sectional) cannot exclude reverse causality (e.g. it could well be that the twin with fewer psychotic symptoms in the first place is for some reason more likely to consume psychedelics than their co-twin with more psychotic symptoms).

Put simply, the use of a cross-sectional design for this study means you cannot exclude reverse causality i.e., is it instead the case that those who had previously experienced manic/psychotic symptoms were less inclined to use psychedelics than others, due to concerns about the risk of adverse effects of psychedelic drugs? It is vital that the temporal relationship between psychedelic substance use and psychotic/manic symptoms is considered and tested widely so that we can determine the direction of this association.

Another concern is the lack of information about the type, dose and frequency of psychedelic substance use. These are very important questions when interpreting the role of psychedelics and mental health outcomes. Without that information, individuals who use high doses of psychedelics once a week, and individuals who have micro-dosed once, are all in one sample.

Finally, there are a few methodological considerations. The polygenic risk score for bipolar was not associated with manic symptoms, which the authors say may be linked to the small sample size for such a polygenic study, or may be due to the underreporting of manic symptoms in the study. The challenge of self-report and underreporting also must be considered for substance use. All substance use measures were collected using retrospectively using self-report. While a common data collection technique, this approach may lead to underreporting of substance use history, due to social stigma or memory loss over time (Khalili et al., 2021). Previous research has suggested collection of biological data (e.g., urine tests) is a more accurate measure of substance use. However, this assumes recent usage, which also makes it an imperfect solution for research.

Implications for practice

This is an interesting exploratory study in a large sample, and offers some unexpected findings of the role of psychedelics in naturalistic environments (although reverse causality needs to be explored in future studies).

When considering the clinical implications of this study, one stark finding emerges; 99% of those who reported using psychedelics also had a lifetime use of other drugs (alcohol, tobacco, cannabis, stimulants, sedatives, opioids, inhalants, performance enhancers). Adjustment for these demonstrated that psychedelic use had an inverse association with manic and psychotic symptoms. In research, adjustments are done to control for covariates and confounders, in order to potentially identify links that may be obscured otherwise. However, in real life clinical practice, this study suggests that individuals who will attend having only used psychedelics will be extremely infrequent. Without adjusting for one’s use of other drugs, psychedelics were associated with higher levels of psychotic and manic symptoms. Additionally, with a cross-sectional design, it’s impossible to exclude reverse causality, and as the authors themselves discuss, it’s equally possible that those who have previously had psychotic or manic symptoms, were less likely to take psychedelics, leading to this result. Longitudinal quantitative studies, and qualitative studies about individual motivations for substance use, could help improve our understanding of this result.

Additionally, information about previous substance use is lacking, beyond dose and frequency, the question remains as to whether these substances were used concurrently, or at different times. It’s possible that the use of cannabis and psychedelics concurrently may increase risk in ways not possible to observe in a study which adjusts for cannabis use. While research has observed an interest in micro-dosing as a self-administered treatment for mental disorders (Cameron et al., 2020), this large sample of young people appears to suggest very few use only psychedelics. Other substances, like cannabis, have repeatedly been linked with higher rates of psychotic phenomena (Staines et al., 2023) and manic symptoms (Gibbs et al., 2015). Therefore, understanding the interaction between concurrent substance use and psychedelics is crucial.

Statement of interests

No conflicts of interest.

Links

Primary paper

Simonsson O, Mosing MA, Osika W, et al. Adolescent Psychedelic Use and Psychotic or Manic Symptoms. JAMA Psychiatry. Published online March 13, 2024. doi:10.1001/jamapsychiatry.2024.0047

Other references

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