Navigating the Nuance: Psychedelics, Psychosis, and Mania – A Look at the Evidence

Balancing Hope with Caution

The resurgence of interest in psychedelic compounds like psilocybin, LSD, and ayahuasca for treating a range of mental health conditions has brought with it both immense hope and a critical need for caution. As research explores their potential benefits for depression, anxiety, and PTSD, an important question arises: what are the risks, particularly for individuals who may be vulnerable to conditions like psychosis or mania? The relationship between psychedelic use and these serious mental states is complex and not yet fully understood. While modern clinical trials for psychedelic-assisted therapy typically exclude individuals with a personal or family history of psychotic or bipolar disorders, the increasing naturalistic (non-clinical) use of these substances means that understanding these potential risks is more urgent than ever. This article aims to explore the current scientific understanding of this nuanced issue, examining studies that present differing findings and discussing what this means for individuals considering psychedelic psychotherapy. Our goal is to provide a professional yet approachable overview for those seeking clarity on this important safety consideration. The concern that psychedelics might trigger or worsen psychotic or manic symptoms is not new. Historically, these substances have been anecdotally linked to such adverse events, which has contributed to their stigmatization and the stringent exclusion criteria in clinical research (Strassman, 1984). Psychosis involves a loss of contact with reality, often including hallucinations (seeing or hearing things that aren't there) and delusions (fixed, false beliefs). Mania, a hallmark of bipolar disorder, is characterized by periods of abnormally elevated mood, energy, racing thoughts, and impulsive behavior, which can sometimes include psychotic features. Given that psychedelics themselves induce profound alterations in perception, thought, and mood, it's understandable why there would be concerns about their impact on individuals predisposed to these conditions. However, the scientific picture is far from black and white, with recent research offering a more intricate and sometimes contradictory view.

Mixed Signals: Examining the Conflicting Research

The scientific literature on psychedelics and their link to psychosis or mania presents a mixed bag of findings, underscoring the complexity of the issue. Some studies suggest potential risks, while others indicate a more benign or even potentially protective association in certain contexts. It is crucial to look at these studies carefully, considering their methodologies, the populations studied, and the context of psychedelic use (e.g., controlled clinical setting versus unsupervised naturalistic use).One line of research, such as the longitudinal study published in Psychological Medicine by Simonsson et al. (2025, as per the Cambridge Core source), explores these associations in naturalistic users. This type of research is vital because it reflects real-world use patterns outside the carefully controlled environment of a clinical trial. The study by Simonsson and colleagues aimed to investigate associations between naturalistic psychedelic use and changes in the severity of psychotic or manic symptoms, with a particular focus on individuals with histories of schizophrenia or bipolar I disorder. Their findings, based on a large U.S. sample, suggest that the picture is not straightforward. For instance, they noted that prior work had not deeply investigated the quality of the acute psychedelic experience (e.g., challenging versus insightful experiences) and its association with these symptoms, nor had it always specified the type of psychotic or bipolar disorder, which is critical for understanding disorder-specific interactions. Conversely, other research, such as the study whose abstract was found on Liebert Pub (Dourron et al., 2025, psymed.2024.0036), suggests that naturalistic psychedelic use may not be associated with psychotic symptoms, even among those with a personal or family history of psychotic or bipolar disorders. This cross-sectional study involving 548 participants found that while a personal history of psychotic disorders was associated with greater magical ideation, referential thinking, and auditory hallucinations, the estimated number of lifetime psychedelic use occasions was not associated with any of the measured psychotic symptoms after adjusting for covariates. Interestingly, they even found an interaction where auditory hallucinations were less severe as psychedelic use occasions increased among those with a personal history of psychotic disorder, though no such relationship was found for those without such a history. This study concludes that further work is needed to probe the risk-benefit profile for people typically excluded from clinical trials. These contrasting findings highlight several important points:

1. Context Matters: The setting, intention, dosage, and support available during psychedelic use can significantly influence outcomes. Uncontrolled use, high doses, or use in psychologically vulnerable states without support may carry different risks than use in a therapeutic setting.
2. Individual Vulnerability: Pre-existing personal or family history of psychotic or bipolar disorders appears to be a key factor. However, even within these groups, the risk may not be uniform. Genetic predispositions are also being explored as potential moderators of risk (Simonsson, Mosing, et al., 2024b, as cited in Simonsson et al., 2025).
3. Type of Psychedelic and Symptoms: Different psychedelic compounds may have different risk profiles, and the specific symptoms (e.g., positive psychotic symptoms like hallucinations vs. negative symptoms or manic symptoms) may be differentially affected.
4. Methodological Differences: Cross-sectional studies (like Dourron et al., 2025) provide a snapshot in time, while longitudinal studies (like Simonsson et al., 2025, and Honk et al., 2024, as cited in Simonsson et al., 2025) track changes over time, offering different types of insights. Both have limitations, and a comprehensive understanding requires synthesizing evidence from various study designs.

Understanding the Mechanisms: Why Might Psychedelics Pose a Risk (or Not)?

The primary mechanism through which classical psychedelics like psilocybin and LSD exert their effects is by acting on serotonin 2A (5-HT2A) receptors in the brain. The serotonin system is known to be involved in mood regulation, perception, and cognition, and dysregulation in this system has been implicated in both psychotic and mood disorders. It's hypothesized that the intense activation of 5-HT2A receptors by psychedelics could, in vulnerable individuals, destabilize brain networks in a way that triggers or exacerbates psychotic or manic processes. This is particularly a concern for individuals who may already have an underlying dysregulation in their dopamine or glutamate systems, which are also critically involved in psychosis. However, the story is more complex. Psychedelics also promote neural plasticity – the brain's ability to form new connections and reorganize itself. In some contexts, this plasticity could be therapeutic, helping to break rigid patterns of thought and behavior associated with conditions like depression. But in individuals with a predisposition to psychosis or mania, this same plasticity, if not properly guided or if occurring in an already unstable system, could potentially lead to maladaptive changes or a worsening of symptoms. It's like a powerful tool that can be used for construction or deconstruction, depending on the existing foundation and how it's wielded. Recent research also points to the role of the default mode network (DMN), a brain network that is overactive in depression and involved in self-referential thought. Psychedelics are known to acutely decrease DMN activity, which is thought to contribute to their therapeutic effects by allowing for a temporary dissolution of rigid self-constructs and an openness to new perspectives. However, alterations in DMN connectivity are also observed in psychosis, and it's an area of active research to understand how psychedelic-induced changes in this network might interact with an individual's underlying vulnerability. Interestingly, some researchers are exploring whether certain aspects of the psychedelic experience, or specific compounds, might even have a role in reducing certain psychotic symptoms in specific populations, as hinted at by the Dourron et al. (2025) finding regarding auditory hallucinations. This is a highly speculative and early area of research, but it underscores the need to move beyond a simplistic "psychedelics are bad for psychosis" narrative and explore the nuances.

Navigating Uncertainty: Advice for Individuals

For individuals with a personal or family history of psychotic or bipolar disorders who are considering psychedelic psychotherapy, the current research landscape offers more questions than definitive answers, but some guidance can be inferred:

1. Extreme Caution is Warranted: Given the potential risks and the exclusion criteria in most clinical trials, individuals with these histories should approach the idea of psychedelic use with extreme caution and engage in thorough consultation with mental health professionals who are knowledgeable about both their condition and psychedelic research.
2. Transparency with Providers: If considering psychedelic use, it is absolutely crucial to be transparent with healthcare providers about one's psychiatric history. This information is vital for assessing potential risks.
3. Controlled Settings are Key: If, after careful consideration and professional consultation, a decision is made to explore psychedelics (which is generally not recommended outside of rigorous research protocols for these populations), it should ideally be within a legally sanctioned and medically supervised research setting, if such opportunities become available and appropriate. Unsupervised, naturalistic use carries significantly higher and less predictable risks.
4. Stay Informed: The research in this area is rapidly evolving. Staying informed about the latest findings from reputable sources can help in making more educated decisions. However, it's important to critically evaluate information and be wary of overly simplistic claims, whether positive or negative.
5. Focus on Established Treatments: While psychedelic research is promising for many, individuals with established psychotic or bipolar disorders should continue to prioritize and engage with evidence-based treatments that are known to be safe and effective for their specific conditions.

It is also important for the psychedelic research community and clinicians to develop better screening tools and risk assessment strategies. Understanding the specific genetic markers, neurobiological profiles, or psychological traits that might predict adverse reactions is a critical area for future research. This could help to identify individuals who are at particularly high risk and should avoid psychedelics, as well as potentially identifying those for whom the benefits might outweigh the risks, even with a pre-existing vulnerability, under very specific and controlled conditions.

Conclusion: A Call for Continued Research and Responsible Dialogue

The relationship between psychedelic use and the risk of psychosis or mania is a critical area of ongoing investigation. The current evidence presents a complex picture, with some studies suggesting potential risks, particularly in vulnerable individuals or with uncontrolled use, while others find no strong association or even hint at more nuanced interactions. It is clear that a one-size-fits-all answer does not apply. Factors such as individual predisposition, the specific substance used, dosage, setting, and the presence of therapeutic support all likely play significant roles in determining outcomes. For those uncertain about psychedelic psychotherapy, especially if there is a personal or family history of psychotic or bipolar disorders, the message is one of caution and the need for thorough, individualized assessment by qualified professionals. The allure of a potentially transformative therapy must be balanced against the imperative to "first, do no harm." As research continues to shed light on these intricate relationships, the hope is that we can better delineate the risk factors and develop clear guidelines to ensure that psychedelic therapies, if they become more mainstream, are used safely and responsibly. This requires continued rigorous scientific inquiry, open and honest dialogue about both the benefits and the risks, and a commitment to prioritizing patient well-being above all else.

Disclaimer: Psychedelic Assisted Psychotherapy has not been approved by any regulatory agencies in the United States, and the safety and efficacy are still not formally established at the time of this writing.

References

Dourron, H. M., Bradley, M., Simonsson, O., Copes, H., Grossman, D., Shallcross, R. A., & Hendricks, P. S. (2025). Naturalistic Psychedelic Use and Psychotic Symptoms: A Cross-Sectional Study of Individuals with a Personal or Family History of Psychotic or Bipolar Disorders. Psychedelic Medicine. Published online April 3, 2025. https://www.liebertpub.com/doi/abs/10.1089/psymed.2024.0036  (Abstract accessed)

Simonsson, O., Goldberg, S. B., Osika, W., Stenfors, C. U. D., Chaturvedi, S., Swords, C. M., Narayanan, J., & Hendricks, P. S. (2025). Longitudinal associations of naturalistic psychedelic use with psychotic and manic symptoms. Psychological Medicine, 55(Issue number if available), page range if available. Published online March 31, 2025. Cambridge University Press. https://www.cambridge.org/core/journals/psychological-medicine/article/longitudinal-associations-of-naturalistic-psychedelic-use-with-psychotic-and-manic-symptoms/ABAF067C1F81F4711F32D97AC74BB146

Strassman, R. J. (1984). Adverse reactions to psychedelic drugs. A review of the literature. The Journal of Nervous and Mental Disease, 172(10), 577-595. https://journals.lww.com/jonmd/Abstract/1984/10000/Adverse_Reactions_to_Psychedelic_Drugs__A_Review.1.aspx