This systematic review found credible case reports of an association between use of psychedelic drugs and schizophrenia spectrum psychosis, and similar case reports of an association with affective disorder, including both depression and bipolar disorder. Both types of disorder were seen in individuals without a previous psychiatric history and were not, or at least were not wholly, attributable to concurrent use of other drugs, since we excluded cases where there was co-existent substance use apart from alcohol and cannabis.

Our ability to find only 17 case reports of psychosis in individuals who used psychedelic drugs contrasts with a relatively entrenched view in psychiatry and society as a whole that such drugs are strongly associated with this form of psychiatric disorder. For example, several well-known rock musicians who developed schizophrenia are widely considered to be ‘acid casualties’. It also contrasts with a previous study: Smart and Bateman (1967) reported that they had been able to trace reports of 225 adverse reactions to LSD, of which 142 took the form of prolonged psychotic reactions. However, how this number was arrived at was not explained by the authors, and it seems probable that they included sources beyond case reports, e.g. counting patients who had participated in clinical studies of LSD psychosis. One possible reason for the relative paucity of case reports we found is that we were strict about excluding cases where other drugs (apart from cannabis) were also used. Another could be that interest in psychosis as a complication of psychedelic use was at its highest at a time when the concept of schizophrenia was broad, i.e. before the introduction of DSM-III in 1980. However, it has to be said we did not have to exclude many cases for this latter reason.

As noted in the introduction, a longstanding view has been that affective disorder is not a significant complication of psychedelic drug use. When such states have been commented on, they have mostly been considered to take the form of depression, with one review documenting only a single case of a ‘motor excitatory’ state (Smart & Bateman, 1967). In contrast we found as many case reports of affective disorder as of schizophrenia spectrum disorder. Such a finding is arguably not unexpected, given that psychedelics exert their effect on the serotonin system, which has been implicated, and continues to be implicated, in depression for over 50 years (Jauhar, Cowen, & Browning, 2023). Serotonin has also been implicated in bipolar disorder, albeit with less consistent findings (Mahmood & Silverstone, 2001), and with little investigation in recent years. Nevertheless, the ‘bidirectionality’ of the association, i.e. the existence of case reports of both depression and mania after psychedelic drug use, goes against any simplistic conceptualization of the link with serotonin, if there is one.

Could it be that the major psychiatric association of psychedelic drug use is actually with affective disorder, with cases of schizophrenia spectrum disorder being largely or wholly the result of misdiagnosis? While in some ways attractive, this is probably not a tenable position, for two reasons. Firstly, while affective symptoms were present in a proportion of the schizophrenia spectrum cases we found, there were other cases where no affective component was discernible from the descriptions given. Secondly, psychedelic drugs are capable of inducing psychotic symptoms during intoxication itself. Thus, Klee and Weintraub (1959) reported four healthy volunteers who developed sometimes quite elaborate persecutory and referential delusions, and in one case auditory hallucinations, when given LSD under experimental conditions. There is also contemporary evidence to the same effect: Griffiths et al. (2011) described the occurrence of delusions or paranoid thinking in 8 of 18 volunteers while taking psilocybin; examples included believing that a person close to the participant had died, or that the experimenters were malevolently manipulating them. It also seems probable that at least some of the (fortunately rare) cases of individuals who jumped to their deaths, otherwise harmed themselves or committed murder while taking psychedelic drugs (e.g. Asselborn, Wennig, & Yegles, 2000; Blacha et al., 2013; Le Dare, Gicquel, Baert, Morel, & Bouvet, 2020; Reich & Hepps, 1972) did so in response to delusions and/or hallucinations.

Two contemporary population surveys (Johansen & Krebs, 2015; Krebs & Johansen, 2013) found no evidence that recreational use of psychedelics was associated with increased rates of poor mental health, as indexed in various ways. Similarly, a 2020 meta-analysis of 24 studies that examined post-acute effects of psilocybin, ayahuasca and LSD given in clinical or experimental settings (Goldberg et al., 2020) found no evidence of any more than transient adverse effects. Our findings, whilst not directly comparable in terms of methodology, paint a different picture: psychedelic drugs, even when taken only one or a few times, can be followed by major psychiatric adverse events. A recent study using a different methodology from ours also had findings that could be seen as pointing in the same direction. Bremler, Katati, Shergill, Erritzoe, and Carhart-Harris (2023) advertised on social media for individuals who had experienced negative psychological effects after taking psychedelics or MDMA lasting for longer than 72 hours. Those who reported the most severe adverse effects were then invited for an in-person interview. Fifteen participants took part in this second phase, of whom seven took psychedelics only (i.e. not MDMA), and had no previous history of major psychiatric illness. The symptoms they described included anxiety/panic, depression, loss of the ability to experience pleasure, suicidal thoughts, intrusive or obsessive thoughts and behaviors, as well as paranoia/delusional thinking, derealization, distractibility and elevated mood in one case. Two users were diagnosed with bipolar disorder after taking LSD, although both reported experiencing similar symptoms prior to consumption.

Our review of case reports adds detail to the existing, rather sparse descriptive literature on flashbacks. Notably, the experiences described went beyond the conventional view that they take the form simply of ‘psychedelic’ visual phenomena like geometric patterns, distortions and afterimages, but instead could sometimes include formed and sometimes complex images, as well as auditory and occasionally somatosensory experiences. Our findings here are in line with those of Vis, Goudriaan, Ter Meulen, and Blom (2021) who systematically reviewed case reports of HPPD/flashbacks, employing a similar but broader strategy than ours, including MDMA- and cannabis-related experiences and not excluding cases where there was comorbid major psychiatric illness or a history of other drug use. They found formed visual hallucinations, such as faces, skulls, and animals in 9.3% of cases.

We additionally found that flashbacks were not only a consequence of prolonged use of psychedelics but, as with psychosis and major affective disorder, could sometimes develop after taking such drugs only one or a few times. This finding contrasts with those of a questionnaire survey of healthy subjects who took psilocybin between 1 and 4 times as part of a series of experimental studies (Studerus, Kometer, Hasler, & Vollenweider, 2011), which found that only 1 of 90 participants reported the occurrence of flashback-like visual phenomena, and that these were infrequent, brief, and ceased within three days after taking the drug. Rates were higher in another study (Muller et al., 2022), which found that 13 of 142 healthy volunteers who took part in clinical trials of LSD or psilocybin and who had used illicit drugs apart from cannabis no more than 10 times reported flashbacks after participating. The experiences were mostly pleasant or neutral in this study.

The case report literature supports the view that flashbacks are commonly associated with psychiatric symptomatology, and this mostly takes the form of anxiety and depression. Depression, in particular, could sometimes become persistent. Anxiety could accompany the flashbacks themselves, but sometimes extended beyond them to a fear of developing an attack. Our findings remain open on the issue of whether flashbacks are ever ‘benign’, i.e. that they occur without the distress or interference with functioning that would lead to a diagnosis of HPPD: we found 11 out of 29 case reports where no associated psychiatric symptomatology was reported (and one more where the only symptom was worry). However, there are grounds for suspecting that relevant psychiatric description was simply lacking in some of these cases.

In conclusion, this systematic review of case studies supports the view that both psychosis and major affective disorder subsequent to psychedelic drug use exist, highlighting a potential risk in the therapeutic application of these drugs if they are ever approved, and more generally in recreational use. The major limitation of a review of this type is that, while it can say something about the nature of the individual psychiatric complications encountered, it cannot establish rates for their occurrence. Another limitation is that we were unable to apply diagnostic criteria to the case material; because of the wide variation in the richness of the clinical detail provided, this would have resulted in an unacceptably high number of unclassifiable diagnoses. Finally, due to the vagaries of reporting, it is possible that some of the cases included may have been in individuals who used other drugs besides psychedelics. Social and psychological factors contributing to the emergence of psychiatric disorders in response to psychedelic use would also be likely to have been under-reported, if they were reported at all.