Results

It is important to consider the different types of settings where ayahuasca or DMT were administered or ingested, since they can be an important variable when evaluating the occurrence of the psychotic episodes reported in the present review. These settings could be basically divided between controlled and uncontrolled contexts. The controlled contexts include ritual or religious ayahuasca use, both within the setting of any of the Brazilian ayahuasca religions ( Santo Daime and União do Vegetal , for example) and in organized retreats and workshops; the controlled settings also include experimental and clinical contexts where ayahuasca or DMT are administered. In the controlled settings, some form of screening, preparation, guidance, and integration are usually present. The uncontrolled or recreational settings could be characterized in those contexts where ayahuasca or DMT are used outside a religious, ritual or experimental/clinical framework, and usually do not have any form of screening, preparation, guidance, and integration.

Paterson presented the case of a 42-year-old man (apparently North American, not specified) that suffered a psychotic episode associated with repeated use of smoked DMT [ Paterson et al. 2015 ]. The subject had no personal psychiatric history, but had an extensive history of multiple substance use disorders [alcohol, tobacco, cannabis, 3, 4-methylenedioxymethamphetamine (MDMA, ecstasy), hydrocodone] associated with legal problems (e.g. driving while intoxicated, fined for cannabis possession). Moreover, he had a family history of alcoholism, bipolar disorder, and obsessive–compulsive disorder. When the subject was 39-years old, he had successfully completed a drug-treatment program, but resumed cannabis use afterwards. Just 3 weeks before his hospitalization (at age 42 years), he began smoking DMT, later informing that he had smoked DMT no more than 10 times. At the time of his hospitalization, the subject had several stressors occurring in his life, such as eviction from his apartment, unemployment, and his mother’s death. He arrived at the emergency department, brought by the police, presenting agitated, bizarre, and disinhibited behavior, time disorientation, disorganized thought, and delusions (e.g. being ‘navigated by the stars’). Due to his agitation, he need emergency medication (benzodiazepines) and was admitted to an inpatient psychiatry unit. Over the next 12 days, the subject was hyperverbal and intrusive, and presented paranoid and grandiose delusions (e.g. being able to read minds, interact with ‘aliens’, and control distant events and persons by adopting specific body postures). These body postures were performed by the subject before and for several days after his admission, and were possibly associated with the transient (5 days) elevated creatinine kinase level (2732 units/l) observed upon admission. During these 12 days, the subject was treated with antipsychotics (quetiapine, olanzapine, risperidone) and drugs for controlling impulsivity (divalproex sodium), anxiety (gabapentin), and to improve sleep (hydroxyzine). By day 14, he showed improved insight and judgment, and was discharged on day 21 to a residential drug-treatment program, with no further psychotic symptoms. At 6 months after discharge, he remained treatment compliant and started to reduce his antipsychotic treatment (quetiapine), and was drug and symptom free. Importantly, although the subject stated the he was a long-term cannabis user, and recent cannabis use could have contributed to the psychotic episode, urine toxicology performed 3 days after admission was negative for cannabinoids. According to the authors, since cannabinoids usually persist in the urine of chronic users for several days, this negative result could indicate that the subject had a lower level of cannabis use or was not using cannabis in the weeks before the psychotic episode. Moreover, the negative result suggests that DMT was the main drug associated with the patient’s psychotic symptoms.

Warren and colleagues reported a brief description (letter) of a case of a 24-year-old man from rural South Australia that was admitted to hospital after suffering a psychotic episode associated with continuous use of a smokable powder made of DMT-containing plants [ Warren et al. 2013 ]. After being introduced to DMT by his friends and encouraged to investigate about the drug on the internet, the subject collected the leaves, bark, and seeds from two DMT-rich plants ( Phalaris aquatica and an unidentified Acacia species), dried and grounded the botanical material into a fine powder, and then added the powder to a pipe where he regularly used tobacco and cannabis. According to the authors, in the year before his admission the subject was smoking this material with increasing frequency, and in the last 6 months before the admission, the subject developed ‘a complex delusional spiritual belief system and was pursuing enlightenment.’ This pattern of increased use and delusional thinking led the subject to a hospital admission for presenting positive symptoms of schizophrenia. Importantly, the subject had a family history of psychotic disorder (not specified), and also an extensive prior experience with tobacco, cannabis, methamphetamines, and DMT. These factors complicate the assessment of the possible role of DMT in this episode.

Umut and colleagues described the case of a 19-year-old North American male who experienced sudden and dramatic psychotic symptoms immediately after consuming a solution of DMT and cannabis (route of administration not specified, but probably smoked) [ Umut et al. 2011 ]. He had no personal or family psychiatric history, but had been using cannabis for the last 3 years before the episode: in the first 1.5 years, he used cannabis ‘rarely and irregularly’, but in the last 1.5 years he was using 1–2 joints/day. The subject lived in Turkey and had just returned from a 3-month period living abroad with his father, 40 days before the episode. In the evening when he returned home, the subject experienced an episode of psychotic mania characterized by continuous swearing, delusional ideas (such as believing that he was a king), increased speech, excessive money spending and joyfulness, inappropriate dressing and behavior (such as dancing in the streets and being rapidly familiar and getting friendly with people he did not know before). Because he had no psychiatric history, this psychotic mania episode was later associated with his 3-year period of continuous cannabis use. His mother thought that these symptoms were related to his happiness in returning home, and they did not seek any treatment. After this episode, the subject used cannabis a few more times and 15 days later, a friend offered him a DMT/cannabis solution (probably smoked). After using this solution, the subject experienced intense psychotic symptoms such as feeling that he was being directed by another power, seeing musical sounds in the sky, contacting creatures from outer space, and believing that people could read his thoughts and were saying numbers to him while he was walking in the street, among other symptoms. His mother got worried with these sudden and dramatic symptoms and started looking for help, taking him to a private hospital where cannabis metabolites were detected in the subject’s urine 20 days after DMT consumption. It is not clear in the report when exactly the subject went to this hospital or what happened in those 20 days, but it seems that the subject did not receive any treatment in this period. The subject received a prescription (not specified) in the private hospital, but did not use the medication. After being convinced, he was brought to another hospital 3 days later, where he received a 12-day inpatient antipsychotic treatment (haloperidol, risperidone). After being discharged, the subject continued to take his medications (risperidone) regularly and was followed for approximately 2.5 months, and the psychotic symptoms gradually remitted. The authors concluded that DMT exacerbated the psychotic symptoms of a previous ongoing cannabis-induced psychotic mania.

Ayahuasca

Lima and colleagues reported the incidence of psychiatric occurrences from data collected in an institutional study of the União do Vegetal (UDV) to monitor the psychological health of its members [Lima et al. 2002; Lima and Tófoli, 2011]. The UDV is a Brazilian syncretic religion that regularly uses ayahuasca in a ritual setting twice monthly, but often as frequently as several times per week [Labate et al. 2009].

In a conference abstract, Lima and colleagues reported results from UDV members from the period of 1996–2000 [Lima et al. 2002]. Lima and Tófoli reviewed and updated the previous data, presenting results from 1994 to 2007 [Lima and Tófoli, 2011]. Lima and colleagues reported seven cases of psychotic disorders in the UDV context [Lima et al. 2002]. According to their report, two cases did not present any relation with ayahuasca; in three cases, ayahuasca apparently increased symptoms of previous psychotic episodes; in one case, ayahuasca was associated with other factors (not specified), and only one case presented immediate temporal relation with ayahuasca and there were no psychotic antecedents. The authors affirmed that this incidence of psychotic disorders is similar to that of the general population, although they did not inform the sample size of the study nor how they calculated this incidence.

Lima and Tófoli reported data from 1994 to 2007 and stated that there were 51 cases of psychiatric occurrences among UDV members, 29 of which were psychotic disorders: schizophrenia (n = 9), acute and transient psychotic disorders (n = 4), unspecified nonorganic (n = 2), severe depressive episode with psychotic symptoms (n = 4), substance-induced psychosis (n = 6), and bipolar affective disorder with psychotic manic episode (n = 4) [Lima and Tófoli, 2011]. Until 2007, 18 of these cases (62%) were subjects that were no longer participating in ayahuasca rituals, while 11 were still participating. Moreover, detailed evaluation of the cases showed that in only 19 of the 29 (65.5%) ayahuasca seemed to be the main contributing factor. In the other 10 cases, there was no immediate temporal relation between ayahuasca intake and the psychotic episode, suggesting that ayahuasca might not have significantly contributed for the development of the case. Among the cases related to ayahuasca intake, in four cases there was an immediate temporal relation between ayahuasca consumption and the psychotic episode, and subjects had no psychiatric history; in five cases there was an immediate temporal relation between ayahuasca intake and the psychotic episode, but subjects had a psychiatric history with or without an active symptomatology; in 10 cases there was no immediate temporal relation between ayahuasca consumption and the psychotic episode, but ayahuasca may have contributed with others factors for the development of the case. It is important to note that, according to the authors, even in the cases were ayahuasca may have produced a psychotic episode in subjects without a psychiatric history, the detailed examination of the cases suggested the presence of traces of premorbid personality factors that could also influence the occurrence of a psychotic episode.

Gable made a comment on the data presented by the UDV in the legal battle that this group won regarding their right to use ayahuasca in the United States [Supreme Court of the United States, 2005; Gable, 2007]. Gable reported that over a period of 5 years, the UDV documented between 13 and 24 cases in which ayahuasca might have been a contributing factor in a psychotic incident. Although the exact years were not specified, it seems that the data were obtained from 2000 to 2005, since the Supreme Court report was published in 2005. Thus, it seems highly probable that at least part of this sample was previously reported by Lima and Tófoli, since they reported data from within the UDV context in this same period (from 1994 until 2007) [Lima and Tófoli, 2011]. According to the document from the Supreme Court of the United States [Supreme Court of the United States, 2005], the United States ‘government claims that hoasca (note from the authors: hoasca is the name of ayahuasca within the UDV context) has caused 24 psychotic incidents in Brazil over a period of 5–6 years’. Nevertheless, ‘a review of the entire record, however, reveals that only 8–13 arguably psychotic incidents have been documented’. These incidents occurred from an estimated total of 25 000 servings of ayahuasca according to Gable, but the document from the Supreme Court of the United States informed the total of 250 000 servings [Gable, 2007]. Both references failed to inform how these numbers were estimated. Gable reported that the rate of psychotic episodes in the UDV context is under 1% (0.052–0.096%, considering 13–24 episodes in 25.000 servings) [Gable, 2007], which is similar to the estimated prevalence rate of psychosis/schizophrenia in the general population [Stilo and Murray, 2010]. If we consider the 8–13 ‘arguably psychotic incidents’ occurring reported in 250 000 servings, as reported by the document from the Supreme Court of the United States, the rate is even lower: 0.0032–0.0052%. Furthermore, the document from the Supreme Court of the United States stated that ‘many or most of these psychological problems were transient and resolved’, and that ‘a review of the case histories in the record reveals that in many of those, either no truly psychotic incident was identified or no causal link to hoasca was found’.

Dos Santos and Strassman reported the case of a 21-year-old Brazilian male who experienced two consecutive psychotic episodes after participation in ayahuasca rituals [dos Santos and Strassman, 2008]. The episodes were separated by 1 year from each other, and both occurred during the rituals but endured several days/weeks afterwards. Neither the subject nor his parents had a history of psychosis. The subject had used other hallucinogens (LSD and psilocybin) on several occasions, but did not report any adverse effects associated with these experiences. He was also a nearly daily cannabis user for the preceding 6 years before the first psychotic episode, with no significant adverse effects associated with this pattern of cannabis use. Before the first psychotic episode, the subject had already used ayahuasca ‘more or less twice per month, for about 2 years’, without incident. Sometimes he used cannabis concurrently, also without incident. However, during one particular ayahuasca ritual, the subject ingested ayahuasca and combined its use with cannabis, and sometime later (not specified) he experienced very intense paranoid and suicidal ideas. Moreover, the subject also superficially cut himself with a sharp-edged ceremonial item during the ritual. Psychotic/paranoid symptoms persisted for 2–3 weeks, and only subsided and resolved after a 1-year antipsychotic treatment (risperidone). During this year, the subject did not use ayahuasca, cannabis, or other drugs, and remained symptom free. At 1 year later, after the treatment had finished, the subject wished to continue participation in ayahuasca rituals. He ingested ayahuasca again in three separated ceremonies, and was not using cannabis any more. Although no adverse reactions occurred in the first two rituals, during the third one, he again experienced paranoid and suicidal ideation. As in the first episode, symptoms persisted for 2–3 weeks and only resolved after another year of risperidone treatment. The previous use of other hallucinogens and the concomitant use of cannabis by this subject with no personal or family history of psychotic disorders makes it difficult to establish the exact role of ayahuasca in this case, especially regarding the first episode. In the second one, although it happened a year later and there was no concomitant use of cannabis, the subject might have developed a sensibility or predisposition to psychotic experiences after his first episode.

We had the opportunity to follow-up this case until 2016. After the second episode and treatment, the subject continued to use cannabis daily and occasionally used other hallucinogenic [LSD, psilocybin, ketamine, 2, 5-dimethoxy-4-iodophenethylamine (2C-I)] and nonhallucinogenic drugs [MDMA, γ-hydroxybutyric acid (GHB), alcohol, tobacco, amphetamines, cocaine, heroin], but did not use ayahuasca anymore. Approximately 1 year after the second treatment, the subject experimented with MDMA on four occasions separated by 3–4 months, and had another paranoid/psychotic episode in the fourth occasion, followed by another year of successful risperidone treatment. Some months after this third treatment, the subject experimented the hallucinogenic phenethylamine 2C-I and had another paranoid episode, again followed by a year of risperidone treatment. A last psychotic episode occurred some months after the last treatment, and this time it was apparently associated with excessive alcohol intake. This episode was also successfully treated with risperidone for another year. The subject did not use any hallucinogen after this last episode and did not have other psychotic symptoms afterwards. Interestingly, he continued to use cannabis daily until 2016, including during all antipsychotic treatments, apparently without increases in psychotic symptoms.

Szmulewicz and colleagues reported the case of a 30-year-old Argentinian man who developed a manic episode after participating in a 4-day ayahuasca retreat [Szmulewicz et al. 2015]. The subject had traveled to Brazil for 3 months before to learn about South American tribes, and 2 weeks before the travel he experienced a 10-day period compatible with a hypomanic episode: increased energy, self-esteem, and goal-directed activity, sleep disorder, pressured speech, and running thoughts. Although there was no previous diagnosis of manic or depressive episodes, there was a prior history, as the subject stated that he had experienced this kind of hypomanic episodes several times before. Moreover, his father had been diagnosed with bipolar affective disorder type I. According to the subject and his mother, he did not present any manic symptoms before the ayahuasca ritual. At 2 days after the last ayahuasca use (the number of ayahuasca doses was not specified), the subject began to experience mystical and paranoid delusional ideas, auditory hallucinations, racing thoughts, disorganized behavior, elevated energy, and euphoria. Afterwards (time not specified), the subject was admitted to a psychiatric hospital in Brazil, where he received antipsychotic/benzodiazepine treatment (risperidone and clonazepam) for a month. After this period, he was symptom-free, was discharged with the same medications, and traveled back to Argentina to continue treatment. When he arrived in a hospital in Argentina, the subject had a depressive episode characterized by significant anhedonia, hopelessness, apathy, ideas of ruin, and clinophilia (tendency to spend extra time in bed, without necessarily sleeping). Surprisingly, the authors suggested that this was not a case of a psychotic/mania episode induced by ayahuasca, but an ‘antidepressant-induced mania due to excessively prolonged use of a substance with antidepressant properties’ in a man with a personal history of hypomania and a family history of bipolar disorder. Interestingly, the authors stated that this ‘substance with antidepressant properties’ was harmine, one of the main ayahuasca components [McKenna and Riba, 2015]. It is not clear why the authors suggested that ayahuasca and harmine were not part of the same ‘substance’.

One last unpublished case was reported by phone to one of us and involved a 40-year-old woman who suffered a psychotic crisis during an ayahuasca weekend retreat She attended the retreat for self-improvement purposes following the advice of a friend that told her that ayahuasca was a potential tool for helping to solve daily difficulties and that she could experience beneficial effects by participating in the retreat. The subject had no history of mental health problems nor had psychiatric family antecedents. She had a history of occasional cannabis use years before the episode, always in small quantities. Also, some months before the ayahuasca retirement, she experimented with a medium dose of MDMA in a house setting with her partner, having a good experience. The subject took ayahuasca on two occasions: on Friday night and in Saturday evening. The subject did not experience side effects during the Friday session and she spent all Saturday in a normal state. But just before taking ayahuasca in the Saturday session, she started to manifest an incoherent discourse, according to the friend that was with her at the retreat. About 10–15 minutes after taking ayahuasca, before the psychoactive effects have begun, she started to develop paranoid ideas, delusional thinking and aberrant behavior. The content of her speech was related with personal events involving aspects of her life and aspects of the life of some of her relatives and near friends, including possible past traumatic experiences not remembered until that moment. She remained in that state for more than 24 hours. All Sunday night she stayed awake, talking endlessly in a constant and incoherent monologue with evident suffering and uncontrolled movements. On Monday, a psychologist attending the ceremony suggested to the guides to administer an antipsychotic (2 mg of risperidone). Less than 30 min after taking risperidone her psychotic symptomatology disappeared, and she asked to the people in the retreat what has happened to her. In the following hours, she slowly remembered the content of the session, and after being almost 48 hours awake and in a psychotic state she finally slept. After 7 hours of sleep, she woke up again in a psychotic state that lasted for 2 days, when she was finally taken to a hospital, where she received antipsychotic treatment (haloperidol) and her psychotic state was again interrupted. The antipsychotic treatment was maintained for a few months, and she did not experience psychotic symptoms anymore. One of us had the opportunity to talk with her by phone at some moment while she was in the psychotic state and to interview by phone some other people present in the retreat and her partner along all the psychotic process. After the haloperidol treatment, we lost contact with the patient, but 1 year later, we could interview her again. The psychotic symptoms never came back and she had a normal life, although she preferred not to talk about what happened in the ceremony since she just wanted to forget it. Our institution does not require ethics approval for reporting individual cases, and the subject provided written informed consent for including the reported information in this article.