Ayahuasca is prepared with the prolonged decoction of two plants, the jagube vine (Banisteriopsis caapi) and the chacrona, or ‘queen bush’ (Psychotria viridis) [1]. In the mid-1930s, a series of religious groups such as the Santo Daime, Barquinha, and União do Vegetal emerged in Brazil, incorporating the use of ayahuasca as a central sacrament. Subsequently, in the latter half of the century, the dissemination of the psychoactive brew expanded worldwide. Since the 2000s, scientific interest in the substance has grown, with several observational and clinical studies being carried out in order to better understand the effects of ayahuasca tea [2]. Ayahuasca may be classified as a classic hallucinogen since the leaves of the P. viridis bush are rich in DMT (N,N-dimethyltryptamine), a hallucinogenic tryptamine considered the main psychoactive substance in ayahuasca, acting as a 5-HT_1A/2A/2C serotonin receptor agonist ^[2][3][2,3]. The vine B. caapi, in turn, is rich in β-carbolines, such as harmine and tetrahydroharmine (THH), and—in lower concentrations—harmaline, harmol, and harmalol. Harmine, THH, and harmaline are reversible inhibitors of the enzyme monoamine oxidase-A (MAO-A), and THH also has selective serotonin reuptake inhibition activity ^[3][4][5][3,4,5]. DMT (present in P. viridis) does not have psychoactive properties when ingested orally, due to degradation via MAO-A. However, peripheral inhibition of MAO-A via β-carbolines (especially via harmine) allows DMT to reach the central nervous system and produce psychoactive effects [6]. The literature has described the anxiolytic, antidepressant, and antiaddictive effects of ayahuasca. The main findings related to potential anxiolytic and antidepressant effects were derived from preclinical studies and phase I and phase II clinical trials involving patients diagnosed with major depressive disorder ^{[7][8][9][10]}[7,8,9,10]. More recently, a pilot, proof-of-concept, randomized, placebo-controlled trial suggested that ayahuasca could modulate anandamide levels in patients with social anxiety disorder [11]. Anti-addictive effects are reported in observational and preclinical studies ^[12][13][12,13]. In addition, other possible beneficial effects on personality traits, cognition, and eating disorders have been reported in observational studies [14].

Overall, there were no reports of serious adverse effects of ayahuasca use in controlled settings, indicating relative safety [15]. Ayahuasca has been shown to be safe for cardiovascular health in healthy volunteers and patients, with only a small increase in blood pressure and heart rate measurements being described during the peak effect, alongside other common and usually mild adverse effects, such as transient nausea, vomiting, and headaches ^{[5][11][15][16][17]}[5,11,15,16,17]. Furthermore, there are few reports of psychological adverse reactions (PARs) in clinical trials with ayahuasca, which are mostly described through case studies. A descriptive systematic review reported three case series and two case reports describing psychotic episodes associated with ayahuasca ingestion and three case reports describing psychotic episodes associated with smoked DMT [18]. A report described seven cases of acute and challenging psychological experiences after using ayahuasca in ritual settings [19]. A recent study survey based on more than 10,836 subjects found that 60% of the sample reported some kind of mental adverse event, but 88% of them considered that event as part of a positive growth process [20]. These results led the researchers to conclude that the concept of adverse events should be reframed when referring to hallucinogens since part of their action consists precisely of passing through psychologically challenging experiences. Among the controlled studies, there is one report of a PAR, described as a moment of disorientation and anxiety, which was resolved with verbal management [21]. ResearcheOurs' group reported only two cases of PARs in the clinical studies carried out during the last 10 years (80 ayahuasca administrations in total); one of them was a young woman with social anxiety disorder, and the other was a healthy young woman [22]. In both cases, it was possible to observe transient anxiety symptoms during the peak of the ayahuasca effect, and only verbal and environmental management was carried out (it was not necessary to use medications) [22]. More recently, the International Center for Ethnobotanical Education, Research and Service (ICEERS) published a global report about ayahuasca consumption and mortality [23]. In this reseaporcht, between 1994 and 2022, a total of 58 deaths were identified across the world as being possibly related to the consumption of ayahuasca, but it is also highlighted that in many cases, ayahuasca did not even play an indirect role [23]. The authors consider that the number of reported deaths is low compared to the number of people who use ayahuasca around the world each year [23]. Also, most of the cases apparently could have been avoided if they had incorporated rigorous screening, the training of personnel to deal with possible adverse events, and psychological support [23].

Ibogaine was first isolated in 1901, and it was explored as a treatment for asthenia, being commercially available in France from 1939 to 1970 under the name of Lambarène as a neuromuscular stimulant. In 1957, Ciba Pharmaceutical (now Novartis) secured a patent for the utilization of ibogaine to reduce tolerance to opioid analgesics. In the late 1950s and during the 1960s, ibogaine was used as an auxiliary tool in psychotherapeutic processes ^[24][25][24,25]. Between the years of 1962 and 1963, a New York psychedelic enthusiast named Howard Lotsof first reported the anti-addictive properties of ibogaine on heroin dependence during recreational use ^{[24][25][26][27]}[24,25,26,27]. Based on the possible efficacy of ibogaine in the treatment of drug addiction, the Medication Development Division of the National Institute on Drug Abuse (NIDA) in the United States supported preclinical and clinical research on ibogaine, and a phase I/II study with ibogaine on cocaine users was authorized by the Food and Drug Administration (FDA) between 1993 and 1995. However, after the death of a patient in the Netherlands in 1993, in an uncontrolled context (where it was not possible to establish a direct cause between the use of ibogaine and the patient’s death), NIDA-funded treatments were suspended, and only research support for preclinical research continued ^[24][25][26][24,25,26]. After these events, medical research on ibogaine was reduced, and its use in alternative and non-medical contexts grew until a large network of patients and therapists was formed, where thousands of people sought to treat their drug addictions with ibogaine. It is estimated that in 2006 alone, more than 3000 people were treated with ibogaine in the world, and it is believed that these numbers have been progressively increasing in recent years [27].

Ona and colleagues, through an updated systematic review, analyzed the adverse effects of ibogaine in humans from 2015 to 2020 (the adverse effects from 1990 to 2008 were previously reviewed by Alper and colleagues in 2012 [28]). In the 18 studies analyzed, the authors classified the adverse effects as acute (<24 h), predominantly encompassing cardiological (such as increased QTc interval), gastrointestinal, neurological, and clinical manifestations, or prolonged adverse effects (>24 h), which included persistent cardiac abnormalities as well as the emergence of psychiatric and neurological symptoms. The authors also highlighted the heterogeneity of the products and doses administered [29]. This profile of adverse effects may pose a threat to the safety of iboga consumption. Over 25 fatalities associated with the administration of ibogaine have been reported in the scientific literature, with the majority of these occurrences manifesting within the initial 72 h window ^{[28][30][31][32][33]}[28,30,31,32,33]. In most of these cases, the fatality seems to have been caused by the interaction of ibogaine with pre-existing cardiovascular abnormalities or with the concomitant use of other drugs. It is noteworthy that the majority of these cases occurred within uncontrolled settings, under unknown conditions of cardiovascular monitoring and medical supervision, and frequently involved the administration of high or indeterminate doses of ibogaine. Within this frame of reference, Rocha and colleagues conducted a systematic review to assess the utilization of ibogaine in clinical contexts and to analyze the settings [34]. In this resviearchw, six articles were included with an additional three studies in the development phase (as documented on ClinicalTrials.gov (accessed on 10 December 2020)). The reduced number of studies with different designs, restricted number of samples, and multiple ibogaine dose administrations posed challenges for comprehensive result analysis. However, through a qualitative analysis, it was possible to conclude that it is necessary to use ibogaine in a setting that offers safety to the participant, with cardiac monitoring and medical and psychiatric evaluation throughout the process, in addition to having trained professionals to deal with any side effects. In the article, the authors recommend the systematic recording of the setting in which ibogaine was applied so that it is possible to compare and develop protocols that guarantee safety [34].