Antidepressant Effects of Ayahuasca in Humans: Comparison
Please note this is a comparison between Version 1 by Rafael Guimarães Dos Santos and Version 3 by Amina Yu.

Ayahuasca is a psychedelic preparation usually made by the decoction of Banisteriopsis caapi and Psychotria viridis, or Diplopterys cabrerana, plants endemic to the Amazonian Basin where the brew is traditionally used in ritualistic contexts. B. caapi is known to contain a class of substances called β-carbolines or harmala alkaloids, mainly harmine, tetrahydroharmine (THH), and harmaline. These substances are known to selectively and reversibly inhibit the enzyme monoamine oxidase type A (MAO-A), which is believed to be their main mechanism of action. On the other hand, P. viridis is a source of dimethyltryptamine (DMT), a serotoninergic psychedelic belonging to the same pharmacological class of substances as lysergic acid diethylamide (LSD) and psilocybin. The main mechanism of action for DMT and related psychedelic substances is widely accepted to be agonism at the serotonin receptors 5-HT1A,2A,2C, with the 2A subtype being the primary molecular target and its activation dose-dependently related to the psychoactive effects these substances cause. 

  • ayahuasca
  • DMT
  • antidepressant
  • psychedelic

1. A Brief Review of the Current Evidence for the Antidepressant Effects of Ayahuasca in Humans

As with other classical psychedelics such as psilocybin and LSD, published research regarding the therapeutic effects of ayahuasca has grown steadily in the last two decades. Although preliminary and still lacking further and more thorough evaluation, results so far have been promising, especially regarding the antidepressant and anxiolytic effects the brew seems to exert. Grob et al. (1996) [1][66] performed the first observational study with frequent ritual ayahuasca practitioners that reported possible antidepressant effects of the brew. Similar results have been demonstrated in observational studies in the following years by other groups [2][3][4][5][6][24,29,32,67,68]. The first preliminary open-label clinical trial investigating the antidepressant effects of ayahuasca was published by theour group in 2015 [7][37], which was followed by a complementary study that expanded the sample in 2016 [8][40]. The first randomized, placebo-controlled trial (RCT) investigating the antidepressant effects of ayahuasca replicated the positive results found in the preliminary clinical trial [9][38]. Nevertheless, small sample sizes, single-dose administration, short time assessments, and alkaloid dose standardization are limitations that still need to be addressed in future research on the topic. Table 1 below summarizes the current evidence regarding ayahuasca’s antidepressant effects in depressed patients, which was basically derived from two clinical trials (one open and one placebo-controlled).
Table 1.
Clinical trials that investigated ayahuasca’s potential for the treatment of depression and related research.
[21][78] measured the levels of alkaloids in 29 samples of ayahuasca from different religions where it is consumed. Again, a wide variation in alkaloid levels was demonstrated in the different samples, with DMT ranging from 0 to 14.15 mg/mL, harmine from 0.45 to 22.85 mg/mL, THH from 0.48 to 23.8 mg/mL, and harmaline from <0.01 to 0.9 mg/mL [21][78]. Santos et al. (2017) [22][79] validated a solid-phase extraction technique to quantify the alkaloids of 20 ayahuasca samples, where the levels of DMT, harmine, harmaline, THH, tryptamine, and harmalol were evaluated in concentrations ranging from 0.3 to 36,7 mg/ml. Souza et al. (2019) [23][80] quantified DMT, harmine, THH, and harmaline in 38 ayahuasca samples. DMT was reported in concentrations from 0.62 to 3.4 mg/mL, harmine from 4.14 to 18.16 mg/mL, THH from 4.02 to 30.88 mg/mL, and for harmaline from 0.4 to 3.92 mg/mL. Table 2 below summarizes the data for studies that evaluated alkaloid levels in at least eight ayahuasca samples.
Table 2.
Ayahuasca’s alkaloid concentration reported in studies with at least 8 different samples.
DMT: N,N-Dimethyltryptamine; THH: Tetrahydroharmine. 1 Individual values for each analysis not specified by the authors. The values presented represent the minimum and maximum of all analyses.
Even across clinical trials with healthy and depressed patients, there is still a lack of standardization of the dosage administered to participants. Table 3 below illustrates this variation.
Table 3.
Ayahuasca’s alkaloid concentrations and dosages from clinical trials with ayahuasca.

BDNF: Brain-Derived Neurotrophic Factor; BPRS: Brief Psychiatric Rating Scale; CADDS: Dissociative States Rating Scale; Administered by the Clinician; HAM-D: Hamilton Depression Rating Scale; HRS: Hallucinogen Rating Scale; MADRS: Montgomery–Asberg Depression Scale; MADRS-SI: Montgomery-Asberg Depression Scale suicidal intent subscale; MEQ30: Mystical Experiences Questionnaire; YMRS: Clinician-Administered Dissociative States Rating Scale. 1 Preliminary study; 2 Definitive study including patients from the preliminary study; 3 Original study. All other studies that share the same design were derived from this experiment (randomized controlled trial).

2. Safety and Tolerability of Ayahuasca Administration

Although there is no formal report of deaths caused by ayahuasca intake, the lack of regulation over its production and consumption in some countries can result in medical tourism scenarios [14][72]. Excessive optimism of psychedelics’ therapeutic properties portraited in mediatic coverage can mask the consequences of reckless use, namely interaction with other psychoactive substances (such as Selective Serotonin Reuptake Inhibitors (SSRIs)) and with previous medical conditions, which can produce lifelong health impairments [14][15][72,73].
Ayahuasca consumption at reported doses in observational studies and clinical trials causes a wide variety of effects, of which some are desired, some are unwanted, and/or can be considered adverse events (AEs). Regarding randomized, blinded (single or double), and placebo-controlled trials, a recent review evaluated the occurrence of adverse events following ayahuasca administration to healthy volunteers and treatment-resistant depressive patients in 11 distinct trials (n = 108 ayahuasca administrations) [16][74]. On one hand, most common AEs reported were gastrointestinal malaise, nausea, vomiting, headaches, and mild-to-moderate transient increases in heart rate and blood pressure [16][74]. These AEs were all expected and known to occur with ayahuasca and other psychedelic administration such as LSD and psilocybin [16][17][74,75]. On the other hand, there were more clinically significant reports of anxiety, confusion, emotional distress, depersonalization, and dysphoric state manifestations after ayahuasca administration, although these are much less common. However, there are currently no reports of psychotic states, lasting AEs, trial dropouts, or the need for medical interventions in any case, even in more significant situations. All reported AEs were transient and resolved on their own with researcher’s psychological support [16][74].
Regarding the occurrence of more significant adverse events in clinical trials with ayahuasca performed by theour group, there is a detailed report of the two instances where these effects had to be managed by theour research team, how the situation was resolved, and an initial nine step guideline on managing this kind of occurrence [18][76]. Overall, it seems that as with other psychedelic administration, a cautious and detailed selection of the volunteers who are allowed to participate in the trials and a supportive setting constructed by researchers has been demonstrated to be enough to reduce and manage the occurrence of AEs in clinical trials. Nevertheless, there is still the need for further research with bigger samples to confirm the preliminary findings we that werehave so far for the occurrence of both positive and negative effects.

3. Ayahuasca’s Alkaloid Content

The concentrations of psychoactive alkaloids in ayahuasca vary greatly due to the lack of standardization in the quantity and quality of the plants used in its production, the region where it is produced, cultural aspects related to its use, and the desired final concentration of the drink [19][77]. Previous studies that quantified the alkaloid levels present in diverse ayahuasca samples reported a wide range of concentrations. For example, the content of alkaloids reported by McKenna et al. (1984) [20][5] ranged from 0.15 mg/mL of harmine, 0.05 mg/mL of THH, and 0.125 mg/mL of DMT, to 4.67 mg/mL of harmine, 1.60 mg/mL of THH, 0.41 mg/mL of harmaline, and 0.60 mg/mL of DMT in a dose. Callaway (2005)
DMT: N, N-Dimethyltryptamine; NA: Not Analyzed; ND: Not Detected; THH: Tetrahydroharmine. 1 Administration of three different doses; 2 Administration of two different doses; 3 Administration of two equal doses in four hours apart.
This variation in alkaloid administration in investigations where ayahuasca is used is one of the major challenges associated with its possible use as an antidepressant. Although clinical research with ayahuasca is still in its infancy, the necessity for standardizing dosages given in different trials is becoming more apparent. In the current state, it is difficult to directly compare results amongst the published research. Furthermore, with the current published data it is very challenging to determine the optimal DMT to β-carboline ratio and dosages that maximize the therapeutic effects while also minimizing the occurrence of AEs. This and other challenges associated with standardized ayahuasca medicinal use (and other psychedelics) go beyond the main focus of this article and have been thoroughly discussed elsewhere [16][17][18][33][74,75,76,87].

43. Pharmacokinetics of Ayahuasca

The human pharmacokinetics of ayahuasca were evaluated for the first time in a study by Callaway et al. (1999) [34][88] after the administration of 2 mL/kg of ayahuasca (with alkaloid concentrations: harmine 1.70 mg/mL, harmaline 0.20 mg/mL, THH 1.07 mg/mL, and DMT 0.24 mg/mL). In this study, the following values of maximum concentration (CMAX) and time to reach CMAX (TMAX) were found in blood analysis: DMT—CMAX 15.8 ± 4.4 ng/mL, TMAX 107.5 ± 32.5 min; harmine—CMAX 114.8 ± 61.7 ng/mL, TMAX 102.0 ± 58.3 min; THH—CMAX 91.0 ± 22.0 ng/mL, TMAX 174.0 ± 39.6 min; harmaline—CMAX 6.3 ± 3.1 ng/mL, TMAX 145.0 ± 66.9 min. Another investigation looking at plasma alkaloid levels after administration of a low dose (standardized at 0.6 mg/kg DMT) and a high dose (standardized at 0.85 mg/kg DMT) of lyophilized ayahuasca was performed by Riba et al. (2003) [27][11]. In this study, CMAX values were found for DMT of 12.14 ng/mL and 17.44 ng/mL for low and high doses, respectively, with TMAX of 1.5 hours after administration for both doses. Dos Santos et al. (2011) [29][1] measured plasma DMT levels after administration of placebo, one dose and two consecutive doses of ayahuasca four hours apart, at a standardized dose of 0.75 mg/kg DMT. The mean ± SD of maximum concentration values was 13.97 ± 9.35 ng/mL for ayahuasca preceded by placebo and 32.57 ± 20.96 ng/mL for ayahuasca preceded by ayahuasca, suggesting a non-linear increase in DMT levels after administration of two consecutive doses of ayahuasca, likely due to prolonged peripheral MAO-A inhibition [29][1]. Another study by the same research group demonstrated a comparison with a single dose of ayahuasca (standardized at 1 mg/kg of DMT) and 20 mg of dextroamphetamine [30][84]. The mean ± SD of maximum plasma DMT concentration values was 11.8 ± 6.4 ng/mL. The median time at which CMAX was reached was 1.8 hours (range 1 to 4.5 hours) after administration [30][84].
According to these data, itwe could be ean estimated that th the nM levels of the alkaloids at CMAX. Considering a single ayahuasca administration, the mean CMAX for DMT of the cited studies where CMAX was measured was (15.8 + 12.14 + 17.44 + 13.97 + 11.8)/5 = 14.23 ng/mL. The molar mass of DMT is 188.274, which results in a 75.58 nM mean maximum plasma concentration. At first this concentration appears to be lower than the required to interact with certain molecular targets, but there is an evidence-based proposed mechanism through which DMT can reach high local concentrations within neurons of the CNS [35][36][60,89]. Briefly, this three-step mechanism starts with the crossing of DMT through the blood-brain barrier (BBB) via uptake across the endothelial plasma membrane. To cross the BBB, DMT is actively transported through the endothelial plasma membrane via Mg2+ and ATP-dependent uptake [37][38][39][90,91,92]. Although  we are not aware of an investigation regarding the precise mechanism by which this accomplished are not awared of, it is possible that the Organic Cation Transporter (OTC) family of transporters is involved, since it can transport other closely related monoamines, such as serotonin [40][93].
This is corroborated to happen given the results from studies that verified the accumulation of DMT and other tryptamines in the brain after peripheral administration [38][41][42][43][91,94,95,96]. It has been shown that DMT promptly enters the CNS and is kept there after excretion in urine has stopped (24 hours), being detected up to 7 days after administration [44][97]. Next, cell-membrane serotonin transporter (SERT) uptakes DMT to inside the neurons, where VMAT2 promotes its sequestration and accumulation within vesicles [36][89]. Here DMT is protected from MAO degradation and can be stored several days before being released when the correct stimuli are given [44][97]. The proposed mechanism and investigations that support it are evidence of DMT’s role as an important cellular messenger, since there is a considerable physiological effort and prioritization to transport, accumulate, and store it within the CNS [36][89]. Furthermore, it shows that DMT must have molecular activity endogenously in a much lower average concentration environment inside the human body, in the absence of exogenous intake [36][89]. If this molecule is active within this relatively hostile environment to its existence, exogenously administered DMT in tandem with peripheral degradation inhibition provided by MAO-A deactivation from β-carbolines surely augments its concentrations to levels high enough to influence other molecular targets it would otherwise not be capable of influencing. The current evidence for the action of DMT and β-carbolines within these possible targets is discussed with more detail in the next sections.
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