Ruffell, S., Netzband, N., Bird, C., Young, A. H., & Juruena, M. F. (2020). The pharmacological interaction of compounds in ayahuasca: a systematic review. Brazilian Journal of Psychiatry, 42, 646-656. DOI:10.1590/1516-4446-2020-0884

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Study Rationale

As various scholars and companies debate which chemicals in ayahuasca are required to achieve positive outcomes, questions remain regarding which components are essential, how they interact, and what happens if they are removed. The monoamine oxidase inhibitors (MAOIs) in ayahuasca allow for the bioavailability of N,N-Dimethyltryptamine (DMT) (Mckenna, 2004), however, it is currently unclear as to whether these compounds interact synergistically or merely additively. As such, a review of the available literature surrounding the pharmacology of ayahuasca was conducted.

Methodology

The PubMed, PsycINFO, and Web of Science databases were searched through September 2019 for the following terms: (ayahuasca OR DMT OR dimethyltryptamine) AND (B-carboline OR constituents OR chemistry OR harmine OR harmaline OR harmala alkaloids OR tetrahydroharmine OR harmalol OR MAOI OR monoamine oxidase inhibitor OR pharmacology OR pharmacokinetics OR pharmacodynamics OR psychopharmacology OR synergy). The reference lists of relevant studies were checked for additional papers, and secondary searches were performed using related keywords. A total of 2,141 papers were identified, of which 1,957 were extracted, following the removal of duplicates. A review of the titles and abstracts eliminated all but 202 papers, which were screened in greater detail for eligibility. The abstracts, methods, and findings of these papers were assessed, reducing the number to 57 for full text analysis. A total of 16 studies examined the pharmacology of ayahuasca as a brew or its known active compounds, either isolated or synergistically, and were included in the review. Only papers that had undergone full peer review and were published in English were included. The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (Moher et al., 2009).

Summary of Results

Table 1

Summary of studies included in systematic review

Authors	Title	Findings	Further comments
McKenna et al. (1984)	Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and ß-carboline constituents of ayahuasca	-Showed MAOI effect in vitro.  -Proposes that inhibition experiments using mixtures of ß-carbolines indicate that their effects in combination are additive, rather than synergistic or antagonistic.	-Original proposal regarding DMT deamination prevention via MAOI in harmala alkaloids from P. viridis.
Callaway et al. (1994)	Platelet serotonin uptake sites increased in drinkers of ayahuasca	-Increased number of serotonin mRNA transporter sites in regular ayahuasca drinkers against control group.	-Shows an increased number of binding sites in platelets. -No evidence of this for DMT alone, which is suggestive of a synergistic effect.
Strassman et al. (1994)	Dose-response study of N, N-dimethyltryptamine in humans	-Peak DMT blood levels and subjective effects were seen within 2 minutes after drug administration and were negligible at 30 minutes. -DMT dose-dependently elevated blood pressure, heart rate, pupil diameter, and rectal temperature, in addition to elevating blood concentrations of ß-endorphin, corticotropin, cortisol, and prolactin. Growth hormone blood levels rose equally in response to all doses of DMT, and melatonin levels were unaffected. -Threshold doses for significant effects relative to placebo were also hallucinogenic (> 0.2 mg/kg) -Subjects exposed five or more times to 3,4-methylenedioxymethamphetamine had less robust pupil diameter effects than those exposed two times of less. -Evidence that DMT is unique in the inability to develop tolerance to its psychological effects.	-Dose-response data for IV DMT fumarate, neuroendocrine, cardiovascular, autonomic, and subjective effects in a group of experienced hallucinogen users.
Smith et al. (1998)	Agonist properties of N, N-dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors	-DMT fully substituted for DOI. Intact choroid plexus was used to evaluate the agonist properties at endogenous 5-HT2C receptors. -DMT was a partial agonist at 5-HT2C receptors in this native preparation. -DMT behaves as an agonist at both 5-HT2A and 5-HT2C receptors. -One difference was evident in that the 5-HT2C, but not the 5-HT2A, receptor showed a profound desensitization to DMT over time (suggestive of limited application for repeat prescription).	-Evidence of DMT 5HT2a(c) agonism.
Callaway et al. (1999)	Pharmacokinetics of Hoasca alkaloids in healthy humans	-THH shows PK profile independent to harmine. -Affinities and other PK values provided.	-Evidence that THH alone may be a weak SSRI. -Implies further synergistic effects on the serotonin system.
Ott (1999)	Pharmahuasca: human pharmacology of oral DMT plus harmine	-MAO inhibition from simultaneous ingestion of ß-carbolines confirmed by eight self-experimenters. -Results of a total of some 70 bioassays are summarized and the literature on this subject is reviewed.	-Evidence that DMT and harmine in tablet form create similar effects to ayahuasca, further reinforcing the DMT MAOI interaction. -When orally ingested, DMT without harmine is non-active.
Glennon et al. (2000)	Binding of ß-carbolines and related agents at 5-HT2, 5-HT1A, dopamine (D2) and benzodiazepine receptors	-Affinity scores at 5-HT2 for harmine/harmaline.	-Shows that other harmala alkaloids also bind to the 5HT2 receptors, further suggesting synergistic potential in the serotonergic system.
Riba et al. (2003)	Human pharmacology of ayahuasca	-Diastolic blood pressure significant increase. -Heart rate moderate increase. -Increased urinary normetanephrine excretion. -Deaminated monoamine metabolite levels did-not decrease (contrary to typical MOAI effect profile). -The negligible harmine plasma levels found suggest a predominantly peripheral (gastrointestinal and liver) site of action for harmine.	-Double-blind placebo controlled clinical trial using freeze-dried ayahuasca. -PK angle. -Small sample size (n=18).
Riba et al. (2006)	Increased frontal and paralimbic activation following ayahuasca	-Significant activation of frontal and paralimbic brain regions. -Increased blood perfusion observed bilaterally in anterior insula, gather intensity in right hemisphere, and anterior cingulate/frontal medial cortex of right hemisphere. -Increases observed in left amygdala/parahippocampal gyrus. -Concludes that ayahuasca interacts with neural systems that are central to interoception and emotional processing.	-Double-blind placebo controlled clinical trial using freeze-dried ayahuasca. -Neuroimaging angle. -Used SPECT.
Fortunato et al. (2010)	Chronic administration of harmine elicits antidepressant-like effects and increases BDNF levels in rat hippocampus	-Increased BDNF protein levels in rat hippocampus. -Concludes that findings within support the hypothesis that harmine could bring about behavioural and molecular effects.	-Further evidence that the synergistic mechanisms of DMT + harmine are more than just effects of MAOIs.
Santos and Strassman (2011)	Autonomic, neuroendocrine, and immunological effects of ayahuasca: a comparative study with D-amphetamine	-Significant increases in prolactin. -Percentage of CD3/4 were decreased, natural killer cells increased. -Maximum changes occurred around 2 hours, returned to baseline after 24 hours. -Focuses on the synergistic effects of ayahuasca rather than individual action of compounds. -Immunological, rather than neuropsychological, perspective.	-Focuses on the synergistic effects of ayahuasca rather than individual action of compounds. -Immunological, rather than neuropsychological, perspective.
McIlhenny et al. (2011)	Methodology for determining the major constituents and metabolites of the Amazonian botanical medicine ayahuasca in human urine	-Showed that the major metabolite of a DMT is the corresponding DMT-NO, the first time this metabolite has been described in in vivo studies in humans. -Very little DMT detected in urine, despite the MAOI. -Major alkaloid excreted was THH. -List of other products and metabolites quantified.	-Provides methodology for identifying and quantifying constituents of ayahuasca in human urine. -PK data of tested samples provided. Excretion and metabolism of THH should be further investigated.
McIlhenny et al. (2012)	Methodology for determining major constituents of ayahuasca and its metabolites in blood	-DMT concentrations lower than DMT-NO at all time points. -Harmine and harmaline present in most samples. -Plasma DMT-NO concentrations three to four times higher than DMT. -DMT-NO forms rapidly after drug administration.	-Single methodology combining HPLC and gas chromatography to identify ayahuasca constituents in blood following oral consumption. -First report of presence of DMT-NO in human blood following ayahuasca/DMT administration. -Method for the most complete profile of DMT, harmala alkaloids, and metabolite concentrations. -THH levels peaked at around 4.5 hours.
Riba et al. (2012)	Metabolism and disposition of N, N-dimethyltryptamine and harmala alkaloids after oral administration of ayahuasca	-Less than 1% of DMT excreted unchanged. -The recovery of each harmala alkaloid plus its 0-demethylated metabolite varied greatly (between 9 and 65%). -Fifty per cent was recovered as indole-3-acetic acid or DMT-NO. -Ten per cent was other MAO-independent compounds. -Recovery of DMT plus metabolites reached 68%. -Harmol, harmalol, and THH conjugates were abundant in urine.	-PK study with implications regarding alternative metabolic routes for DMT other than biotransformation by MAO. -Freeze-dried ayahuasca. -Urine samples obtained. -Small sample (n=10).
Morales-García et al. (2017)	The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen ayahuasca, stimulate adult neurogenesis in vitro	-Significant neurogenesis in adult hippocampal cells in vitro with harmine.	-Suggests that ayahuasca brew may have more complex synergistic properties than we currently understand. -Shows that harmine alone could be partially responsible for the neurological changes seen in ayahuasca users.
Sampedro et al. (2017)	Assessing the psychedelic “after-glow” in ayahuasca users: post-acute neurometabolic and functional connectivity changes are associated with enhanced mindfulness capacities	-Magnetic resonance spectroscopy showed post-acute reductions in glutamate + glutamine, creatine, and N-acetylaspartate+N- acetylaspartylglutamate in the posterior cingulate cortex. -Connectivity was increased between the posterior cingulate cortex and the anterior cingulate cortex, and between the anterior cingulate cortex and limbic structures in the right medial temporal lobe. -Glutamate + glutamine reductions correlated with increases in the “nonjudging” subscale of the Five Facets Mindfulness Questionnaire-Increased anterior cingulate cortex-medial temporal lobe connectivity correlated with increased scores on the self-compassion questionnaire. -Post-acute neural changes predicted sustained elevations in nonjudging 2 months later.	-DMN activity decrease and increased neural connectivity to other areas of the brain. -Supported by other studies on 5HT2a agonists. -Long-term neurological differences found after ayahuasca administration.

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Integration with extant literature

This systematic review shows that two of the constituents in ayahuasca, DMT and harmine, have been studied significantly more than the secondary harmala alkaloids (MAOIs). It appears there may be more synergistic mechanisms present than we currently understand. This is derived from data pertaining to individual constituents, which often shows overlapping biochemical and pharmacokinetic action. It is unclear at present whether these actions are of a true synergistic nature or are additive. Evidence suggests, despite the lack of solid data on synergy, that ayahuasca may have promising antidepressant qualities.

Increasing numbers of studies are being published focusing on DMT and other serotonin agonists (Carhart-Harris et al., 2021; Mitchell et al., 2021; Mithoefer et al., 2018; Palhano-Fontes et al., 2019; Ross et al., 2016; Rucker et al., 2019; Schartner & Timmermann, 2020; Strassman, 2000; Timmermann et al., 2019; Timmermann, Spriggs, et al., 2018). There is, however, a vast number of anthropological and qualitative articles which emphasise the importance of Banisteriopsis caapi. Traditional ayahuasca is composed of the Banisteriopsis caapi vine, with a DMT containing plant, usually Psychotria viridis, with the vine being the only consistent requirement for the brew (McKenna et al., 1984). In the Peruvian Amazon the term ayahuasca is also commonly used to indicate the vine only.

The harmala alkaloids reduce the deamination of DMT by MAO-A during first-pass metabolism, resulting in the subsequent absorption and distribution of this potent psychedelic (Yritia et al., 2002). The alkaloids are derived from β-carbolines, and their potential psychotropic properties have been discussed since research into psychedelic substances began (Naranjo, 1967). In recent times, researchers have started to focus their attention on the β-carbolines and their role in treating mental health conditions (Dos Santos & Hallak, 2017). The β-carbolines have been demonstrated to have a variety of biological actions, including anxiolytic, anticonvulsant and sedative effects, largely due to their interactions with serotonin and benzodiazepine receptors (Cao et al., 2007).

Papers that assess the levels of constituents in various brews and compare these to therapeutic outcomes have been summarised in Table 2. Due to the lack of heterogeneity between the study designs it is difficult to draw meaningful conclusions by comparing the outcomes of the studies. The table does however demonstrate that the ratio of constituents, as well as the dose of the brew, has an impact on mental health outcomes.

Table 2

Summary table of studies reporting constituency and psychometrics (i.e., depression, anxiety, wellbeing, and perceived peak experiences)

Reference	Tradition	Design	Sample Size (n)	DMT (mg/ml)	THH (mg/ml)	HRL (mg/ml)	HRM (mg/ml)	Total Dosing Sessions
Osório et al. (2015)	Church – Santo Diame	Open label RCT	6	0.8	NA	NA	0.21	1
Gonzalez et al. (2021)	Traditional – Shipibo	Observational	200	2	1-2	0.37-0.65	2	1 to 12
González et al. (2020)	Traditional – Shipibo	Observational	50	2	1-2	0.37-0.65	2	4 to 9
Uthaug et al. (2018)	Neo-Shamanic	Observational	30	1.90	NA	4.9	2.4	1
Uthaug et al. (2018)	Shamanic	Observational	27	0.95	NA	0.35	6.305	1
Palhano-Fontes et al. (2019)	Church – Barquinha	Placebo Control RCT	29 (14 active, 15 control)	0.36	1.2	0.24	1.86	1
Uthaug et al. (2021)	Neo-Shamanic	Placebo Control Observational	30 (14 active, 16 control)	3.6	NA	0.7	10.1	2

Depression

P

Value

(Cohen’s D)

Anxiety:

P

Value

Wellbeing:

P

Value

Peak:

P Value

Reference

Scale

T1-T2

T1-T3

Dep T1-T4

Scale

T1-T2

T1-T3

T1-T4

Scale

T1-T2

T1-T3

T1-T4

Scale

Peak T1

Osório et al. (2015)

HAM-D MADRS

0.01 0.01

0.01 0.003

0.11 0.009

BPRS-AD

0.02

0.02

0.02

–

–

–

–

–

–

Gonzalez et al. (2021)

–

–

–

–

–

–

–

–

PWBS

0.01

0.01

0.01

–

–

González et al. (2020)

SA-45 D

0.001

0.01

0.1

SA-45 D

0.001

0.001

0.01

WHO-QOL-B

0.001

0.001

–

–

–

Uthaug et al. (2018)

DASS-21

0.001

0.001

–

DASS-21

NS

NS

–

SWLS

0.027

NS

–

EDI

0.001

Uthaug et al. (2018)

DASS-21

0.001

0.001

–

DASS-21

NS

NS

–

SWLS

0.027

NS

–

EDI

0.001

Palhano-Fontes et al. (2019)

MADRS HAM-D

0.04 (0.84)

0.04 (0.84)

0.0001 (1.49) 0.019 (0.98)

–

–

–

–

–

–

–

–

MEQ HRS

0.004 0.0001

Uthaug et al. (2021)

DASS-21

0.017

–

–

DASS-21

0.032

–

–

–

–

–

–

EDI

NS

It should be noted that some of the papers did not document tetrahydroharmine levels (Osório et al., 2015; Uthaug et al., 2021; Uthaug et al., 2018). This is the only constituent in the brew that has been demonstrated to function as an selective serotonin reuptake inhibitor (SSRI) and an MAOI, both used in the treatment of depression, with SSRIs being the current gold standard (Brunoni et al., 2009; Callaway et al., 1999). While it is unclear if this omission was from the brew altogether or simply from the constituency analysis, these particular studies coincidentally described non-significant changes in anxiety, wellbeing, and peak experience measures. Furthermore, due to inconsistencies in dose administration and consistency ratios between studies, the extent to which outcomes related to dose response and pharmacokinetics remains unclear. Nonetheless, these studies suggest that the harmala alkaloids do have a role in psychometric changes alongside DMT.

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The Properties of the Harmala Alkaloids

Each of the harmala alkaloids has been associated with different effects, psychologically, pharmacologically, and pharmacokinetically. Table 3 summaries the therapeutic and psychoactive effects of each of the harmala alkaloids and Table 4 provides an overview of their pharmacokinetic profile.

Table 3

The therapeutic and psychoactive effects of the harmala alkaloids

Therapeutic and psychoactive effects	Reference	Harmine	Harmaline	Tetrahydroharmine
Antidepressant properties	(McKenna et al., 1984)	X	X	X
Anxiolytic properties	(Ebrahimi-Ghiri et al., 2019) (Khan et al., 2013)	Not assessed	X	Not assessed
Increases serotonin and norepinephrine	(McKenna et al., 1984)	X	X	X
Raises dopamine levels in CNS	(Pimpinella & Palmery, 1995)	X	X	Not assessed
Anti-addictive properties	(Aricioglu-Kartal et al., 2003; Brierley & Davidson, 2012; Owaisat et al., 2012)	X	Not assessed	Not assessed
Diabetes management – mitogenic for human beta cells (Likely target DYRK1A)	(Wang et al., 2015)	X	Not assessed	Not assessed
Induce brain plasticity and neurogenesis	(Morales-García et al., 2017)	(Harmine metabolite harmol)	X	X
Upregulates 5-HT receptor density	(Callaway et al., 1994; McKenna et al., 1998)	Not assessed but unlikely (Graham et al., 1987)	Not assessed but unlikely  (Graham et al., 1987)	X
Hallucinogenic properties (at high doses)	(Buckholtz & Boggan, 1977; Naranjo, 1967; River & Lindgren, 1972)	Gunn and Marshall (1920) suggest it is at 2mg/kg i.v. or 8mg/kg po	1 mg./kg. i.v. or 4 mg./kg. po  (Naranjo, 1967)	?300mg but unclear  (Gunn & Marshall, 1920)
Increases the number of nerve progenitor cells (may be important in treatment of damage by drug use)	(Dakic et al., 2016)	X	Not assessed	Not assessed

Hallucinations, vomiting, confusion, and ataxia are thought to be due to central nervous system stimulation by MAOIs (Hamill et al., 2019). In a study by Glennon et al. (2000), the harmala alkaloids were found to bind to 5-HT2 receptors with a similar affinity to DMT. The psychedelic properties of both harmaline and harmine are thought to arise from their binding at the 5-HT receptors (Riba et al., 2003). 

Table 4

Overview of Pharmacokinetics	DMT	Harmine	Harmaline	Tetrahydroharmine
Pharmacokinetics profile (Callaway et al., 1999)	–	Pharmacokinetic profile correlates with that of DMT	–	Pharmacokinetic profile independent of harmine
Cmax (ng/ml)	15.8 ± 4.4	114.8 ± 61.7	6.3 ± 3.1	91.0 ± 22.0
Tmax (min)	107.5 ± 32.5	102.0 ± 58.3	145.0 ± 66.9	174.0 ± 39.6
AUC (mg min/ml)	5.60 ± 4.53	22.88 ± 11.69	–	47.78 ± 25.88
T 1/2 (min)	259.4 ± 207.2	115.5 ± 60.1	–	531.9 ± 290.8
IC50 (μM) (Passos et al., 2014)	–	MAO IC50 = 0.013 MAO-A IC50 = 0.002 MAO-B IC50 = 20	MAO IC50 = 0.016 MAO-A IC50 = 0.003 MAO-B IC50 = 25	MAO IC50 = 1.77 MAO-A IC50 = 0.074 MAO-B IC50 = 100
5HT2A binding capacity (Ki)  (Glennon et al., 2000)	–	397	5010	>10000

Harmine

Of all the β-carboline alkaloids in ayahuasca, harmine is present in the highest concentration. It is associated with numerous therapeutic effects, such as astrocytic function restoration, anti-inflammatory effects, human neural progenitor cell the proliferation, and increases in levels of BDNF (Abelaira et al., 2013; Dos Santos & Hallak, 2017; Liu et al., 2017; Morales-Garcia et al., 2020; Morales-García et al., 2017). Other research has also indicated the role of harmine in the treatment of addiction, specifically in reducing relapse rates from methamphetamine, cocaine, and alcohol via dopamine neurotransmission (Aricioglu-Kartal et al., 2003; Owaisat et al., 2012). Harmine also displays affinity at both the DYRK1A and imidazoline I2 binding sites, a property which has potential in the pharmacological management of drug dependence (Brierley & Davidson, 2012). Dakic et al. (2016) also report that harmine exerts proliferative effects in human neural progenitors, by inhibiting DYRK1A. This has been suggested as a potential mechanism behind the antidepressant effects of the brew. Harmine may also have potential in the management of diabetes, and has shown potential in improving glycaemic control, increasing islet mass, and inducing beta cell proliferation (Wang et al., 2015).

Glutamine synthetase and glial-specific excitatory amino-acid transporter expression (glutamate transporter-1 (GLT-1), glutamate/aspartate transporter (GLAST)) can be altered in the brain tissue of those suffering from depression (Bernard et al., 2011; Choudary et al., 2005). Several different investigations utilising animal models have shown GLT-1 protein and gene expression are increased by harmine, as is the uptake of glutamate (Li et al., 2011; Liu et al., 2017; Sun et al., 2014). Harmine has also been found to protect against the effects of chronic unpredictable stress in mice, such as reduced levels of glial fibrillary acidic protein (Liu et al., 2017). This suggests that its antidepressant action may be due to the renewal of astrocytic function. In addition, Liu et al. (2017) found harmine enhanced outcomes in the forced swimming test and also protected mice against stress when undergoing the tail suspension test.

BDNF signal restoration is hypothesised to mediate the antidepressant effects of harmine. Fortunato and colleagues showed this by administering harmine to rats both acutely (Fortunato et al., 2009) and chronically (Fortunato et al., 2010), finding improvements in both the open field and forced swimming tests. Both studies also demonstrated increased hippocampal BDNF levels, when compared to treatment with imipramine. Liu et al. (2017) found when mice were exposed to chronic unpredictable stress and were not given harmine, levels of BDNF did not increase, nor did hippocampal neurogenesis occur. These findings suggest harmine may result in molecular and behavioural outcomes like antidepressants drugs.

Morales-García et al. (2017) found that tetrahydroharmine, harmaline, and harmol (the metabolite of harmine), induce neurogenesis in adults in vitro via neural stem cell differentiation, migration, and proliferation. The authors conclude that the Banisteriopsis caapi β-carbolines appear to have the ability to induce brain plasticity, thereby showing potential in the treatment of various neurological and psychiatric conditions. Interestingly, in a subsequent study Morales-Garcia et al. (2020) showed that DMT led to the generation of new neurones via activation of the sub granular hippocampal dentate gyrus – the predominant neurogenic niche in adults. This research, conducted in mice, showed subsequent improvements in memory, demonstrating the functional relevance of the above findings. Furthermore, SIGMAR-1 activation appeared to underlie the neurogenic effects of DMT. The authors conclude that DMT induces the growth of new hippocampal neurones, promotes the migration of neuroblasts and regulates neural stem cell proliferation, largely via sub granular neurogenic niche activation, improving memory and spatial learning tasks as well as inducing neurogenesis (Morales-Garcia et al., 2020). The authors further highlight the potential antidepressant properties associated with neurogenesis, with DMT showing a considerably more potent neurogenic profile than the β-carbolines (Morales-Garcia et al., 2020; Morales-García et al., 2017).

Harmaline

Harmaline has been demonstrated to have numerous pharmacological functions including hypothermic and vasorelaxant activity, antitumoral, antimicrobial, antiplatelet, antileishmanial, and antiplasmodial effects (Khan et al., 2013). It has been found to be effective in managing various conditions associated with microbes, such as Candida albicans, Proteus vulgaris, Staphylococcus aureus, Aspergillus niger, and Escherichia coli (Wink et al., 1998). Harmaline has been shown to minimise the proliferation of cells in vitro when investigating promyelocytic cell lines in humans, with the optimal dose being 6–10 µg/mL and higher doses of 15–30 µg/mL generally considered cytotoxic (Zaker et al., 2007). Naranjo (1967) found harmaline was hallucinogenic at 4 mg/kg when taken orally – about half the amount required to achieve psychedelic effects when compared to harmine. Of all the harmala alkaloids, harmaline is usually present in the lowest concentrations. Despite this, it exerts various pharmacological effects, such as antimicrobial and vasorelaxant properties, as well as being an anxiolytic and an antidepressant (Ebrahimi-Ghiri et al., 2019; Khan et al., 2013).

Tetrahydroharmine

Platelet serotonin uptake sites appear to increase in those who drink ayahuasca. This is thought to be associated with positive mental health effects, largely as this is deemed to be indicative of neuronal serotonin uptake activity, although the degree to which this actually reflects neuronal activity is debated (Callaway et al., 1994). Callaway hypothesised that tetrahydroharmine was responsible for the upregulation of 5HT uptake sites. He therefore commenced daily dosing with tetrahydroharmine over a six-week period, conducting SPECT scans of his own brain before and after the period of treatment. Central 5-HT receptor density was found to increase in his prefrontal cortex. Upon ceasing to consume tetrahydroharmine, SPECT scans revealed over several weeks that the density slowly returned to pre-dosing levels. Despite clear methodological issues, this one-man experiment suggests tetrahydroharmine may have potentially significant effects (McKenna et al., 1998).

Interestingly, tetrahydroharmine is the only component of the brew that is known to function as an SSRI, albeit weakly (Callaway et al., 1999). The psychoactive effects induced by tetrahydroharmine are less prominent than that of harmine, with harmaline having the strongest effect of all the harmala alkaloids (Naranjo, 1967). Gunn and Marshall (1920) provided an oral administration of 300mg tetrahydroharmine to a single volunteer, who described similar hallucinogenic effects to 100mg of harmaline. Although limited conclusions can be derived from this single experiment, the results suggest the hallucinogenic effects of tetrahydroharmine are roughly one-third that of harmaline.

Callaway et al. (1999) noted that in the ayahuasca-using church, the UDV, teas with higher levels of tetrahydroharmine relative to harmine and harmaline were favoured by both church elders and the congregation.Findings in the Santo Daime confirm this observation (Kaasik et al., 2021). Callaway connected the variation of the relative concentration of tetrahydroharmine in ayahuasca brews to its variability in Banisteriopsis caapi. Kaasik et al. (2021) show that it may also depend on the preparation of the brew. Tetrahydroharmine is the reduction product of harmaline, and consequently levels of THH are generally found to be higher in preparations that are brewed for longer (Kaasik et al., 2021).

Although no quantitative data exists comparing the therapeutic effects of DMT combined with other harmala alkaloid containing plants such as Peganum harmala (Syrian Rue) to Banisteriopsis caapi, reports describing subjective experience can be consulted. Differences appear to exist and have been recorded in various forums, such as online forums and psychonautical guides to plant medicine: ‘substituting, say, Syrian rue for the ayahuasca vine, even though the rue contains the same harmala alkaloids, does apparently make an experiential difference. The experience with rue has been described as crystalline, cold, overwhelming, erratic, and uncaring, compared with that of the ayahuasca vine, which has been described as warm, organic, friendly, and purposeful’ (Beyer, 2009)p253. It should however be noted that the ratios in Syrian Rue are quite different to that of Banisteriopsis caapi, with Rue containing much higher levels of harmaline and lower levels of tetrahydroharmine (Moloudizargari et al., 2013). It is possible that this difference in ratio accounts for the qualitatively different experiences suggested above.

Study Relevance

Prior to this study there had not been a systematic attempt to elucidate the pharmacological basis of ayahuasca. Not only is this necessary to better understand its therapeutic effects and safety profile, but also to determine how specific components in the brew result in therapeutic outcomes.

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