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Simon Ruffell

Simon Ruffel is a psychiatrist with a PhD in Amazonian ayahuasca and mental health. He is the co-founder of Onaya Science and CMO and senior research fellow at the Psychae Institute.

Latest posts by Simon Ruffell (see all)

• Participation in an Indigenous Amazonian-led Ayahuasca Retreat Associated with Increases in Nature Relatedness – A Pilot Study - March 21, 2024
• A Phenomenology of Subjectively Relevant Experiences Induced by Ayahuasca in Upper Amazon Vegetalismo Tourism - November 9, 2023
• The Pharmacological Interaction of Compounds in Ayahuasca: A Systematic Review - October 26, 2023

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

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

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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)

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

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

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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Art by Mariom Luna.

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Psychonautic Judaism: The Psychedelic Renaissance and the Future of Judaism

Chacruna Institute - May 25, 2021

Wednesday, June 9th, 2021 from 12-1:30pm PST REGISTER FOR THIS EVENT HERE There is growing enthusiasm in Jewish communities about possible ancient use and modern applications of plant medicine in Jewish spiritual development.  Psychedelic Judaism introduce new potential modes of  healing...

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