OPEN Foundation

M. Valle

Ayahuasca improves emotion dysregulation in a community sample and in individuals with borderline-like traits

Abstract

Background

Research suggests that mindfulness-based interventions may improve mindfulness-related capacities (e.g., decentering, non-judging, and non-reacting) and emotion regulation. Previously, our group reported that ayahuasca could be a potential analogue of mindfulness practice. The main aim of the current study was to examine the effects of ayahuasca on emotional regulation and mindfulness-related capacities. Secondarily, we sought to explore the effects of ayahuasca on individuals with borderline personality disorder (BPD) traits.

Method

This is an observational study of 45 volunteers who participated in an ayahuasca session. The volunteers completed various self-report instruments designed to measure emotional dysregulation (Difficulties in Emotion Regulation Scale (DERS)) and mindfulness traits (Five Facet Mindfulness Questionnaire (FFMQ)–Short Form and Experiences Questionnaire (EQ)) prior to and 24 h after the ayahuasca session. The volunteers were divided into two subgroups based on their score on the McLean Screening Instrument for BPD (MSI-BPD). Twelve participants were grouped into the BPD-like traits subgroup while the rest of them were included in the non-BPD-like subgroup. We performed within-subjects and between-group analyses.

Results

Overall, the participants showed significant improvements on the FFMQ subscales observingacting with awarenessnon-judging, and non-reacting and also significantly improved on decentering (EQ scale) and on the DERS subscales emotional non-acceptanceemotional interference, and lack of control. The BPD-like subgroup also showed significant improvements on the DERS subscales emotional interference and lack of control but not in mindfulness capacities.

Conclusions

These findings suggest a potential therapeutic effect for ayahuasca in emotion regulation and mindfulness capacities (including decentering, acceptance, awareness, and sensitivity to meditation practice). Based on these results, we believe that ayahuasca therapy could be of value in clinical populations, such as individuals with BPD, affected by emotion dysregulation.

Domínguez-Clavé, E., Soler, J., Pascual, J. C., Elices, M., Franquesa, A., Valle, M., … & Riba, J. (2018). Ayahuasca improves emotion dysregulation in a community sample and in individuals with borderline-like traits. Psychopharmacology, 1-8., 10.1007/s00213-018-5085-3
Link to full text

Assessing the psychedelic “after-glow” in ayahuasca users: post-acute neurometabolic and functional connectivity changes are associated with enhanced mindfulness capacities

Abstract

BACKGROUND:
Ayahuasca is a plant tea containing the psychedelic 5-HT2A agonist N,N-dimethyltryptamine and harmala monoamine-oxidase inhibitors. Acute administration leads to neurophysiological modifications in brain regions of the default mode network, purportedly through a glutamatergic mechanism. Post-acutely, ayahuasca potentiates mindfulness capacities in volunteers and induces rapid and sustained antidepressant effects in treatment-resistant patients. However, the mechanisms underlying these fast and maintained effects are poorly understood. Here, we investigated in an open-label uncontrolled study in 16 healthy volunteers ayahuasca-induced post-acute neurometabolic and connectivity modifications and their association with mindfulness measures.
METHODS:
Using 1H-magnetic resonance spectroscopy and functional connectivity, we compared baseline and post-acute neurometabolites and seed-to-voxel connectivity in the posterior and anterior cingulate cortex after a single ayahuasca dose.
RESULTS:
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.
CONCLUSIONS:
These results support the involvement of glutamate neurotransmission in the effects of psychedelics in humans. They further suggest that neurometabolic changes in the posterior cingulate cortex, a key region within the default mode network, and increased connectivity between the anterior cingulate cortex and medial temporal lobe structures involved in emotion and memory potentially underlie the post-acute psychological effects of ayahuasca.
Sampedro, F., de la Fuente Revenga, M., Valle, M., Roberto, N., Domínguez-Clavé, E., Elices, M., … & Friedlander, P. (2017). Assessing the psychedelic “after-glow” in ayahuasca users: post-acute neurometabolic and functional connectivity changes are associated with enhanced mindfulness capacities. International Journal of Neuropsychopharmacology. 10.1093/ijnp/pyx036
Link to full text

Assessing the psychedelic "after-glow" in ayahuasca users: post-acute neurometabolic and functional connectivity changes are associated with enhanced mindfulness capacities

Abstract

Background:

Ayahuasca is a plant tea containing the psychedelic 5-HT2A agonist N,N-dimethyltryptamine and harmala monoamine-oxidase inhibitors. Acute administration leads to neurophysiological modifications in brain regions of the default mode network, purportedly through a glutamatergic mechanism. Post-acutely, ayahuasca potentiates mindfulness capacities in volunteers and induces rapid and sustained antidepressant effects in treatment-resistant patients. However, the mechanisms underlying these fast and maintained effects are poorly understood. Here, we investigated in an open-label uncontrolled study in 16 healthy volunteers ayahuasca-induced post-acute neurometabolic and connectivity modifications and their association with mindfulness measures.

Methods:

Using 1H-magnetic resonance spectroscopy and functional connectivity, we compared baseline and post-acute neurometabolites and seed-to-voxel connectivity in the posterior and anterior cingulate cortex after a single ayahuasca dose.

Results:

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.

Conclusions:

These results support the involvement of glutamate neurotransmission in the effects of psychedelics in humans. They further suggest that neurometabolic changes in the posterior cingulate cortex, a key region within the default mode network, and increased connectivity between the anterior cingulate cortex and medial temporal lobe structures involved in emotion and memory potentially underlie the post-acute psychological effects of ayahuasca. Sampedro, F., de la Fuente Revenga, M., Valle, M., Roberto, N., Domínguez-Clavé, E., Elices, M., … & Friedlander, P. (2017). Assessing the psychedelic “after-glow” in ayahuasca users: post-acute neurometabolic and functional connectivity changes are associated with enhanced mindfulness capacities. International Journal of Neuropsychopharmacology. 10.1093/ijnp/pyx036

Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans

Abstract

Ayahuasca is an Amazonian psychotropic plant tea typically obtained from two plants, Banisteriopsis caapi and Psychotria viridis. It contains the psychedelic 5-HT2A and sigma-1 agonist N,N-dimethyltryptamine (DMT) plus β-carboline alkaloids with monoamine-oxidase (MAO)-inhibiting properties. Although the psychoactive effects of ayahuasca have commonly been attributed solely to agonism at the 5-HT2A receptor, the molecular target of classical psychedelics, this has not been tested experimentally. Here we wished to study the contribution of the 5-HT2A receptor to the neurophysiological and psychological effects of ayahuasca in humans. We measured drug-induced changes in spontaneous brain oscillations and subjective effects in a double-blind randomized placebo-controlled study involving the oral administration of ayahuasca (0.75mg DMT/kg body weight) and the 5-HT2A antagonist ketanserin (40mg). Twelve healthy, experienced psychedelic users (5 females) participated in four experimental sessions in which they received the following drug combinations: placebo+placebo, placebo+ayahuasca, ketanserin+placebo and ketanserin+ayahuasca. Ayahuasca induced EEG power decreases in the delta, theta and alpha frequency bands. Current density in alpha-band oscillations in parietal and occipital cortex was inversely correlated with the intensity of visual imagery induced by ayahuasca. Pretreatment with ketanserin inhibited neurophysiological modifications, reduced the correlation between alpha and visual effects, and attenuated the intensity of the subjective experience. These findings suggest that despite the chemical complexity of ayahuasca, 5-HT2A activation plays a key role in the neurophysiological and visual effects of ayahuasca in humans.

Valle, M., Maqueda, A. E., Rabella, M., Rodríguez-Pujadas, A., Antonijoan, R. M., Romero, S., … & Feilding, A. (2016). Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans. European Neuropsychopharmacology. http://dx.doi.org/10.1016/j.euroneuro.2016.03.012

Link to full text

Naltrexone but not ketanserin antagonizes the subjective, cardiovascular and neuroendocrine effects of salvinorin-A in humans

Abstract

Background: Salvinorin-A is a terpene found in the leaves of the plant Salvia divinorum. When administered to humans, salvinorin-A induces an intense but short-lasting modified state of awareness, sharing features with those induced by the classical serotonin-2A (5-HT2A) receptor agonist psychedelics. However, unlike substances such as psilocybin or mescaline, salvinorin-A shows agonist activity at the kappa-opioid receptor (KOR) rather than at the 5-HT2A receptor. Here we assessed the involvement of KOR- and 5-HT2A-agonism in the subjective, cardiovascular, and neuroendocrine effects of salvinorin-A in humans.

Methods: We conducted a placebo-controlled, randomized, double-blind study with two groups of 12 healthy volunteers with experience with psychedelic drugs. There were four experimental sessions. In Group-1 participants received the following treatment combinations: placebo+placebo, placebo+salvinorin-A, naltrexone+placebo and naltrexone+salvinorin-A. Naltrexone, a nonspecific opioid receptor antagonist, was administered at a dose of 50 mg orally. In Group-2 participants received the treatment combinations: placebo+placebo, placebo+salvinorin-A, ketanserin+placebo and ketanserin+salvinorin-A. Ketanserin, a selective 5-HT2A antagonist, was administered at a dose of 40 mg orally.

Results: Inhalation of 1 mg of vaporized salvinorin-A led to maximum plasma concentrations at 1 and 2 minutes after dosing. When administered alone, salvinorin-A severely reduced external sensory perception and induced intense visual and auditory modifications, increased systolic blood pressure, and cortisol and prolactin release. These effects were effectively blocked by naltrexone, but not by ketanserin.

Conclusions: Results support kappa opioid receptor agonism as the mechanism of action underlying the subjective and physiological effects of salvinorin-A in humans, and rule out the involvement of a 5-HT2A-mediated mechanism.

Maqueda, A. E., Valle, M., Addy, P. H., Antonijoan, R. M., Puntes, M., Coimbra, J., … & Barker, S. (2016). Naltrexone but not ketanserin antagonizes the subjective, cardiovascular and neuroendocrine effects of salvinorin-A in humans. International Journal of Neuropsychopharmacology, pyw016. http://dx.doi.org/10.1093/ijnp/pyw016
Link to full text

Salvinorin-A induces intense dissociative effects, blocking external sensory perception and modulating interoception and sense of body ownership in humans

Abstract

Background: Salvinorin-A is a terpene with agonist properties at the kappa-opioid receptor, the binding site of endogenous dynorphins. Salvinorin-A is found in Salvia divinorum, a psychoactive plant traditionally used by the Mazatec people of Oaxaca, Mexico, for medicinal and spiritual purposes. Previous studies with the plant and salvinorin-A have reported psychedelic-like changes in perception but also unusual changes in body awareness and detachment from external reality. Here we comprehensively studied the profile of subjective effects of increasing doses of salvinorin-A in healthy volunteers with special emphasis on interoception.

Methods: A placebo and three increasing doses of vaporized salvinorin-A (0.25, 0.50, and 1 mg) were administered to eight healthy volunteers with previous experience in the use of psychedelics. Drug effects were assessed using a battery of questionnaires that included among others: the Hallucinogen Rating Scale (HRS), the Altered States of Consciousness (APZ), and a new instrument that evaluates different aspects of body awareness: the Multidimensional Assessment for Interoceptive Awareness (MAIA).

Results: Salvinorin-A led to a disconnection from external reality, induced elaborate visions and auditory phenomena, and modified interoception. The lower doses increased somatic sensations, but the high dose led to a sense of a complete loss of contact with the body.

Conclusions: Salvinorin-A induced intense psychotropic effects characterized by a dose-dependent gating of external audio-visual information and an inverted-U dose-response effect on body awareness. These results suggest a prominent role for the kappa opioid receptor in the regulation of sensory perception, interoception and the sense of body ownership in humans.

Maqueda, A. E., Valle, M., Addy, P. H., Antonijoan, R. M., Puntes, M., Coimbra, J., … & Riba, J. (2015). Salvinorin-A induces intense dissociative effects, blocking external sensory perception and modulating interoception and sense of body ownership in humans. International Journal of Neuropsychopharmacology, pyv065. http://dx.doi.org/10.1093/ijnp/pyv065
Link to full text

Metabolism and disposition of N,N-dimethyltryptamine and harmala alkaloids after oral administration of ayahuasca

Abstract

Ayahuasca is an Amazonian psychotropic plant tea obtained from Banisteriopsis caapi, which contains β-carboline alkaloids, chiefly harmine, harmaline and tetrahydroharmine. The tea usually incorporates the leaves of Psychotria viridis or Diplopterys cabrerana, which are rich in N,N-dimethyltryptamine (DMT), a psychedelic 5-HT2A/1A/2C agonist. The β-carbolines reversibly inhibit monoamine-oxidase (MAO), effectively preventing oxidative deamination of the orally labile DMT and allowing its absorption and access to the central nervous system. Despite increased use of the tea worldwide, the metabolism and excretion of DMT and the β-carbolines has not been studied systematically in humans following ingestion of ayahuasca. In the present work, we used an analytical method involving high performance liquid chromatography (HPLC)/electrospray ionization (ESI)/selected reaction monitoring (SRM)/tandem mass spectrometry(MS/MS) to characterize the metabolism and disposition of ayahuasca alkaloids in humans. Twenty-four-hour urine samples were obtained from 10 healthy male volunteers following administration of an oral dose of encapsulated freeze-dried ayahuasca (1.0 mg DMT/kg body weight). Results showed that less than 1% of the administered DMT dose was excreted unchanged. Around 50% was recovered as indole-3-acetic acid but also as DMT-N-oxide (10%) and other MAO-independent compounds. Recovery of DMT plus metabolites reached 68%. Harmol, harmalol, and tetrahydroharmol conjugates were abundant in urine. However, recoveries of each harmala alkaloid plus its O-demethylated metabolite varied greatly between 9 and 65%. The present results show the existence in humans of alternative metabolic routes for DMT other than biotransformation by MAO. Also that O-demethylation plus conjugation is an important but probably not the only metabolic route for the harmala alkaloids in humans.

Riba, J., McIlhenny, E. H., Valle, M., Bouso, J. C., & Barker, S. A. (2012). Metabolism and disposition of N, N‐dimethyltryptamine and harmala alkaloids after oral administration of ayahuasca. Drug testing and analysis, 4(7-8), 610-616. 10.1002/dta.1344
Link to full text

Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics

Abstract

The effects of the South American psychotropic beverage ayahuasca on subjective and cardiovascular variables and urine monoamine metabolite excretion were evaluated, together with the drug’s pharmacokinetic profile, in a double-blind placebo-controlled clinical trial. This pharmacologically complex tea, commonly obtained from Banisteriopsis caapi and Psychotria viridis, combines N,N-dimethyltryptamine (DMT), an orally labile psychedelic agent showing 5-hydroxytryptamine2A agonist activity, with monoamine oxidase (MAO)-inhibiting β-carboline alkaloids (harmine, harmaline, and tetrahydroharmine). Eighteen volunteers with prior experience in the use of psychedelics received single oral doses of encapsulated freeze-dried ayahuasca (0.6 and 0.85 mg of DMT/kg of body weight) and placebo. Ayahuasca produced significant subjective effects, peaking between 1.5 and 2 h, involving perceptual modifications and increases in ratings of positive mood and activation. Diastolic blood pressure showed a significant increase at the high dose (9 mm Hg at 75 min), whereas systolic blood pressure and heart rate were moderately and nonsignificantly increased. Cmax values for DMT after the low and high ayahuasca doses were 12.14 ng/ml and 17.44 ng/ml, respectively. Tmax (median) was observed at 1.5 h after both doses. The Tmax for DMT coincided with the peak of subjective effects. Drug administration increased urinary normetanephrine excretion, but, contrary to the typical MAO-inhibitor effect profile, deaminated monoamine metabolite levels were not decreased. This and the negligible harmine plasma levels found suggest a predominantly peripheral (gastrointestinal and liver) site of action for harmine. MAO inhibition at this level would suffice to prevent first-pass metabolism of DMT and allow its access to systemic circulation and the central nervous system.

Ayahuasca, also known by the names Daime, Yajé, Natema, and Vegetal, is a psychotropic plant tea used by shamans throughout the Amazon Basin in traditional medicine, rites of passage, and magico-religious practices (Schultes and Hofmann, 1982; Dobkin de Rios, 1984). This ancient pattern of use has given way to a more widespread and frequent consumption by members of a number of modern Brazilian-based syncretic religious groups, mainly the Santo Daime and the Uniao do Vegetal, which have incorporated the use of the beverage in their rituals (Dobkin de Rios, 1996). In recent years, groups of followers of these Brazilian religions have become established in the United States and in several European countries, including Germany, Great Britain, Holland, France, and Spain (Anonymous, 2000). As a larger number of people have come into contact with ayahuasca, the tea has begun to attract the attention of biomedical researchers (Callaway et al., 1999; Riba et al., 2001b).

Ayahuasca is obtained by infusing the pounded stems of the malpighiaceous vine Banisteriopsis caapi either alone or, more frequently, in combination with the leaves of Psychotria viridis (rubiaceae) in Brazil, Peru, and Ecuador or Diplopterys cabrerana (malpighiaceae), used mainly in Ecuador and Colombia (Schultes and Hofmann, 1980; McKenna et al., 1984). P. viridis and D. cabrerana are rich in the psychedelic indole N,N-dimethyltryptamine (DMT; Rivier and Lindgren, 1972; Schultes and Hofmann, 1980), whereas B. caapi contains substantial amounts of β-carboline alkaloids, mainly harmine and tetrahydroharmine (THH), and to a lesser extent harmaline and traces of harmol and harmalol (Rivier and Lindgren, 1972; McKenna et al., 1984).

DMT is structurally related to the neurotransmitter serotonin and, like better-characterized psychedelics such as LSD and mescaline, binds to 5-hydroxytryptamine 2A receptors in the central nervous system (CNS), where it acts as an agonist (Pierce and Peroutka, 1989; Smith et al., 1998). Studies in humans have shown that when administered parenterally, DMT provokes dramatic modifications in perception, the sense of self and reality that can be very intense but relatively short in duration (Strassman et al., 1994). The drug also exerts marked autonomic effects elevating blood pressure, heart rate, and rectal temperature, and causes mydriasis (Strassman and Qualls, 1994). Unlike the vast majority of known psychedelic phenethylamines, tryptamines, and ergolines, DMT is orally inactive (Ott, 1999), apparently due to metabolism by monoamine oxidase (MAO; Suzuki et al., 1981). Interestingly, harmine and harmaline, and, to a lesser extent, THH, are potent MAO inhibitors (Buckholtz and Boggan, 1977; McKenna et al., 1984). In 1968, Agurell and coworkers (cited in Ott, 1999, p. 172) postulated that the interaction between β-carbolines and DMT in ayahuasca “might result in specific pharmacological effects”. It is now a widely accepted hypothesis that following ayahuasca ingestion, MAO inhibition brought about by harmine, given that it is more potent than THH and is present in the tea in larger amounts than harmaline (McKenna et al., 1984), prevents the enzymatic degradation of DMT, allowing its absorption. It has also been speculated that β-carbolines may contribute to the overall central effects of ayahuasca by blocking brain MAO and weakly inhibiting serotonin reuptake, which combined would lead to enhanced neurotransmitter levels and modulate the effects of DMT (Callaway et al., 1999).

In the present paper we report a double-blind placebo-controlled crossover clinical trial conducted with ayahuasca, in which subjective and cardiovascular effects, and alkaloid pharmacokinetics were assessed in a group of healthy volunteers experienced in psychedelic drug use. Additionally, urine monoamine metabolites were studied to measure in vivo the MAO-inhibitory effects of ayahuasca. In this respect, the neurotransmitters norepinephrine, epinephrine, and dopamine are physiologically degraded by MAO and catechol-O-methyltransferase (COMT) to produce deaminated and methylated metabolites, respectively. Serotonin, on the other hand, is exclusively metabolized by MAO to produce a deaminated compound. In vivo and in vitro studies have shown that when MAO is pharmacologically inhibited, the levels of MAO-dependent deaminated metabolites decrease and those of COMT-dependent methylated metabolites increase. In humans, MAO inhibitors decrease, after acute administration, the urinary excretion of vanillylmandelic acid (VMA), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), the deaminated metabolites of norepinephrine/epinephrine, dopamine, and serotonin, respectively, while increasing that of metanephrine and normetanephrine, the methylated metabolites of epinephrine and norepinephrine, respectively (Pletscher, 1966; Koulu et al., 1989). Monoamine metabolites have both a CNS and a non-CNS origin, and their assessment in urine does not give information regarding the organ in which MAO was inhibited. Nevertheless, this approach can identify dose-response relationships after drug administration and allows for the study of the time course of MAO inhibition.

Riba, J., Valle, M., Urbano, G., Yritia, M., Morte, A., & Barbanoj, M. J. (2003). Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics. Journal of Pharmacology and Experimental Therapeutics, 306(1), 73-83. 10.1124/jpet.103.049882
Link to full text

2 April - New Insights on Addiction & Psychedelic Healing Followed by a Live Q&A!

X