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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
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Activities of extract and constituents of Banisteriopsis caapi relevant to parkinsonism

Abstract

Dopamine deficiency is characteristic of Parkinson’s disease (PD) and treatments aim at elevating levels by administration of its precursor l-dihydroxyphenylalanine (l-DOPA), or inhibiting monoamine oxidases (MAOs), thus preventing its breakdown. Reports of improvements in PD patients treated with Banisteriopsis caapi extracts stimulated investigation of B. caapi stem extract and its two ingredients, harmine and harmaline for these activities.

Tests for MAO inhibition using liver homogenate showed that extract and harmaline showed a concentration-dependent inhibition of MAO A (IC50 1.24 μg/ml and IC50 4.54 nM, respectively) but had little effect on MAO B activity.

The extract at 2.5 mg/ml caused a highly significant increase in release of [3H]dopamine from rat striatal slices, as did 200 μM harmine and 6 μM harmaline. In both these experiments, the amount of harmine present could not account for the total activity of the extract.

The ability of harmine and harmaline to stimulate dopamine release is a novel finding. These results give some basis to the reputed usefulness of B. caapi stem extract in the treatment of PD.

Schwarz, M. J., Houghton, P. J., Rose, S., Jenner, P., & Lees, A. D. (2003). Activities of extract and constituents of Banisteriopsis caapi relevant to parkinsonism. Pharmacology Biochemistry and Behavior, 75(3), 627-633. 10.1016/S0091-3057(03)00129-1
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Clonazepam treatment of lysergic acid diethylamide-induced hallucinogen persisting perception disorder with anxiety features.

Abstract

An unique and intriguing characteristic of lysergic acid diethylamide (LSD) and LSD-like substances is the recurrence of some of the symptoms which appear during the intoxication, in the absence of recent intake of hallucinogens. Hallucinogen persisting perception disorder (HPPD) is a condition in which the re-experiencing of one or more perceptual symptoms causes significant distress or impairment in social, occupational or other important areas of functioning and may be extremely debilitating. Benzodiazepines are one of the recommended agents for the treatment of HPPD but it is unclear which of them may be more helpful. The goal of our investigation was to assess the efficacy of clonazepam in the treatment of LSD-induced HPPD. Sixteen patients fulfilled entrance criteria. All complained of HPPD with anxiety features for at least 3 months and were drug free at least 3 months. They received clonazepam 2 mg/day for 2 months. Follow-up was continued for 6 months. They were weekly evaluated during the 2 months of clonazepam administration and monthly during the follow-up period using the Clinical Global Impression Scale, a Self-report Scale and Hamilton Anxiety Rating Scale. Patients reported a significant relief and the presence of only mild symptomatology during the clonazepam administration. This improvement was clearly sustained and persisted during a 6-month follow-up period. This study suggests that high potency benzodiazepines like clonazepam, which has serotonergic properties, may be more effective than low-potency benzodiazepines in the treatment of some patients with LSD-induced HPPD.

Lerner, A. G., Gelkopf, M., Skladman, I., Rudinski, D., Nachshon, H., & Bleich, A. (2003). Clonazepam treatment of lysergic acid diethylamide-induced hallucinogen persisting perception disorder with anxiety features. International clinical psychopharmacology, 18(2), 101-105.
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Effects of the 5-HT2A Agonist Psilocybin on Mismatch Negativity Generation and AX-Continuous Performance Task: Implications for the Neuropharmacology of Cognitive Deficits in Schizophrenia

Abstract

Previously the NMDA (N-methyl-D-aspartate) receptor (NMDAR) antagonist ketamine was shown to disrupt generation of the auditory event-related potential (ERP) mismatch negativity (MMN) and the performance of an ‘AX’-type continuous performance test (AX-CPT)–measures of auditory and visual context-dependent information processing–in a similar manner as observed in schizophrenia. This placebo-controlled study investigated effects of the 5-HT(2A) receptor agonist psilocybin on the same measures in 18 healthy volunteers. Psilocybin administration induced significant performance deficits in the AX-CPT, but failed to reduce MMN generation significantly. These results indirectly support evidence that deficient MMN generation in schizophrenia may be a relatively distinct manifestation of deficient NMDAR functioning. In contrast, secondary pharmacological effects shared by NMDAR antagonists and the 5-HT(2A) agonist (ie disruption of glutamatergic neurotransmission) may be the mechanism underlying impairments in AX-CPT performance observed during both psilocybin and ketamine administration. Comparable deficits in schizophrenia may result from independent dysfunctions of 5-HT(2A) and NMDAR-related neurotransmission.

Umbricht, D., Vollenweider, F. X., Schmid, L., Gruebel, C., Skrabo, A., Huber, T., & Koller, R. (2003). Effects of the 5-HT2A agonist psilocybin on mismatch negativity generation and AX-continuous performance task: implications for the neuropharmacology of cognitive deficits in schizophrenia. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology, 28(1), 170-181. http://dx.doi.org/10.1038/sj.npp.1300005
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Effects of different subanaesthetic doses of (S)-ketamine on psychopathology and binocular depth inversion in man

Abstract

The role of the N-methyl-D-aspartate (NMDA) neurotransmitter system in relation to psychoses is not completely understood, but represent a challenge in neurobiological research. The psychotic states induced by NMDA antagonists such as phencyclidine and ketamine have been described as being most similar to schizophrenia and the NMDA system has been implicated in the pathogenesis of schizophrenia. Binocular depth inversion, an illusion of visual perception, has been shown to be impaired in psychotic and psychotomimetic states in healthy and schizophrenic subjects. In this study, pictures of natural and artificial objects were presented stereoscopically to 12 healthy male volunteers and depth perception assessed using an operationalized method. The effects of the psychotomimetic S-enantiomer of the anaesthetic ketamine in two different subanaesthetic doses were compared with those of a placebo. In spite of dose dependence and grave subjective and significant objective psychopathology, no significant impairment of binocular depth perception was found with (S)-ketamine. Implications related to memory function, perceptogenesis and ‘bottom-up’ processing in ketamine model psychosis and schizophrenia are discussed.

Passie, T., Karst, M., Borsutzky, M., Wiese, B., Emrich, H. M., & Schneider, U. (2003). Effects of different subanaesthetic doses of (S)-ketamine on psychopathology and binocular depth inversion in man. Journal of Psychopharmacology, 17(1), 51-56. http://dx.doi.org/10.1177/0269881103017001698
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The Antipodes of the Mind: Charting the Phenomenology of the Ayahuasca Experience

antipodesThis is a pioneering cognitive psychological study of Ayahuasca, a plant-based Amazonian psychotropic brew. Benny Shanon presents a comprehensive charting of the various facets of the special state of mind induced by Ayahuasca, and analyses them from a cognitive psychological perspective. He also presents some philosophical reflections. Empirically, the research presented in this book is based on the systematic recording of the author’s extensive experiences with the brew and on the interviewing of a large number of informants: indigenous people, shamans, members of different religious sects using Ayahuasca, and travellers. In addition to its being the most thorough study of the Ayahuasca experience to date, the book lays the theoretical foundations for the psychological study of non-ordinary states of consciousness in general.

Benny Shanon is Professor at the Department of Psychology of the Hebrew University of Jerusalem and holder of the Mandel Chair in Cognition.

The Antipodes of the Mind: Charting the Phenomenology of the Ayahuasca Experience, by Benny Shanon, Oxford University Press, 496 pages.

Buy this book at bookdepository.com and support the OPEN Foundation.

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The Antipodes of the Mind: Charting the Phenomenology of the Ayahuasca Experience

This is a pioneering cognitive psychological study of Ayahuasca, a plant-based Amazonian psychotropic brew. Benny Shanon presents a comprehensive charting of the various facets of the special state of mind induced by Ayahuasca, and analyses them from a cognitive psychological perspective. He also presents some philosophical reflections. Empirically, the research presented in this book is based on the systematic recording of the author’s extensive experiences with the brew and on the interviewing of a large number of informants: indigenous people, shamans, members of different religious sects using Ayahuasca, and travellers. In addition to its being the most thorough study of the Ayahuasca experience to date, the book lays the theoretical foundations for the psychological study of non-ordinary states of consciousness in general.

Benny Shanon is Professor at the Department of Psychology of the Hebrew University of Jerusalem and holder of the Mandel Chair in Cognition.

The Antipodes of the Mind: Charting the Phenomenology of the Ayahuasca Experience, door Benny Shanon, Oxford University Press, 496 pagina’s.

Koop dit boek via bookdepository.com en steun daarmee Stichting OPEN.

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Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up

Abstract

Seventy detoxified heroin-addicted patients were randomly assigned to one of two groups receiving ketamine psychotherapy (KPT) involving two different doses of ketamine. The patients of the experimental group received existentially oriented psychotherapy in combination with a hallucinogenic (“psychedelic”) dose of ketamine (2.0 mg/kg im). The patients of the control group received the same psychotherapy combined with a low, non-hallucinogenic (non-psychedelic), dose of ketamine (0.2 mg/kg im). Both the psychotherapist and patient were blind to the dose of ketamine. The therapy included preparation for the ketamine session, the ketamine session itself, and the post session psychotherapy aimed to help patients to integrate insights from their ketamine session into everyday life. The results of this double blind randomized clinical trial of KPT for heroin addiction showed that high dose (2.0 mg/kg) KPT elicits a full psychedelic experience in heroin addicts as assessed quantitatively by the Hallucinogen Rating Scale. On the other hand, low dose KPT (0.2 mg/kg) elicits “sub-psychedelic” experiences and functions as ketamine-facilitated guided imagery. High dose KPT produced a significantly greater rate of abstinence in heroin addicts within the first two years of follow-up, a greater and longer-lasting reduction in craving for heroin, as well as greater positive change in nonverbal unconscious emotional attitudes than did low dose KPT.

Krupitsky, E., Burakov, A., Romanova, T., Dunaevsky, I., Strassman, R., & Grinenko, A. (2002). Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up. Journal of substance abuse treatment, 23(4), 273-283. http://dx.doi.org/10.1016/S0740-5472(02)00275-1
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Topographic pharmaco-EEG mapping of the effects of the South American psychoactive beverage ayahuasca in healthy volunteers

Abstract

Aims: Ayahuasca is a traditional South American psychoactive beverage used in Amazonian shamanism, and in the religious ceremonies of Brazilian-based syncretic religious groups with followers in the US and several European countries. This tea contains measurable amounts of the psychotropic indole N,N-dimethyltryptamine (DMT), and β-carboline alkaloids with MAO-inhibiting properties. In a previous report we described a profile of stimulant and psychedelic effects for ayahuasca as measured by subjective report self-assessment instruments. In the present study the cerebral bioavailability and time-course of effects of ayahuasca were assessed in humans by means of topographic quantitative-electroencephalography (q-EEG), a noninvasive method measuring drug-induced variations in brain electrical activity.

Methods: Two doses (one low and one high) of encapsulated freeze-dried ayahuasca, equivalent to 0.6 and 0.85 mg DMT kg−1 body weight, were administered to 18 healthy volunteers with previous experience in psychedelic drug use in a double-blind crossover placebo-controlled clinical trial. Nineteen-lead recordings were undertaken from baseline to 8 h after administration. Subjective effects were measured by means of the Hallucinogen Rating Scale (HRS).

Results: Ayahuasca induced a pattern of psychoactive effects which resulted in significant dose-dependent increases in all subscales of the HRS, and in significant and dose-dependent modifications of brain electrical activity. Absolute power decreased in all frequency bands, most prominently in the theta band. Mean absolute power decreases (95% CI) at a representative lead (P3) 90 min after the high dose were −20.20±15.23 µV2 and −2.70±2.21 µV2 for total power and theta power, respectively. Relative power decreased in the delta (−1.20±1.31% after 120 min at P3) and theta (−3.30±2.59% after 120 min at P3) bands, and increased in the beta band, most prominently in the faster beta-3 (1.00±0.88% after 90 min at P3) and beta-4 (0.30±0.24% after 90 min at P3) subbands. Finally, an increase was also seen for the centroid of the total activity and its deviation. EEG modifications began as early as 15–30 min, reached a peak between 45 and 120 min and decreased thereafter to return to baseline levels at 4–6 h after administration.

Conclusions: The central effects of ayahuasca could be objectively measured by means of q-EEG, showing a time pattern which closely paralleled that of previously reported subjective effects. The modifications seen for the individual q-EEG variables were in line with those previously described for other serotonergic psychedelics and share some features with the profile of effects shown by pro-serotonergic and pro-dopaminergic drugs. The q-EEG profile supports the role of 5-HT2 and dopamine D2-receptor agonism in mediating the effects of ayahuasca on the central nervous system.

Riba, J., Anderer, P., Morte, A., Urbano, G., Jané, F., Saletu, B., & Barbanoj, M. J. (2002). Topographic pharmaco‐EEG mapping of the effects of the South American psychoactive beverage ayahuasca in healthy volunteers. British journal of clinical pharmacology, 53(6), 613-628. 10.1046/j.1365-2125.2002.01609.x
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The pharmacology of psilocybin

Abstract

Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamin e) is the major psychoactive alkaloid of some species of mushrooms distributed worldwide. These mushrooms represent a growing problem regarding hallucinogenic drug abuse. Despite its experimental medical use in the 1960s, only very few pharmacological data about psilocybin were known until recently. Because of its still growing capacity for abuse and the widely dispersed data this review presents all the available pharmacological data about psilocybin.

Passie, T., Seifert, J., Schneider, U., & Emrich, H. M. (2002). The pharmacology of psilocybin. Addiction Biology, 7(4), 357-364. http://dx.doi.org/10.1080/1355621021000005937

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Psychedelics and Acceptance and Commitment Therapy (ACT): A Process-Based Approach - September 15th