OPEN Foundation

Psychopharmacology

Role of Serotoninergic Neurons and 5-HT Receptors in the Action of Hallucinogens

January 1, 2000 / Neuroscience, Other subjects, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By /

Abstract

Brain serotonin receptors and serotoninergic pathways have received increasing attention as targets for a wide variety of therapeutic agents. Perhaps peculiar to this realm, however, are the so-called hallucinogenic drugs, which presently lack demonstrated therapeutic utility, and still remain, as they have for at least the past 50 years, pharmacological curiosities. Research into their mechanism of action is generally poorly funded, and we know relatively little about how they affect the brain, despite their continued popularity as recreational drugs among a significant proportion of the population.

Nichols, D. E. (2000). Role of serotoninergic neurons and 5-HT receptors in the action of hallucinogens. In Serotoninergic Neurons and 5-HT Receptors in the CNS (pp. 563-585). Springer Berlin Heidelberg. http://dx.doi.org/10.1007/978-3-642-60921-3_21

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Pharmacokinetics of Hoasca alkaloids in healthy humans

June 1, 1999 / Ayahuasca, DMT, Ethnobotany, Indigenous use, Papers, Psychopharmacology, Publications / By / , , , , , ,

Abstract

N,N-Dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine (THH) are the characteristic alkaloids found in Amazonian sacraments known as hoasca, ayahuasca, and yajè. Such beverages are characterized by the presence of these three harmala alkaloids, where harmine and harmaline reversibly inhibit monoamine oxidase A (MAO-A) while tetrahydroharmine weakly inhibits the uptake of serotonin. Together, both actions increase central and peripheral serotonergic activity while facilitating the psychoactivity of DMT. Though the use of such ‘teas’ has be known to western science for over 100 years, little is known of their pharmacokinetics. In this study, hoasca was prepared and administered in a ceremonial context. All four alkaloids were measured in the tea and in the plasma of 15 volunteers, subsequent to the ingestion of 2 ml hoasca/kg body weight, using gas (GC) and high pressure liquid chromatographic (HPLC) methods. Pharmacokinetic parameters were calculated and peak times of psychoactivity coincided with high alkaloid concentrations, particularly DMT which had an average Tmax of 107.5±32.5 min. While DMT parameters correlated with those of harmine, THH showed a pharmacokinetic profile relatively independent of harmine’s.

Callaway, J. C., McKenna, D. J., Grob, C. S., Brito, G. S., Raymon, L. P., Poland, R. E., … & Mash, D. C. (1999). Pharmacokinetics of Hoasca alkaloids in healthy humans. Journal of ethnopharmacology, 65(3), 243-256. 10.1016/S0378-8741(98)00168-8
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Do entheogen-induced mystical experiences boost the immune system? Psychedelics, peak experiences, and wellness

January 1, 1999 / Ayahuasca, Cacti / Mescaline, DMT, Iboga / Ibogaine, LSD, Medicine, Mushrooms / Psilocybin, Mystical experiences, Papers, Psychology, Psychopharmacology, Publications, Salvia / Salvinorin A / By /

Abstract

Daily events that boost the immune system (as indicated by levels of salivary immunoglobulin A), some instances of spontaneous remission, and mystical experiences seem to share a similar cluster of thoughts, feelings, moods, perceptions, and behaviors. Entheogens – psychedelic drugs used in a religious context – can also produce mystical experiences (peak experiences, states of unitive consciousness, intense primary religious experiences) with the same cluster of effects. When this happens, is it also possible that such entheogen-induced mystical experiences strengthen the immune system? Might spontaneous remissions occur more frequently under such conditions? This article advances the so called “Emxis hypothesis” – that entheogen-induced mystical experiences influence the immune system.

Roberts, T. B. (1999). Do entheogen-induced mystical experiences boost the immune system? Psychedelics, peak experiences, and wellness. Advances in Mind-Body Medicine, 15, 139-147.
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Psilocybin induces schizophrenia‐like psychosis in humans via a serotonin‐2 agonist action

December 1, 1998 / Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Publications / By / , , , ,

Abstract

Psilocybin, an indoleamine hallucinogen, produces a psychosis-like syndrome in humans that resembles first episodes of schizophrenia. In healthy human volunteers, the psychotomimetic effects of psilocybin were blocked dose-dependently by the serotonin-2A antagonist ketanserin or the atypical antipsychotic risperidone, but were increased by the dopamine antagonist and typical antipsychotic haloperidol. These data are consistent with animal studies and provide the first evidence in humans that psilocybin-induced psychosis is due to serotonin-2A receptor activation, independently of dopamine stimulation. Thus, serotonin-2A overactivity may be involved in the pathophysiology of schizophrenia and serotonin-2A antagonism may contribute to therapeutic effects of antipsychotics.

Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F., Bäbler, A., Vogel, H., & Hell, D. (1998). Psilocybin induces schizophrenia‐like psychosis in humans via a serotonin‐2 agonist action. Neuroreport, 9(17), 3897-3902. https://dx.doi.org/doi:10.1097/00001756-199812010-00024
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Serotonergic Agents That Activate 5HT2A Receptors Prevent NMDA Antagonist Neurotoxicity

July 2, 1997 / Ketamine, Other subjects, Other substances, Papers, Psychopharmacology, Psychosis, Publications / By / , , , ,

Abstract

Phencyclidine, ketamine, and other agents that block NMDA glutamate receptors trigger a schizophrenia-like psychosis in humans and induce pathomorphological changes in cerebrocortical neurons in rat brain. Accumulating evidence suggests that a complex network disturbance involving multiple transmitter receptor systems is responsible for the neuronal injury, and it is proposed that a similar network disturbance is responsible for the psychotomimetic effects of NMDA antagonists, and might also be involved in the pathophysiology of schizophrenia. In the present study we present evidence that serotonergic agents possessing 5HT2A agonist activity prevent NMDA antagonist neurotoxicity in rat brain. It isproposed that 5HT2A agonists may also prevent the psychotomimetic effects of NMDA antagonists. Among the 5HT2A agonists examined and found to be neuroprotective are LSD and related hallucinogens. The apparent contradiction in proposing that these agents might have antipsychotic properties is resolved by evidence linking their hallucinogenic activity to agonist action at 5HT2C receptors, whereas antipsychotic activity would be attributable to agonist action at 5HT2A receptors.

Farber, N. B., Hanslick, J., Kirby, C., McWilliams, L., & Olney, J. W. (1998). Serotonergic Agents That Activate 5HT2A Receptors Prevent NMDA Antagonist Neurotoxicity. Neuropsychopharmacology, 18(1), 57-62. http://dx.doi.org/doi:10.1016/S0893-133X(97)00127-9

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Ketamine psychedelic therapy (KPT): a review of the results of ten years of research

January 1, 1997 / Addiction, Ketamine, Neuroscience, Papers, Personality, Psychiatry, Psychology, Psychopharmacology, Publications / By / ,

Abstract

Ketamine is a prescription drug used for general anesthesia. In subanesthetic doses, it induces profound psychedelic experiences and hallucinations. The subanesthetic effect of ketamine was the hypothesized therapeutic mechanism in the authors’ use of ketamine-assisted psychotherapy for alcoholism. The results of a controlled clinical trial demonstrated a considerable increase in efficacy of the authors’ standard alcoholism treatment when supplemented by ketamine psychedelic therapy (KPT). Total abstinence for more than one year was observed in 73 out of 111 (65.8%) alcoholic patients in the KPT group, compared to 24% (24 out of 100 patients) of the conventional treatment control group (p < 0.01). The authors’ studies of the underlying psychological mechanisms of KPT have indicated that ketamine-assisted psychedelic therapy of alcoholic patients induces a harmonization of the Minnesota Multiphasic Personality Inventory (MMPI) personality profile, positive transformation of nonverbalized (mostly unconscious) self-concept and emotional attitudes to various aspects of self and other people, positive changes in life values and purposes, important insights into the meaning of life and an increase in the level of spiritual development. Most importantly, these psychological changes were shown to favor a sober lifestyle. The data from biochemical investigations showed that pharmacological action of KPT affects both monoaminergic and opioidergic neurotransmitter metabolism, i.e., those neurochemical systems which are involved in the pathogenesis of alcohol dependence. The data from EEG computer-assisted analysis demonstrated that ketamine increases theta activity in cerebrocortical regions of alcoholic patients. This is evidence of the reinforcement of limbic cortex interaction during KPT session.

Krupitsky, E. M., & Grinenko, A. Y. (1997). Ketamine psychedelic therapy (KPT): a review of the results of ten years of research. Journal of psychoactive drugs, 29(2), 165-183. https://dx.doi.org/10.1080/02791072.1997.10400185

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Receptor binding profile suggests multiple mechanisms of action are responsible for ibogaine's putative anti-addictive activity

April 2, 1995 / Addiction, Iboga / Ibogaine, Papers, Psychopharmacology, Publications / By / , , , , , ,

Abstract

The indole alkaloid ibogaine (NIH 10567, Endabuse) is currently being examined for its potential utility in the treatment of cocaine and opioid addiction. However, a clearly defined molecular mechanism of action for ibogaine’s putative anti-addictive properties has not been delineated. Radioligand binding assays targeting over 50 distinct neurotransmitter receptors, ion channels, and select second messenger systems were employed to establish a broad in vitro pharmacological profile for ibogaine. These studies revealed that ibogaine interacted with a wide variety of receptors at concentrations of 1-100 microM. These included the mu, delta, kappa, opiate, 5HT2, 5HT3, and muscarinic1 and 2 receptors, and the dopamine, norepinephrine, and serotonin uptake sites. In addition, ibogaine interacted with N-methyl-D-aspartic acid (NMDA) associated ion and sodium ion channels as determined by the inhibition of [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][3H]MK-801 and [3H]bactrachotoxin A 20-alpha-benzoate binding (BTX-B), respectively. This broad spectrum of activity may in part be responsible for ibogaine’s putative anti-addictive activity.

Sweetnam, P. M., Lancaster, J., Snowman, A., Collins, J. L., Perschke, S., Bauer, C., & Ferkany, J. (1995). Receptor binding profile suggests multiple mechanisms of action are responsible for ibogaine’s putative anti-addictive activity. Psychopharmacology, 118(4), 369-376.
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Differences Between the Mechanism of Action of MDMA, MBDB, and the Classic Hallucinogens. Identification of a New Therapeutic Class: Entactogens

January 1, 1986 / MDMA, Neuroscience, New substances, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By /

Nichols, D. E. (1986). Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogens. Identification of a new therapeutic class: entactogens. Journal of psychoactive drugs, 18(4), 305-313. http://dx.doi.org/10.1080/02791072.1986.10472362
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Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and beta-carboline constituents of ayahuasca

April 1, 1984 / Ayahuasca, DMT, Ethnobotany, Neuroscience, Other subjects, Papers, Psychopharmacology, Publications / By / , ,

Abstract

Ayahuasca is a hallucinogenic beverage derived by boiling the bark of the Malpighiaceous liana Banisteriopsis caapi together with the leaves of various admixture plants, viz. Psychotria viridis, Psychotria carthagenensis, or Diplopterys cabrerana. B. caapi contains harmine, harmaline, and tetrahydroharmine while the admixtures contain N,N-dimethyltryptamine (DMT). DMT, a potent hallucinogen, is inactive orally due to degradation by visceral monoamine oxidase (MAO). The β-carbolines, however, are highly active reversible inhibitors of MAO and may protect the DMT from deamination by MAO and render it orally active. This mechanism has been proposed to underlie the oral activity of ayahuasca but has not been experimentally confirmed. In the present study the constituents of the admixture plants and the alkaloids of eight ayahuasca samples from Peru were qualitatively and quantitatively analyzed using two-dimensional thin-layer chromatography (TLC), high pressure liquid chromatography (HPLC) and gas chromatography/mass spectrometry (GC/MS).

Several B. caapi cultivars were quantitatively compared for variations in alkaloid content. Three admixture plants used rarely in the manufacture of ayahuasca were also screened for alkaloids. A selected sample of β-carbolines were screened for activity as MAO inhibitors using an in vitro assay system, and structure/activity relationships were compared. Inhibition observed with single compounds was compared with the activity of selected samples of ayahuasca which were screened in the system and also with the activity of mixtures of β-carbolines. The levels of DMT and β-carbolines found in the ayahuasca samples examined in the present study were an order of magnitude greater than the levels reported in a previous study. Ayahuasca was found to be an extremely effective inhibitor of MAO in vitro and the degree of inhibition was directly correlated with the concentration of MAO-inhibiting β-carbolines. Inhibition experiments using mixtures of β-carbolines indicated that their effects in combination are additive, rather than synergistic or antagonistic. Implications of the results in understanding the pharmacology of ayahuasca are discussed.

McKenna, D. J., Towers, G. N., & Abbott, F. (1984). Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and β-carboline constituents of ayahuasca. Journal of ethnopharmacology, 10(2), 195-223. 10.1016/0378-8741(84)90003-5
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14 May - Psychedelics & Psychosis with Phoebe Friesen, Dirk Corstens and Chelsea Rose

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