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When the Endogenous Hallucinogenic Trace Amine N,N-Dimethyltryptamine Meets the Sigma-1 Receptor

March 10, 2009 / DMT, Other subjects, Papers, Psychopharmacology, Publications / By / , ,

Abstract

N,N-dimethyltryptamine (DMT) is a hallucinogen found endogenously in human brain that is commonly recognized to target the 5-hydroxytryptamine 2A receptor or the trace amine–associated receptor to exert its psychedelic effect. DMT has been recently shown to bind sigma-1 receptors, which are ligand-regulated molecular chaperones whose function includes inhibiting various voltage-sensitive ion channels. Thus, it is possible that the psychedelic action of DMT might be mediated in part through sigma-1 receptors. Here, we present a hypothetical signaling scheme that might be triggered by the binding of DMT to sigma-1 receptors.

Su, T., Hayashi, T., & Vaupel, D. B. (2009). When the Endogenous Hallucinogenic Trace Amine N,N-Dimethyltryptamine Meets the Sigma-1 Receptor. Science Signaling, 2(61). http://dx.doi.org/10.1126/scisignal.261pe12
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Gaddum and LSD: the birth and growth of experimental and clinical neuropharmacology research on 5-HT in the UK

January 29, 2009 / Depression, LSD, Medicine, Neuroscience, Other subjects, Other substances, Papers, Psychopharmacology, Psychotherapy, Publications / By /

Abstract

The vasoconstrictor substance named serotonin was identified as 5-hydroxytryptamine (5-HT) by Maurice Rapport in 1949. In 1951, Rapport gave Gaddum samples of 5-HT substance allowing him to develop a bioassay to both detect and measure the amine. Gaddum and colleagues rapidly identified 5-HT in brain and showed that lysergic acid diethylamide (LSD) antagonized its action in peripheral tissues. Gaddum accordingly postulated that 5-HT might have a role in mood regulation. This review examines the role of UK scientists in the first 20 years following these major discoveries, discussing their role in developing assays for 5-HT in the CNS, identifying the enzymes involved in the synthesis and metabolism of 5-HT and investigating the effect of drugs on brain 5-HT. It reviews studies on the effects of LSD in humans, including Gaddum’s self-administration experiments. It outlines investigations on the role of 5-HT in psychiatric disorders, including studies on the effect of antidepressant drugs on the 5-HT concentration in rodent and human brain, and the attempts to examine 5-HT biochemistry in the brains of patients with depressive illness. It is clear that a rather small group of both preclinical scientists and psychiatrists in the UK made major advances in our understanding of the role of 5-HT in the brain, paving the way for much of the knowledge now taken for granted when discussing ways that 5-HT might be involved in the control of mood and the idea that therapeutic drugs used to alleviate psychiatric illness might alter the function of cerebral 5-HT.

Green, A. R. (2008). Gaddum and LSD: the birth and growth of experimental and clinical neuropharmacology research on 5‐HT in the UK. British journal of pharmacology, 154(8), 1583-1599., 10.1038/bjp.2008.207
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Endogenous hallucinogens as ligands of the trace amine receptors: A possible role in sensory perception

January 14, 2009 / DMT, Other subjects, Other substances, Papers, Psychopharmacology, Publications / By /

Abstract

While the endogenous hallucinogens, N,N-dimethyltryptamine, 5-hydroxy-N,N-dimethyl-tryptamine and 5-methoxy-N,N-dimethyltryptamine, have been acknowledged as naturally occurring components of the mammalian body for decades, their biological function remains as elusive now as it was at the time of their discovery. The recent discovery of the trace amine associated receptors and the activity of DMT and other hallucinogenic compounds at these receptor sites leads to the hypothesis that the endogenous hallucinogens act as neurotransmitters of a subclass of these trace amine receptors. Additionally, while activity at the serotonin 5-HT2A receptor has been proposed as being responsible for the hallucinogenic affects of administered hallucinogens, in their natural setting the 5-HT2A receptor may not interact with the endogenous hallucinogens at all. Additionally 5-HT2A agonist activity is unable to account for the visual altering effects of many of the administered hallucinogens; these effects may be mediated by one of the endogenous hallucinogen trace amine receptors rather than the serotonin 5-HT2A receptor. Therefore, activity at the trace amine receptors, in addition to serotonin receptors, may play a large role in the sensory altering effects of administered hallucinogens and the trace amine receptors along with their endogenous hallucinogen ligands may serve an endogenous role in mediating sensory perception in the mammalian central nervous system. Thus the theory proposed states that these compounds act as true endogenous hallucinogenic transmitters acting in regions of the central nervous system involved in sensory perception.

Wallach, J. V. (2009). Endogenous hallucinogens as ligands of the trace amine receptors: A possible role in sensory perception. Medical Hypotheses, 72(1), 91–94. http://dx.doi.org/10.1016/j.mehy.2008.07.052
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Gas chromatographic analysis of dimethyltryptamine and beta-carboline alkaloids in ayahuasca, an Amazonian psychoactive plant beverage

January 12, 2009 / Ayahuasca, Chemistry, Other subjects, Papers, Publications / By / , , , , ,

Abstract

Introduction: Ayahuasca is obtained by infusing the pounded stems of Banisteriopsis caapi in combination with the leaves of Psychotria viridis. P. viridis is rich in the psychedelic indole N,N-dimethyltryptamine, whereas B. caapi contains substantial amounts of β-carboline alkaloids, mainly harmine, harmaline and tetrahydroharmine, which are monoamine-oxidase inhibitors. Because of differences in composition in ayahuasca preparations, a method to measure their main active constituents is needed.

Objective: To develop a gas chromatographic method for the simultaneous determination of dimethyltryptamine and the main β-carbolines found in ayahuasca preparations.

Methodology: The alkaloids were extracted by means of solid phase extraction (C18) and detected by gas chromatography with nitrogen/phosphorous detector.

Results: The lower limit of quantification (LLOQ) was 0.02 mg/mL for all analytes. The calibration curves were linear over a concentration range of 0.02–4.0 mg/mL (r2 > 0.99). The method was also precise (RSD < 10%).

Conclusion: A simple gas chromatographic method to determine the main alkaloids found in ayahuasca was developed and validated. The method can be useful to estimate administered doses in animals and humans for further pharmacological and toxicological investigations of ayahuasca.

Pires, A. P. S., De Oliveira, C. D. R., Moura, S., Dörr, F. A., Silva, W. A. E., & Yonamine, M. (2009). Gas chromatographic analysis of dimethyltryptamine and β‐carboline alkaloids in ayahuasca, an amazonian psychoactive plant beverage. Phytochemical Analysis, 20(2), 149-153. 10.1002/pca.1110
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The Pharmacology of Lysergic Acid Diethylamide: A Review

November 11, 2008 / LSD, Other subjects, Papers, Psychology, Psychopharmacology, Publications / By / , , , ,

Abstract

Lysergic acid diethylamide (LSD) was synthesized in 1938 and its psychoactive effects discovered in 1943. It was used during the 1950s and 1960s as an experimental drug in psychiatric research for producing so-called “experimental psychosis” by altering neurotransmitter system and in psychotherapeutic procedures (“psycholytic” and “psychedelic” therapy). From the mid 1960s, it became an illegal drug of abuse with widespread use that continues today. With the entry of new methods of research and better study oversight, scientific interest in LSD has resumed for brain research and experimental treatments. Due to the lack of any comprehensive review since the 1950s and the widely dispersed experimental literature, the present review focuses on all aspects of the pharmacology and psychopharmacology of LSD. A thorough search of the experimental literature regarding the pharmacology of LSD was performed and the extracted results are given in this review. (Psycho-) pharmacological research on LSD was extensive and produced nearly 10,000 scientific papers. The pharmacology of LSD is complex and its mechanisms of action are still not completely understood. LSD is physiologically well tolerated and psychological reactions can be controlled in a medically supervised setting, but complications may easily result from uncontrolled use by layman. Actually there is new interest in LSD as an experimental tool for elucidating neural mechanisms of (states of) consciousness and there are recently discovered treatment options with LSD in cluster headache and with the terminally ill.

Passie, T., Halpern, J. H.,  Stichtenoth, D. O., Emrich, H. M., & Hintzen, A. (2008). The Pharmacology of Lysergic Acid Diethylamide: A Review. CNS Neuroscience & Therapeutics, 14(4), 295–314. http://dx.doi.org/10.1111/j.1755-5949.2008.00059.x
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Hallucinogens as discriminative stimuli in animals: LSD, phenethylamines, and tryptamines

November 1, 2008 / Cacti / Mescaline, DMT, LSD, Mushrooms / Psilocybin, Other subjects, Other substances, Papers, Psychopharmacology, Publications / By /

Abstract

Background: Although man’s first encounters with hallucinogens predate written history, it was not until the rise of the sister disciplines of organic chemistry and pharmacology in the nineteenth century that scientific studies became possible. Mescaline was the first to be isolated and its chemical structure determined. Since then, additional drugs have been recovered from their natural sources and synthetic chemists have contributed many more. Given their profound effects upon human behavior and the need for verbal communication to access many of these effects, some see humans as ideal subjects for study of hallucinogens. However, if we are to determine the mechanisms of action of these agents, establish hypotheses testable in human subjects, and explore the mechanistic links between hallucinogens and such apparently disparate topics as idiopathic psychosis, transcendental states, drug abuse, stress disorders, and cognitive dysfunction, studies in animals are essential. Stimulus control by hallucinogens has provided an intuitively attractive approach to the study of these agents in nonverbal species.

Objective: The intent of this review is to provide a brief account of events from the time of the first demonstration of hallucinogen-induced stimulus control to the present. In general, the review is limited to lysergic acid diethylamide (LSD) and the hallucinogenic derivatives of phenethylamine and tryptamine.

Results: The pharmacological basis for stimulus control by LSD and hallucinogenic phenethylamines and tryptamines is serotonergic in nature. The 5-HT2A receptor appears to be the primary site of action with significant modulation by other serotonergic sites including 5-HT2C and 5-HT1A receptors. Interactions with other neurotransmitters, especially glutamate and dopamine, are under active investigation. Most studies to date have been conducted in the rat but transgenic mice offer interesting possibilities.

Conclusions: Hallucinogen-induced stimulus control provides a unique behavioral tool for the prediction of subjective effects in man and for the elucidation of the pharmacological mechanisms of the action of these agents.

Winter, J. C. (2009). Hallucinogens as discriminative stimuli in animals: LSD, phenethylamines, and tryptamines. Psychopharmacology, 203(2), 251–263. http://dx.doi.org/10.1007/s00213-008-1356-8
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'Hybrid' benzofuran-benzopyran congeners as rigid analogs of hallucinogenic phenethylamines

June 1, 2008 / Chemistry, LSD, Other subjects, Other substances, Papers, Psychopharmacology, Publications / By / , , , , ,

Abstract

Phenylalkylamines that possess conformationally rigidified furanyl moieties in place of alkoxy arene ring substituents have been shown previously to possess the highest affinities and agonist functional potencies at the serotonin 5-HT2A receptor among this chemical class. Further, affinity declines when both furanyl rings are expanded to the larger dipyranyl ring system. The present paper reports the synthesis and pharmacological evaluation of a series of ‘hybrid’ benzofuranyl–benzopyranyl phenylalkylamines to probe further the sizes of the binding pockets within the serotonin 5-HT2A agonist binding site. Thus, 4(a–b), 5(a–b), and 6 were prepared as homologs of the parent compound, 8-bromo-1-(2,3,6,7-tetrahydrobenzo[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”][1,2-b:4,5-b0]difuran-4-yl)- 2-aminopropane 2, and their affinity, functional potency, and intrinsic activity were assessed using cells stably expressing the rat 5-HT2A receptor. The behavioral pharmacology of these new analogs was also evaluated in the two-lever drug discrimination paradigm. Although all of the hybrid isomers had similar, nanomolar range receptor affinities, those with the smaller furanyl ring at the arene 2-position (4a–b) displayed a 4- to 15-fold greater functional potency than those with the larger pyranyl ring at that position (5a–b). When the furan ring of the more potent agonist 4b was aromatized to give 6, a receptor affinity similar to the parent difuranyl compound 2 was attained, along with a functional potency equivalent to 2, 4a, and 4b. In drug discrimination experiments using rats trained to discriminate LSD from saline, 4b was more than two times more potent than 5b, with the latter having a potency similar to the classic hallucinogenic amphetamine 1 (DOB).

Schultz, D. M.,  Prescher, J. A., Kidd, S., Marona-Lewicka, D., Nichols, D. E., & Montea, A. (2008). ‘Hybrid’ benzofuran-benzopyran congeners as rigid analogs of hallucinogenic phenethylamines. Bioorganic & Medicinal Chemistry, 16(11), 6242–6251. http://dx.doi.org/10.1016/j.bmc.2008.04.030
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Selective 5-HT2A agonist hallucinogens: A review of pharmacological interaction and corollary perceptual effects

May 23, 2008 / DMT, LSD, Mushrooms / Psilocybin, Neuroscience, Other subjects, Papers, Psychology, Psychopharmacology, Publications / By /

Abstract

The most potent tryptamine hallucinogens – such as DMT, psilocybin, and LSD – are all active at the 5-HT2A receptor subtype and all produce similar visual perceptual results that are immediately recognizable as uniquely psychedelic. Although it is widely accepted that selective serotonin receptor subtype 2A agonism is directly responsible for producing the distinct hallucinations seen on a psychedelic trip, no single theory has yet explained why this is so. Utilizing what we know about psychedelic tryptamine receptor interaction, sensory processing circuits in the neocortex, and EEG scans of psychedelics in action, this review will propose a novel multi-state theory of psychedelic action which invokes a variety of neural processing mechanisms, including phase-coupled neural oscillators; network excitation, disinhibition, and destabilization; recurrent feedback excitation; and neural circuit spike synchrony and brainwave cohesion to close the knowledge gap between the pharmaceutical interactions of selective 5-HT2A hallucinogens, their direct effects on perception and consciousness at varying dose ranges, and their potential long-term adverse effects.

Kent, J. (2008). Selective 5-HT2A agonist hallucinogens: A review of pharmacological interaction and corollary perceptual effects. Beta Review.

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Effects of varied doses of psilocybin on time interval reproduction in human subjects

April 11, 2008 / Mushrooms / Psilocybin, Other disciplines, Other subjects, Papers, Phenomenology, Psychology, Publications / By / , , ,

Abstract

Action of a hallucinogenic substance, psilocybin, on internal time representation was investigated in two double-blind, placebo-controlled studies: Experiment 1 with 12 subjects and graded doses, and Experiment 2 with 9 subjects and a very low dose. The task consisted in repeated reproductions of time intervals in the range from 1.5 to 5 s. The effects were assessed by parameter κκ of the ‘dual klepsydra’ model of internal time representation, fitted to individual response data and intra-individually normalized with respect to initial values. The estimates View the MathML sourceκˆ were in the same order of magnitude as in earlier studies. In both experiments, κκ was significantly increased by psilocybin at 90 min from the drug intake, indicating a higher loss rate of the internal duration representation. These findings are tentatively linked to qualitative alterations of subjective time in altered states of consciousness.

Wackermann, J., Wittmann, M., Hasler, F., & Vollenweider, F. X. (2008). Effects of varied doses of psilocybin on time interval reproduction in human subjects. Neuroscience letters, 435(1), 51-55. https://dx.doi.org/10.1016/j.neulet.2008.02.006
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The behavioral pharmacology of hallucinogens

January 1, 2008 / Cacti / Mescaline, Chemistry, DMT, LSD, MDMA, Mushrooms / Psilocybin, Other subjects, Papers, Psychopharmacology, Publications / By / , ,

Abstract

Until very recently, comparatively few scientists were studying hallucinogenic drugs. Nevertheless, selective antagonists are available for relevant serotonergic receptors, the majority of which have now been cloned, allowing for reasonably thorough pharmacological investigation. Animal models sensitive to the behavioral effects of the hallucinogens have been established and exploited. Sophisticated genetic techniques have enabled the development of mutant mice, which have proven useful in the study of hallucinogens. The capacity to study post-receptor signaling events has lead to the proposal of a plausible mechanism of action for these compounds. The tools currently available to study the hallucinogens are thus more plentiful and scientifically advanced than were those accessible to earlier researchers studying the opioids, benzodiazepines, cholinergics, or other centrally active compounds. The behavioral pharmacology of phenethylamine, tryptamine, and ergoline hallucinogens are described in this review, paying particular attention to important structure activity relationships which have emerged, receptors involved in their various actions, effects on conditioned and unconditioned behaviors, and in some cases, human psychopharmacology. As clinical interest in the therapeutic potential of these compounds is once again beginning to emerge, it is important to recognize the wealth of data derived from controlled preclinical studies on these compounds.

Fantegrossi, W. E.,  Murnane, K. S., & Reissig, C. J. (2008). The behavioral pharmacology of hallucinogens. Biochemical Pharmacology 75(1), 17–33. http://dx.doi.org/10.1016/j.bcp.2007.07.018
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