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Psychopharmacology

Psychedelics and the Human Receptorome

February 2, 2010 / Cacti / Mescaline, Chemistry, DMT, MDMA, Mushrooms / Psilocybin, Other subjects, Other substances, Papers, Psychopharmacology, Publications / By /

Abstract

We currently understand the mental effects of psychedelics to be caused by agonism or partial agonism of 5-HT2A (and possibly 5-HT2C) receptors, and we understand that psychedelic drugs, especially phenylalkylamines, are fairly selective for these two receptors. This manuscript is a reference work on the receptor affinity pharmacology of psychedelic drugs. New data is presented on the affinity of twenty-five psychedelic drugs at fifty-one receptors, transporters, and ion channels, assayed by the National Institute of Mental Health – Psychoactive Drug Screening Program (NIMH-PDSP). In addition, comparable data gathered from the literature on ten additional drugs is also presented (mostly assayed by the NIMH-PDSP). A new method is introduced for normalizing affinity (Ki) data that factors out potency so that the multi-receptor affinity profiles of different drugs can be directly compared and contrasted. The method is then used to compare the thirty-five drugs in graphical and tabular form. It is shown that psychedelic drugs, especially phenylalkylamines, are not as selective as generally believed, interacting with forty-two of forty-nine broadly assayed sites. The thirty-five drugs of the study have very diverse patterns of interaction with different classes of receptors, emphasizing eighteen different receptors. This diversity of receptor interaction may underlie the qualitative diversity of these drugs. It should be possible to use this diverse set of drugs as probes into the roles played by the various receptor systems in the human mind.

Ray, T. S. (2010). Psychedelics and the Human Receptorome. PLoS ONE, 5(2). http://dx.doi.org/10.1371/journal.pone.0009019
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LSD but not lisuride disrupts prepulse inhibition in rats by activating the 5-HT2A receptor

November 25, 2009 / LSD, Other subjects, Papers, Psychopharmacology, Publications / By / ,

Abstract

Rationale: Compounds that activate the 5-HT2A receptor, such as lysergic acid diethylamide (LSD), act as hallucinogens in humans. One notable exception is the LSD congener lisuride, which does not have hallucinogenic effects in humans even though it is a potent 5-HT2A agonist. LSD and other hallucinogens have been shown to disrupt prepulse inhibition (PPI), an operational measure of sensorimotor gating, by activating 5-HT2A receptors in rats.

Objective: We tested whether lisuride disrupts PPI in male Sprague–Dawley rats. Experiments were also conducted to identify the mechanism(s) responsible for the effect of lisuride on PPI and to compare the effects of lisuride to those of LSD.

Results: Confirming a previous report, LSD (0.05, 0.1, and 0.2 mg/kg, s.c.) reduced PPI, and the effect of LSD was blocked by pretreatment with the selective 5-HT2A antagonist MDL 11,939. Administration of lisuride (0.0375, 0.075, and 0.15 mg/kg, s.c.) also reduced PPI. However, the PPI disruption induced by lisuride (0.075 mg/kg) was not blocked by pretreatment with MDL 11,939 or the selective 5-HT1A antagonist WAY-100635 but was prevented by pretreatment with the selective dopamine D2/D3 receptor antagonist raclopride (0.1 mg/kg, s.c).

Conclusions: The effect of LSD on PPI is mediated by the 5-HT2A receptor, whereas activation of the 5-HT2A receptor does not appear to contribute to the effect of lisuride on PPI. These findings demonstrate that lisuride and LSD disrupt PPI via distinct receptor mechanisms and provide additional support for the classification of lisuride as a non-hallucinogenic 5-HT2A agonist.

Halberstadt, A. L, & Geyer, M. A. (2010). LSD but not lisuride disrupts prepulse inhibition in rats by activating the 5-HT2A receptor. Psychopharmacology, 208(2), 179–189. http://dx.doi.org/10.1007/s00213-009-1718-x
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The Neurochemical Effects of Harmine in Animal Models of Depression

April 26, 2009 / Ayahuasca, Depression, Other substances, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By /

Abstract

Harmine is a β-carboline that acts on the CNS, by inhibiting the enzyme monoamine oxidase type A-MAO. This alkaloid binds with affinity to receptors on serotonin as 5-hydroxytryptamine, 5-HT2C subtypes and 5-HT2A receptors and imidazole (I2). The objective of this study was to investigate the physiological and behavioral effects of acute and chronic administration of harmine (5, 10 and 15 mg / kg) and imipramine (10, 20 and 30 mg / kg) using the forced swimming test (TNF) and the protocol of chronic mild stress (ECM) in an animal model. The results showed that rats treated acutely and chronically with harmine and imipramine reduced the immobility time in the TNF, and increased both climbigns and swimming time of rats compared to saline group, without affecting locomotor activity in the open field test. Both acute and chronic administration of harmine increased factor brain-derived neurotrophic (BDNF) protein levels in the rat hippocampus. Our findings demonstrated that chronic stressful situations induced anhedonia, hypertrophy of adrenal gland weight, increase ACTH circulating levels in rats and increase BDNF protein levels. Interestingly, treatment with harmine for 7 consecutive days, reversed anhedonia, the increase of adrenal gland weight, normalized ACTH circulating levels and BDNF protein levels. Finally, these findings further support the hypothesis that harmine could be a new pharmacological tool for the treatment of depression.

Fortunato, J. J. 2009. The Neurochemical Effects of Harmine in Animal Models of Depression. PhD thesis.
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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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How could MDMA (ecstasy) help anxiety disorders? A neurobiological rationale

March 9, 2009 / Anxiety disorders / PTSD, MDMA, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications / By / ,

Abstract

Exposure therapy is known to be an effective treatment for anxiety disorders. Nevertheless, exposure is not used as much as it should be, and instead patients are often given supportive medications such as serotonin reuptake inhibitors (SSRIs) and benzodiazepines, which may even interfere with the extinction learning that is the aim of treatment. Given that randomized controlled trials are now investigating a few doses of ±3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) in combination with psychotherapy for treatment-resistant anxiety disorders, we would like to suggest the following three mechanisms for this potentially important new approach: 1) MDMA increases oxytocin levels, which may strengthen the therapeutic alliance; 2) MDMA increases ventromedial prefrontal activity and decreases amygdala activity, which may improve emotional regulation and decrease avoidance and 3) MDMA increases norepinephrine release and circulating cortisol levels, which may facilitate emotional engagement and enhance extinction of learned fear associations. Thus, MDMA has a combination of pharmacological effects that, in a therapeutic setting, could provide a balance of activating emotions while feeling safe and in control, as described in case reports of MDMA-augmented psychotherapy. Further clinical and preclinical studies of the therapeutic value of MDMA are indicated.

Johansen, P. Ø., & Krebs, T. S. (2009). How could MDMA (ecstasy) help anxiety disorders? A neurobiological rationale. Journal of Psychopharmacology, 23(4), 389-391. http://dx.doi.org/10.1177/0269881109102787
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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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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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Serotonin-Related Psychedelic Drugs

November 5, 2008 / Cacti / Mescaline, LSD, Mushrooms / Psilocybin, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications / By / , ,

Abstract

Serotonergic hallucinogens include the prototypical compounds such as mescaline, psilocybin, and LSD, representing the chemical classes of phenethylamines, tryptamines, and ergolines. Known as psychedelics, these compounds induce dramatic alterations of perception, affect, consciousness, and the experience of self. As first discovered in animal studies and recently confirmed in humans, the psychological effects of psychedelics are primarily attributable to the activation of the 5-HT2A subtype of serotonin receptors in brain. Research on psychedelic compounds has provided important insights into the neurobiology of consciousness and naturally occurring psychotic states and may lead to further advances in the development of psychiatric pharmacotherapeutics.

Geyer, M. A., Nichols, D. E., & Vollenweider, F. X. (2009). Serotonin-related psychedelic drugs. 10.1016/B978-008045046-9.01160-8
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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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7 May - Psychedelics, Nature & Mental Health with Sam Gandy

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