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The non-hallucinogen 2-bromo-lysergic acid diethylamide as preventative treatment for cluster headache: An open, non-randomized case series

March 26, 2010 / Chemistry, Cluster headache, LSD, Medicine, Neuroscience, Other substances, Papers, Publications / By / , , ,

Introduction

Cluster headache (CH) is a stereotyped primary headache characterized by strictly unilateral severe orbital or periorbital pain and categorized as either episodic or chronic (1,2). Its prevalence is 0.1% (3). Oxygen and sumatriptan are the treatments of choice for individual attacks, whereas verapamil, lithium, corticosteroids and other neuromodulators can suppress attacks during cluster periods (1). All standard medication treatments may be ineffective. Surgical treatment may be an option for medication non-responders, including deep brain (4) or occipital nerve stimulation (5). However, serious complications from brain surgery, including death, can occur (6).

An Internet survey of 53 CH patients reported on claims that psilocybin is better at aborting acute attacks than either oxygen or sumatriptan and that LSD and psilocybin are both better at triggering and extending remission than standard drugs (7). However, due to hallucinogenicity and the absence of established medical indication, these drugs are criminalized and placed within the most restrictive Schedule I of the Controlled Substances Act, which sanctions only limited research use. Although the hallucinogenic properties of LSD and psilocybin are undesirable from both regulatory and patient safety perspectives, it was unclear to us at the outset whether a non-hallucinogenic analog could also provide meaningful relief to CH patients. To address the question of whether the CH relief associated with these two structurally diverse compounds is related to the mechanisms triggering intoxication, we decided to investigate the efficacy of a non-hallucinogenic analog of LSD. LSD’s hallucinogenic effects are completely lost when the double bond in the D ring is saturated and with substitution at R2 (e.g. by bromination in 2-bromo-LSD) (BOL-148) (8). BOL-148 has been studied in volunteers (up to 20 mg per os) (9) and in patients suffering from vascular headaches but not, apparently, in patients with CH (9,10). These past studies [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”][…]

Karst, M., Halpern, J. H., Bernateck, M., & Passie, T. (2010). The non-hallucinogen 2-bromo-lysergic acid diethylamide as preventative treatment for cluster headache: An open, non-randomized case series. Cephalalgia, 30(9), 1140-1144. https://dx.doi.org/10.1177/0333102410363490
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The persistence of the subjective in neuropsychopharmacology: observations of contemporary hallucinogen research

February 26, 2010 / Ayahuasca, Cacti / Mescaline, DMT, Iboga / Ibogaine, Ketamine, LSD, MDMA, Mushrooms / Psilocybin, Neuroscience, Other disciplines, Other subjects, Other substances, Papers, Psychology, Psychopharmacology, Publications, Salvia / Salvinorin A / By /

Abstract

The elimination of subjectivity through brain research and the replacement of so-called ‘folk psychology’ by a neuroscientifically enlightened worldview and self-conception has been both hoped for and feared. But this cultural revolution is still pending. Based on nine months of fieldwork on the revival of hallucinogen research since the ‘Decade of the Brain,’ this paper examines how subjective experience appears as epistemic object and practical problem in a psychopharmacological laboratory. In the quest for neural correlates of (drug-induced altered states of) consciousness, introspective accounts of test subjects play a crucial role in neuroimaging studies. Firsthand knowledge of the drugs’ flamboyant effects provides researchers with a personal knowledge not communicated in scientific publications, but key to the conduct of their experiments. In many cases, the ‘psychedelic experience’ draws scientists into the field and continues to inspire their self-image and way of life. By exploring these domains the paper points to a persistence of the subjective in contemporary neuropsychopharmacology.

Langlitz, N. (2010). The persistence of the subjective in neuropsychopharmacology: observations of contemporary hallucinogen research. History of Human Sciences, 23(1), 37-57. http://dx.doi.org/10.1177/0952695109352413
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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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Cannabis and Ecstasy/MDMA: Empirical Measures of Creativity in Recreational Users

December 25, 2009 / Creativity, MDMA, Other substances, Papers, Psychology, Publications / By / , ,

Abstract

This study investigated the associations between chronic cannabis and Ecstasy/MDMA use and one objective and two subjective measure of creativity. Fifteen abstinent Ecstasy users, 15 abstinent cannabis users, and 15 nondnig-user controls, completed three measures of creativity: the Consequences behavioral test of creativity, self-assessed performance on the Consequences test, and Gough’s Trait Self-Report Creative Adjective Checklist. The Consequences test involved five scenarios where possible consequences had to be devised; scoring was conducted by the standard blind rating (by two independent judges) for “remoteness” and “rarity,” and by a frequency and rarity of responses method. Cannabis users had significantly more “rare-creative” responses than controls (Tukey, p < 0.05); this effect remained significant with gender as a covariate. There were no significant differences between the groups on the number of standard scoring “remote-creative” ideas or for fluency of responses. On self-rated creativity, there was a significant ANOVA group difference (p < 0.05), with Ecstasy users tending to rate their answers as more creative than controls (Tukey comparison; p = 0.058, two-tailed). Ecstasy users did not differ from controls on the behavioral measures of creativity, although there was a borderline trend for self-assessment of greater creativity. Cannabis users produced significantly more “rare-creative” responses, but did not rate themselves as more creative.

Jones, K. A., Blagrove, M., & Parrott, A. C. Cannabis and Ecstasy/MDMA: Empirical Measures of Creativity in Recreational Users. Journal of Psychoactive Drugs, 41(4), 323-329. http://dx.doi.org/10.1080/02791072.2009.10399769
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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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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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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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Human hallucinogen research: guidelines for safety

July 1, 2008 / Ayahuasca, Cacti / Mescaline, DMT, Iboga / Ibogaine, Ketamine, LSD, MDMA, Medicine, Mushrooms / Psilocybin, Neuroscience, Other substances, Papers, Psychiatry, Psychology, Psychopharmacology, Publications, Safety, Salvia / Salvinorin A / By / , ,

Abstract

There has recently been a renewal of human research with classical hallucinogens (psychedelics). This paper first briefly discusses the unique history of human hallucinogen research, and then reviews the risks of hallucinogen administration and safeguards for minimizing these risks. Although hallucinogens are relatively safe physiologically and are not considered drugs of dependence, their administration involves unique psychological risks. The most likely risk is overwhelming distress during drug action (‘bad trip’), which could lead to potentially dangerous behaviour such as leaving the study site. Less common are prolonged psychoses triggered by hallucinogens. Safeguards against these risks include the exclusion of volunteers with personal or family history of psychotic disorders or other severe psychiatric disorders, establishing trust and rapport between session monitors and volunteer before the session, careful volunteer preparation, a safe physical session environment and interpersonal support from at least two study monitors during the session. Investigators should probe for the relatively rare hallucinogen persisting perception disorder in follow-up contact. Persisting adverse reactions are rare when research is conducted along these guidelines. Incautious research may jeopardize participant safety and future research. However, carefully conducted research may inform the treatment of psychiatric disorders, and may lead to advances in basic science.

Johnson, M. W., Richards, W. A., & Griffiths, R. R. (2008). Human hallucinogen research: guidelines for safety.  Journal of Psychopharmacology, 22(6), 603–620. http://dx.doi.org/10.1177/0269881108093587
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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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30 April - Q&A with Rick Strassman

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