OPEN Foundation

Medicine

A possibly sigma-1 receptor mediated role of dimethyltryptamine in tissue protection, regeneration, and immunity

April 26, 2013 / DMT, Medicine, Other subjects, Papers, Publications / By / , , , ,

Abstract

N,N-dimethyltryptamine (DMT) is classified as a naturally occurring serotonergic hallucinogen of plant origin. It has also been found in animal tissues and regarded as an endogenous trace amine transmitter. The vast majority of research on DMT has targeted its psychotropic/psychedelic properties with less focus on its effects beyond the nervous system. The recent discovery that DMT is an endogenous ligand of the sigma-1 receptor may shed light on yet undiscovered physiological mechanisms of DMT activity and reveal some of its putative biological functions. A three-step active uptake process of DMT from peripheral sources to neurons underscores a presumed physiological significance of this endogenous hallucinogen. In this paper, we overview the literature on the effects of sigma-1 receptor ligands on cellular bioenergetics, the role of serotonin, and serotoninergic analogues in immunoregulation and the data regarding gene expression of the DMT synthesizing enzyme indolethylamine-N-methyltransferase in carcinogenesis. We conclude that the function of DMT may extend central nervous activity and involve a more universal role in cellular protective mechanisms. Suggestions are offered for future directions of indole alkaloid research in the general medical field. We provide converging evidence that while DMT is a substance which produces powerful psychedelic experiences, it is better understood not as a hallucinogenic drug of abuse, but rather an agent of significant adaptive mechanisms that can also serve as a promising tool in the development of future medical therapies.

Frecska, E., Szabo, A., Winkelman, M. J., Luna, L. E., & McKenna, D. J. (2013). A possibly sigma-1 receptor mediated role of dimethyltryptamine in tissue protection, regeneration, and immunity. Journal of Neural Transmission, 120(9), 1295-1303. http://dx.doi.org/10.1007/s00702-013-1024-y
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β-Carboline Compounds, Including Harmine, Inhibit DYRK1A and Tau Phosphorylation at Multiple Alzheimer's Disease-Related Sites

May 6, 2011 / Ayahuasca, Medicine, Other subjects, Other substances, Papers, Publications / By / , , , , , ,

Abstract

Harmine, a β-carboline alkaloid, is a high affinity inhibitor of the dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) protein. The DYRK1A gene is located within the Down Syndrome Critical Region (DSCR) on chromosome 21. We and others have implicated DYRK1A in the phosphorylation of tau protein on multiple sites associated with tau pathology in Down Syndrome and in Alzheimer’s disease (AD). Pharmacological inhibition of this kinase may provide an opportunity to intervene therapeutically to alter the onset or progression of tau pathology in AD. Here we test the ability of harmine, and numerous additional β-carboline compounds, to inhibit the DYRK1A dependent phosphorylation of tau protein on serine 396, serine 262/serine 356 (12E8 epitope), and threonine 231 in cell culture assays and in vitro phosphorylation assays. Results demonstrate that the β-carboline compounds (1) potently reduce the expression of all three phosphorylated forms of tau protein, and (2) inhibit the DYRK1A catalyzed direct phosphorylation of tau protein on serine 396. By assaying several β-carboline compounds, we define certain chemical groups that modulate the affinity of this class of compounds for inhibition of tau phosphorylation.

Frost, D., Meechoovet, B., Wang, T., Gately, S., Giorgetti, M., Shcherbakova, I., & Dunckley, T. (2011). β-carboline compounds, including harmine, inhibit DYRK1A and tau phosphorylation at multiple Alzheimer’s disease-related sites. PLoS One, 6(5). https://dx.doi.org/10.1371/journal.pone.0019264

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Composition, Standardization and Chemical Profiling of Banisteriopsis caapi, a Plant for the Treatment of Neurodegenerative Disorders Relevant to Parkinson’s Disease

April 21, 2010 / Ayahuasca, Chemistry, Ethnobotany, Medicine, Other subjects, Papers, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Ethnopharmacological relevance

Banisteriopsis caapi, a woody vine from the Amazonian basin, is popularly known as an ingredient of a sacred drink ayahuasca, widely used throughout the Amazon as a medicinal tea for healing and spiritual exploration. The usefulness of Banisteriopsis caapi has been established for alleviating symptoms of neurological disorders including Parkinson’s disease.

Aim of the study

Primary objective of this study was to develop the process for preparing standardized extracts of Banisteriopsis caapi to achieve high potency for inhibition of human monoamine oxidases (MAO) and antioxidant properties. The aqueous extracts prepared from different parts of the plant collected from different geographical locations and seasons were analyzed by HPLC for principal bioactive markers. The extracts were simultaneously tested in vitro for inhibition of human MAOs and antioxidant activity for analysis of correlation between phytochemical composition of the extracts and bioactivities.

Materials and methods

Reversed-phase HPLC with photodiode array detection was employed to profile the alkaloidal and non-alkaloidal components of the aqueous extract of Banisteriopsis caapi. The Banisteriopsis caapi extracts and standardized compositions were tested in vitro for inhibition of recombinant preparations of human MAO-A and MAO-B. In vitro cell-based assays were employed for evaluation of antioxidant property and mammalian cell cytotoxicity of these preparations.

Results

Among the different aerial parts, leaves, stems/large branches and stem bark of Banisteriopsis caapi, HPLC analysis revealed that most of the dominant chemical and bioactive markers (1, 2, 5, 7–9) were present in high concentrations in dried bark of large branch. A library of HPLC chromatograms has also been generated as a tool for fingerprinting and authentication of the studied Banisteriopsis caapi species. The correlation between potency of MAO inhibition and antioxidant activity with the content of the main active constituents of the aqueous Banisteriopsis caapi extracts and standardized compositions was established. Phytochemical analysis of regular/commercial Banisteriopsis caapi dried stems, obtained from different sources, showed a similar qualitative HPLC profile, but relatively low content of dominant markers 1, 2, 7, and 9, which led to decreased MAO inhibitory and antioxidant potency compared to Banisteriopsis caapi Da Vine.

Conclusion

The ethnopharmacological use of bark of matured stem/large branch of Banisteriopsis caapi as well as whole matured stem is supported by the results obtained in this investigation. Among various constituents of Banisteriopsis caapi, harmine (7), harmaline (6) and tetrahydroharmine (5) are responsible for MAO-A inhibition, while two major proanthocyanidines, epicatechin (8) and procyanidine B2 (9) produce antioxidant effects. The compounds 1–9 can serve as reliable markers for identification and standardization of Banisteriopsis caapi aerial parts, collected in different seasons and/or from different geographical regions.

Wang, Y. H., Samoylenko, V., Tekwani, B. L., Khan, I. A., Miller, L. S., Chaurasiya, N. D., … & Muhammad, I. (2010). Composition, standardization and chemical profiling of Banisteriopsis caapi, a plant for the treatment of neurodegenerative disorders relevant to Parkinson’s disease. Journal of ethnopharmacology, 128(3), 662-671. http://dx.doi.org/10.1016/j.jep.2010.02.013
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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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Banisteriopsis caapi, a unique combination of MAO inhibitory and antioxidative constituents for the activities relevant to neurodegenerative disorders and Parkinson's disease

October 30, 2009 / Ayahuasca, Ethnobotany, Medicine, Other subjects, Papers, Publications / By / , , , , , ,

Abstract

Aim of the study: Parkinson’s disease is a neurological disorder mostly effecting the elder population of the world. Currently there is no definitive treatment or cure for this disease. Therefore, in this study the composition and constituents of the aqueous extract of B. caapi for monoamine oxidases (MAO) inhibitory and antioxidant activities were assessed, which are relevant to the prevention of neurological disorders, including Parkinsonism.

Materials and methods: The aqueous extract of B. caapi stems was standardized and then fractionated using reversed-phase (RP) chromatography. Pure compounds were isolated either by reversed-phase (RP) chromatography or centrifugal preparative TLC, using a Chromatotron®. Structure elucidation was carried out by 1D and 2D NMR, Mass, IR and Circular Dichroism spectroscopy and chemical derivatization. Chemical profiling of the extract was carried out with RP-HPLC. The inhibitory activity of MAO-A, MAO-B, acetylcholinesterase, butyrylcholinesterase and catechol-O-methyl transferase enzymes, as well as antioxidant and cytotoxic activities of both B. caapi extract and isolated compounds were evaluated.

Results: An examination of the aqueous extracts of B. caapi cultivar Da Vine yielded two new alkaloidal glycosides, named banistenoside A (1) and banistenoside B (2), containing “azepino[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-a]tetrahydro-β-carboline” unique carbon framework. One additional new natural tetrahydronorharmine (4), four known β-carbolines harmol (3), tetrahydroharmine (5), harmaline (6) and harmine (7), two known proanthocyanidines (−)-epicatechin (8) and (−)-procyanidin B2 (9), and a new disaccharide β-D-fructofuranosyl-(2→5)-fructopyranose (14) together with known sacharose (15) and β-D-glucose (16) were also isolated. In addition, the acetates of 1, 2, 8, 9, 14 and 15 (compounds 10–13, 17, 18) were also prepared. Harmaline (6) and harmine (7) showed potent in vitro inhibitory activity against recombinant human brain monoamine oxidase (MAO) -A and -B enzymes (IC50 2.5 and 2.0 nM, and 25 and 20 µM, respectively), and (−)-epicatechin (8) and (−)-procyanidin B2 (9) showed potent antioxidant and moderate MAO-B inhibitory activities (IC50 <0.13 and 0.57 µg/mL, and 65 and 35 µM). HPLC analysis revealed that most of the dominant chemical and bioactive markers (1, 2, 5, 7–9) were present in high concentrations in dried bark of large branch. Analysis of regular/commercial B. caapi dried stems showed a similar qualitative HPLC pattern, but relatively low content of dominant markers 1, 2, 7, and 9, which led to decreased MAO inhibitory and antioxidant potency.

Conclusion: Collectively, these results give additional basis to the existing claim of B. caapi stem extract for the treatment of Parkinsonism, including other neurodegenerative disorders.

Samoylenko, V., Rahman, M. M., Tekwani, B. L., Tripathi, L. M., Wang, Y. H., Khan, S. I., … & Muhammad, I. (2010). Banisteriopsis caapi, a unique combination of MAO inhibitory and antioxidative constituents for the activities relevant to neurodegenerative disorders and Parkinson’s disease. Journal of ethnopharmacology, 127(2), 357-367. http://dx.doi.org/10.1016%2Fj.jep.2009.10.030

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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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Unauthorized Research on Cluster Headache

December 3, 2008 / Cacti / Mescaline, Cluster headache, LSD, Medicine, Mushrooms / Psilocybin, Papers, Publications / By /

Perhaps the greatest triumph of unauthorized research on visionary plants and drugs to date is the discovery that small doses of LSD, psilocybin, and LSA (lysergic acid amide) are more effective than any conventional medication in treating the dismal disorder, cluster headache. Five years ago, no one other than cluster headache patients or neurologists had ever heard of cluster headache. Now, treatment of cluster headache is routinely listed among potential therapeutic uses for psychedelics, and has even penetrated popular culture to the point that the character Gregory House, M.D. has used a psychedelic drug to treat headache on the TV show House not once, but twice (Kaplow 2006; Dick 2007)!

The first mention of therapeutic effect from a psychedelic on headache comes from Drs. D. Webster Prentiss and Francis P. Morgan, professors of medicine and pharmacology at Columbian University (now George Washington University), who began to conduct animal and human experiments with peyote in 1894 in order to determine whether or not it had any valuable medicinal properties. Two years later, their report concluded: “The conditions in which it seems probable that the use of mescal buttons will produce beneficial results are the following: In general ‘nervousness,’ nervous headache, nervous irritative cough… [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”][etc.].” In their account are a number of cases, including #5: “The same gentleman reports that his wife formerly used to take the tincture [anhalonium 1] for nervous headaches and that it always relieved her. She has them so seldom now that she does not use it” (Prentiss & Morgan 1896).

Sewell, R. A. (2008). Unauthorized Research on Cluster Headache. The Entheogen Review, 16(4), 117-125.
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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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Response of cluster headache to psilocybin and LSD

June 27, 2006 / Cluster headache, LSD, Medicine, Mushrooms / Psilocybin, Papers, Publications / By / , ,

Abstract

The authors interviewed 53 cluster headache patients who had used psilocybin or lysergic acid diethylamide (LSD) to treat their condition. Twenty-two of 26 psilocybin users reported that psilocybin aborted attacks; 25 of 48 psilocybin users and 7 of 8 LSD users reported cluster period termination; 18 of 19 psilocybin users and 4 of 5 LSD users reported remission period extension. Research on the effects of psilocybin and LSD on cluster headache may be warranted.

Sewell, R. A., Halpern, J. H., & Pope, Jr., H. G. (2006). Response of cluster headache to psilocybin and LSD. Neurology, 66(12), 1920–1922. http://dx.doi.org/10.1212/01.wnl.0000219761.05466.43
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Hallucinogens

January 28, 2004 / Addiction, History, LSD, Medicine, Neuroscience, Other subjects, Other substances, Papers, Psychiatry, Psychopharmacology, Psychosis, Publications, Safety / By /

Abstract

Hallucinogens (psychedelics) are psychoactive substances that powerfully alter perception, mood, and a host of cognitive processes. They are considered physiologically safe and do not produce dependence or addiction. Their origin predates written history, and they were employed by early cultures in a variety of sociocultural and ritual contexts. In the 1950s, after the virtually contemporaneous discovery of both serotonin (5-HT) and lysergic acid diethylamide (LSD-25), early brain research focused intensely on the possibility that LSD or other hallucinogens had a serotonergic basis of action and reinforced the idea that 5-HT was an important neurotransmitter in brain. These ideas were eventually proven, and today it is believed that hallucinogens stimulate 5-HT2A receptors, especially those expressed on neocortical pyramidal cells. Activation of 5-HT2A receptors also leads to increased cortical glutamate levels presumably by a presynaptic receptor-mediated release from thalamic afferents. These findings have led to comparisons of the effects of classical hallucinogens with certain aspects of acute psychosis and to a focus on thalamocortical interactions as key to understanding both the action of these substances and the neuroanatomical sites involved in altered states of consciousness (ASC). In vivo brain imaging in humans using [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”][18F]fluorodeoxyglucose has shown that hallucinogens increase prefrontal cortical metabolism, and correlations have been developed between activity in specific brain areas and psychological elements of the ASC produced by hallucinogens. The 5-HT2A receptor clearly plays an essential role in cognitive processing, including working memory, and ligands for this receptor may be extremely useful tools for future cognitive neuroscience research. In addition, it appears entirely possible that utility may still emerge for the use of hallucinogens in treating alcoholism, substance abuse, and certain psychiatric disorders.

Nichols, D. E. (2004). Hallucinogens. Pharmacology & therapeutics, 101(2), 131-181. https://dx.doi.org/10.1016/j.pharmthera.2003.11.002

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30 April - Q&A with Rick Strassman

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