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Banisteriopsis caapi, a Forgotten Potential Therapy for Parkinson’s Disease?

Abstract

Banisteriopsis caapi, a liana indigenous to the Amazon basin with metagnomigenic properties and possible anti-depressant effects is one of the natural sources of harmala alkaloids. A summary of early trials with extracts of Banisteriopsis caapi and Peganum harmala (from which harmine was first isolated) in the 1920s and 1930s on various forms of parkinsonism is given as well as a brief overview of the known pharmacological properties of harmine. Despite its earlier abandonment because of perceived weaker efficacy than solanaceous alkaloids like scopolamine and hyoscine we propose that harmine should be reconsidered as a potential rapidly acting anti-Parkinsonian agent.

Djamshidian, A., Bernschneider‐Reif, S., Poewe, W., & Lees, A. J. (2015). Banisteriopsis caapi, a Forgotten Potential Therapy for Parkinson’s Disease?. Movement Disorders Clinical Practice. http://dx.doi.org/10.1002/mdc3.12242
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Banisteriopsis caapi, a Forgotten Potential Therapy for Parkinson's Disease?

Abstract

Banisteriopsis caapi, a liana indigenous to the Amazon basin with metagnomigenic properties and possible anti-depressant effects is one of the natural sources of harmala alkaloids. A summary of early trials with extracts of Banisteriopsis caapi and Peganum harmala (from which harmine was first isolated) in the 1920s and 1930s on various forms of parkinsonism is given as well as a brief overview of the known pharmacological properties of harmine. Despite its earlier abandonment because of perceived weaker efficacy than solanaceous alkaloids like scopolamine and hyoscine we propose that harmine should be reconsidered as a potential rapidly acting anti-Parkinsonian agent.

Djamshidian, A., Bernschneider‐Reif, S., Poewe, W., & Lees, A. J. (2015). Banisteriopsis caapi, a Forgotten Potential Therapy for Parkinson’s Disease?. Movement Disorders Clinical Practice. http://dx.doi.org/10.1002/mdc3.12242
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Kappa Opioids, Salvinorin A and Major Depressive Disorder

Abstract

Opioids are traditionally associated with pain, analgesia and drug abuse. It is now clear, however, that the opioids are central players in mood. The implications for mood disorders, particularly clinical depression, suggest a paradigm shift from the monoamine neurotransmitters to the opioids either alone or in interaction with monoamine neurons. We have a special interest in dynorphin, the last of the major endogenous opioids to be isolated and identified. Dynorphin is derived from the Greek word for power, dynamis, which hints at the expectation that the neuropeptide held for its discoverers. Yet, dynorphin and its opioid receptor subtype, kappa, has always taken a backseat to the endogenous b – endorphin and the exogenous morphine that both bind the mu opioid receptor subtype. That may be changing as the dynorphin/ kappa system has been shown to have different, often opposite, neurophysiological and behavioral influences. This includes major depressive disorder (MDD). Here, we have undertaken a review of dynorphin/ kappa neurobiology as related to behaviors, especially MDD. Highlights include the unique features of dynorphin and kappa receptors and the special relation of a plant- based agonist of the kappa receptor salvinorin A. In addition to acting as a kappa opioid agonist, we conclude that salvinorin A has a complex pharmacologic profile , with potential additional mechanisms of action. Its unique neurophysiological effects make Salvinorina A an ideal candidate for MDD treatment research.

T Taylor and Francesca Manzella, G. Kappa Opioids, Salvinorin A and Major Depressive Disorder. Current Neuropharmacology, 13. http://dx.doi.org/10.2174/1570159X13666150727220944
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Current Status of Ketamine and Related Therapies for Mood and Anxiety Disorders

Abstract

Major depressive disorder (MDD) is a leading cause of disability worldwide. Despite a plethora of established treatments, less than one third of individuals with MDD achieve stable remission of symptoms. Given limited efficacy and significant lag time to onset of therapeutic action among conventional antidepressants, interest has shifted to treatments that act outside of the monoamine neurotransmitter systems (e.g., serotonin, norepinephrine, and dopamine). Preclinical and clinical research on the glutamate system has been particularly promising in this regard. Accumulating evidence shows support for a rapid antidepressant effect of ketamine—a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist. The present article reviews the pharmacology, safety, and efficacy of ketamine as a novel therapeutic agent for mood and anxiety disorders. The majority of clinical trials using ketamine have been conducted in patients with treatment-resistant forms of MDD; recent work has begun to examine ketamine in bipolar disorder, post-traumatic stress disorder, and obsessive–compulsive disorder. The impact of ketamine on suicidal ideation is also discussed. The current status and prospects for the identification of human biomarkers of ketamine treatment response and hurdles to treatment development are considered. We conclude by considering modulators of the glutamate system other than ketamine currently in development as potential novel treatment strategies for mood and anxiety disorders.

Costi, S., Van Dam, N. T., & Murrough, J. W. (2015). Current Status of Ketamine and Related Therapies for Mood and Anxiety Disorders. Current Behavioral Neuroscience Reports, 1-10. https://dx.doi.org/10.1007/s40473-015-0052-3
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Acute Biphasic Effects of Ayahuasca

Abstract

Ritual use of ayahuasca, an amazonian Amerindian medicine turned sacrament in syncretic religions in Brazil, is rapidly growing around the world. Because of this internationalization, a comprehensive understanding of the pharmacological mechanisms of action of the brew and the neural correlates of the modified states of consciousness it induces is important. Employing a combination of electroencephalogram (EEG) recordings and quantification of ayahuasca’s compounds and their metabolites in the systemic circulation we found ayahuasca to induce a biphasic effect in the brain. This effect was composed of reduced power in the alpha band (8–13 Hz) after 50 minutes from ingestion of the brew and increased slow- and fast-gamma power (30–50 and 50–100 Hz, respectively) between 75 and 125 minutes. Alpha power reductions were mostly located at left parieto-occipital cortex, slow-gamma power increase was observed at left centro-parieto-occipital, left fronto-temporal and right frontal cortices while fast-gamma increases were significant at left centro-parieto-occipital, left fronto-temporal, right frontal and right parieto-occipital cortices. These effects were significantly associated with circulating levels of ayahuasca’s chemical compounds, mostly N,N-dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine and some of their metabolites. An interpretation based on a cognitive and emotional framework relevant to the ritual use of ayahuasca, as well as it’s potential therapeutic effects is offered.

Schenberg E.E., Alexandre J.F.M., Filev R., Cravo A.M., Sato J.R., Muthukumaraswamy S.D., et al. (2015) Acute Biphasic Effects of Ayahuasca. PLoS ONE 10(9): e0137202. http://dx.doi.org/10.1371/journal.pone.0137202
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Breaking Convention 2015: Looking back (and forward)

BC_report_2Psychedelic researchers gathered from all over the world to present their findings at the third biannual Breaking Convention conference (BC). The conference took place at Greenwich College in London between 10 and 12 July and hosted 140 presenters from about 40 countries as well as performers, artists and musicians. Over 800 people attended the event, which included renowned presenters such as professors David E. Nichols, David J. Nutt and Roland Griffiths, along with a great variety of academics from different disciplines.

According to Dr. Ben Sessa, one of the conference’s organisers, the conference was a success: “We have had a lot of great feedback. BC is a very ‘home grown’ affair, with almost a third of delegates participating in one way or another. People feel a great deal of personal ownership over the conference, which means the atmosphere is great and a lot of important networking gets done.” Sessa was one of the co-founders of BC in 2011, and explains how the conference has built momentum since then: “We set up BC as a platform to showcase psychedelic research and culture. The conference has grown tremendously and we hope it will continue to expand and inspire young people and seasoned enthusiasts to propagate this important subject.”

One of the participants was Michael Kugel, an undergraduate medical science student from Sydney, Australia. He travelled 17.000 kilometres to meet world leading researchers in current medical cannabis and psychedelic research. He thinks his trip was worthwhile and shows that Sessa´s hopes are not in vain. “I’ve met a lot of great people here”, says Kugel. “I met Allan Badiner, author of Zig Zag Zen, who introduced me to MAPS founder Rick Doblin, who in turn told me about a psychiatrist who is trying to get approval in Australia to study MDMA for PTSD in war veterans. At lunch I bumped into Lumír Hanuš, who was part of the team that discovered anandamide [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”][an endogenous cannabinoid, ed.], and who currently works with Raphael Mechoulam. I offered him my (limited) lab skills – we’ll see where that leads. I´m feeling really good about it all so far.”

For Tehseen Noorani, a researcher who has participated in a psilocybin studie at Johns Hopkins along with Roland Griffiths and Matthew Johnson, coming to BC was a no-brainer: “I do research on psychedelics and these conferences are rare. They are also big, so it totally makes sense to come and present work and find out what else is going on. When you´re in this space, you realise how much is going on – there are so many small pockets of activity all over the world.

Noorani thinks it’s important to undertake efforts to further convince funders that psychedelics are a topic worthy of research. “For me there are a lot of sciences,” he said. “I work with pharmacologists and the steps forward for clinical trials seem to be pretty straightforward. As there´s a growing acceptance of the impressive outcomes of strictly scientific research, what we really need now is money.” He also underlined the importance of taking social scientific research around psychedelics more seriously: “My background is in anthropology, and I would say anthropological work needs to be taken more seriously. Firstly, research needs to connect the important anthropological and political questions of today. Secondly, ethnographic research needs to be recognised as serious research by so-called harder sciences, and by the public, because to be interested in psychedelics is to be interested in pretty profound stuff.”

Levente Móró, a consciousness researcher from Finland currently based in Hungary, also found what he came looking for: “Along with the interlaced biennial conference by the OPEN Foundation, BC is the most important European meeting of the international psychedelic science field. I wanted to get updated about the status of current research, to meet old and new fellow researchers, and to put forward my own ideas and receive feedback. The conference provided abundant amounts of knowledge, from all the various fields related to psychedelics. It is nice to receive fresh input and viewpoints, also from outside my own fields of study. Moreover, it has been extremely nice to meet more people from Finland, as a result of the recently organised psychedelic science activism.” A group of academics in Finland, who aim to promote practical research and evidence-based information on psychedelics, organized their first small psychedelic seminar last April, with presentations from Teri Krebs, Murtaza Majeed and Helle Kaasik, among others.

Móró’s own presentation at BC was based on a bioethical analysis of the 1961 Single Convention on Narcotic Drugs he produced with his colleague Imre Bárd, who wasn’t present. He focused on representations of ‘evil’ and demonstrated how the UN drug laws used a language of religious immorality to justify drug prohibition. His presentation, although based on a convention that was signed over half a century ago, found resonance in current legislative practices. One of the hot topics mentioned during many of the BC presentations was the new Psychoactive Substances Bill (2015), proposed by the British government just weeks before the conference. The new bill would increase the regulation of most psychoactive substances (not including alcohol and tobacco) and further complicate psychedelic research. An open letter was published on the conference website, addressed to the British Prime Minister, in which the undersigned urge for the content of the Bill to be reconsidered. It was signed by over 40 professionals, including academics, former and current members of Parliament and police officials.

This more politically active role of psychedelic researchers was welcomed by Levente Móró: “It was nice to see that psychedelic researchers have been getting involved more and more with drug policy reform issues.” Despite the possible tightening of regulatory practices in the UK, Ben Sessa seemed optimistic about the future of psychedelic research. “Psychedelic research requires a major Public Relations drive. Most researchers believe that psychedelic drugs are useful, safe and efficacious tools for medicine, growth and development. But sadly, for the majority of the general public, high levels of stigma and misinformation remain attached to these fascinating substances. This means we need to detach ourselves, to some extent, from the “hippie” genre and demonstrate that ‘normal’, everyday people can use psychedelics safely and with personal and communal benefits. One way of doing this is to increase the exposure of psychedelic medicine to people everywhere through the media. This is partly why I wrote my novel ‘To Fathom Hell Or Soar Angelic’, which was launched at BC15. In the meantime, my clinical colleagues and I continue to carry out robust scientific studies to determine the safety and efficacy of psychedelic therapy.”

One way to relieve the stigma could be for researchers to openly discuss their own experiences. But could this harm their credibility as scientists? Noorani: “As a researcher I would say there´s a real dilemma around admitting to having (not) taken psychedelics in terms of how it legitimises or delegitimises the research you do.” Móró believes that scientific credibility should not rest on the researcher´s person: “Researchers might get insights from their own experiences, or become more motivated to investigate phenomena they find personally fascinating and meaningful. Besides, scientific credibility should not depend on a researcher’s personal background. It should be objectively assessable and independent of the researcher’s non-scientific traits or parameters.”

While Sessa openly discussed his own experiences, he also recognises how legal restrictions might affect the extent to which professionals publicly speak about their use of psychedelics: “I am fortunate to have participated in a number of legal psychedelic research studies in the last 6 years, so I can say, on the record, that I have taken ketamine, LSD and psilocybin in those studies.” Sessa supports the idea that ‘coming out’ about safe and beneficial experiences could be a good way to forward the emancipation of these substances: “This method worked well for driving the normalisation of homosexuality in recent decades. However, I also understand professionals – especially doctors – who feel reluctant to do this. The possession of illegal drugs is still penalised in most countries.”

Next year, the special session of the UN General Assembly Special Session on Drugs (UNGASS) will, among other things, give directions for the future of psychedelic research, and the outcomes will probably be extensively presented, discussed and debated at the next BC in 2017.

This report is based on on-site recorded interviews and post-conference email interviews.

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Ketamine for depression: evidence, challenges and promise

Abstract

Major depressive disorder and bipolar depression are among the most prevalent and disabling mental disorders worldwide. Real-world effectiveness trials in major depressive disorder have underscored that most pharmacological options target monoamines, which are involved in a minority (15-20%) of synaptic contacts in the mammalian brain.

Most synapses (∼50%) use the amino acid glutamate as their primary neurotransmitter, and preclinical models of depression have implicated aberrant glutamatergic neurotransmission for 25 years. More recently, the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine was shown to produce rapid and robust antidepressant effects in patients with treatment-resistant major depressive disorder and bipolar depression.

Zarate, C. A., & Niciu, M. J. (2015). Ketamine for depression: evidence, challenges and promise. World Psychiatry, 14(3), 348-350. http://dx.doi.org/10.1002/wps.20269
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The Prosocial Effects of 3,4-methylenedioxymethamphetamine (MDMA): Controlled Studies in Humans and Laboratory Animals

Abstract

Users of ±3,4-Methylenedioxymethamphetamine (MDMA; ‘ecstasy’) report prosocial effects such as sociability and empathy. Supporting these apparently unique social effects, data from controlled laboratory studies indicate that MDMA alters social feelings, information processing, and behavior in humans, and social behavior in rodents. Here, we review this growing body of evidence. In rodents, MDMA increases passive prosocial behavior (adjacent lying) and social reward while decreasing aggression, effects that may involve serotonin 1A receptor mediated oxytocin release interacting with vasopressin receptor 1A. In humans, MDMA increases plasma oxytocin and produces feelings of social affiliation. It decreases identification of negative facial expressions (cognitive empathy) and blunts responses to social rejection, while enhancing responses to others’ positive emotions (emotional empathy) and increasing social approach. Thus, consistent with drug folklore, laboratory administration of MDMA robustly alters social processing in humans and increases social approach in humans and animals. Effects are consistent with increased sociability, with mixed evidence about enhanced empathy. These neurobiologically-complex prosocial effects likely motivate recreational ecstasy use.

Kamilar-Britt, P., & Bedi, G. (2015). The Prosocial Effects of 3, 4-methylenedioxymethamphetamine (MDMA): Controlled Studies in Humans and Laboratory Animals. Neuroscience & Biobehavioral Reviews. http://dx.doi.org/10.1016/j.neubiorev.2015.08.016
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[Psychedelics and quasi-psychedelics in the light of contemporary research: medical cannabis, MDMA, salvinorin A, ibogaine and ayahuasca]

Abstract

In lack of professional research and appropriate concepts our scientific knowledge of psychedelic agents is limited. According to the long-held official view these drugs are entirely harmful and have no medical use. However, a recent surge of clinical and pharmacological studies in the field indicates that many psychedelic-like agents have therapeutic potentials under proper circumstances. In this paper, from a biomedical and psychological perspective, we provide a brief review of the general effects and promising treatment uses of medical cannabis, 3,4-methylenedioxy-methamphetamine (MDMA), salvinorin A, ibogaine and the dimethyltryptamine-(DMT)-containing ayahuasca. In Hungary – similarly to many other countries – these compounds are classified as “narcotic drugs” and their research is difficult due to strict regulations.

Szabo, A., Kazai, A., Frecska, E., & Brys, Z. (2015). [Psychedelics and quasi-psychedelics in the light of contemporary research: medical cannabis, MDMA, salvinorin A, ibogaine and ayahuasca]. Neuropsychopharmacologia Hungarica: a Magyar Pszichofarmakologiai Egyesulet lapja= official journal of the Hungarian Association of Psychopharmacology, 17(3), 120-128.
Link to full text [Article in Hungarian]

3,4-Methylenedioxymethamphetamine facilitates fear extinction learning

Abstract

Acutely administered 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) has been proposed to have long-term positive effects on post-traumatic stress disorder (PTSD) symptoms when combined with psychotherapy. No preclinical data support a mechanistic basis for these claims. Given the persistent nature of psychotherapeutic gains facilitated by MDMA, we hypothesized that MDMA improves fear extinction learning, a key process in exposure-based therapies for PTSD. In these experiments, mice were first exposed to cued fear conditioning and treated with drug vehicle or MDMA before extinction training 2 days later. MDMA was administered systemically and also directly targeted to brain structures known to contribute to extinction. In addition to behavioral measures of extinction, changes in mRNA levels of brain-derived neurotrophic factor (Bdnf) and Fos were measured after MDMA treatment and extinction. MDMA (7.8mgkg−1) persistently and robustly enhanced long-term extinction when administered before extinction training. MDMA increased the expression of Fos in the amygdala and medial prefrontal cortex (mPFC), whereas increases in Bdnf expression were observed only in the amygdala after extinction training. Extinction enhancements were recapitulated when MDMA (1μg) was infused directly into the basolateral complex of the amygdala (BLA), and enhancement was abolished when BDNF signaling was inhibited before extinction. These findings suggest that MDMA enhances fear memory extinction through a BDNF-dependent mechanism, and that MDMA may be a useful adjunct to exposure-based therapies for PTSD and other anxiety disorders characterized by altered fear learning.

Young, M. B., Andero, R., Ressler, K. J., & Howell, L. L. (2015). 3, 4-Methylenedioxymethamphetamine facilitates fear extinction learning. Translational Psychiatry, 5(9), e634. http://dx.doi.org/10.1038/tp.2015.138

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