OPEN Foundation

OPEN Foundation

Biosynthesis, total synthesis, and biological profiles of Ergot alkaloids

Abstract

While the use of ergot alkaloids in folk medicine has been practiced for millennia, systematic investigations on their therapeutic potential began about 100 years ago. Subsequently, Albert Hofmann’s discovery of lysergic acid diethylamide (LSD) and its intense psychedelic properties garnered worldwide attention and prompted further studies of this compound class. As a result, several natural ergot alkaloids were discovered and unnatural analogs were synthesized, and some were used to treat an array of maladies, including Alzheimer’s and Parkinson’s disease. While LSD was never commercially approved, recent clinical studies have found it can be an innovative and effective treatment option for several psychiatric disorders. Ongoing biosynthetic and total synthetic investigations aim to understand the natural origins of ergot alkaloids, help develop facile means to produce these natural products and enable their continued use as medicinal chemistry lead structures. This review recounts major developments over the past 20 years in biosynthetic, total synthetic, and pharmaceutical studies. Many ergot alkaloid biosynthetic pathways have been elucidated, with some of them subsequently applied toward “green” syntheses. New chemical methodologies have fostered a fast and efficient access to the ergoline scaffold, prompting some groups to investigate biological properties of natural product-like ergot alkaloids. Limited pharmaceutical applications have yet to completely bypass the undesirable side effects of ergotism, suggesting further studies of this drug class are likely needed and will potentially harness major therapeutic significance.

Tasker, N. R., & Wipf, P. (2021). Biosynthesis, total synthesis, and biological profiles of Ergot alkaloids. The Alkaloids. Chemistry and biology, 85, 1–112. https://doi.org/10.1016/bs.alkal.2020.08.001

Link to full text

N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo

Abstract

N,N-dimethyltryptamine (DMT) is a component of the ayahuasca brew traditionally used for ritual and therapeutic purposes across several South American countries. Here, we have examined, in vitro and vivo, the potential neurogenic effect of DMT. Our results demonstrate that DMT administration activates the main adult neurogenic niche, the subgranular zone of the dentate gyrus of the hippocampus, promoting newly generated neurons in the granular zone. Moreover, these mice performed better, compared to control non-treated animals, in memory tests, which suggest a functional relevance for the DMT-induced new production of neurons in the hippocampus. Interestingly, the neurogenic effect of DMT appears to involve signaling via sigma-1 receptor (S1R) activation since S1R antagonist blocked the neurogenic effect. Taken together, our results demonstrate that DMT treatment activates the subgranular neurogenic niche regulating the proliferation of neural stem cells, the migration of neuroblasts, and promoting the generation of new neurons in the hippocampus, therefore enhancing adult neurogenesis and improving spatial learning and memory tasks.

Morales-Garcia, J. A., Calleja-Conde, J., Lopez-Moreno, J. A., Alonso-Gil, S., Sanz-SanCristobal, M., Riba, J., & Perez-Castillo, A. (2020). N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo. Translational psychiatry, 10(1), 331. https://doi.org/10.1038/s41398-020-01011-0

Link to full text

Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study

Abstract

Background: Psilocybin therapy has shown promise as a rapid-acting treatment for depression, anxiety, and demoralization in patients with serious medical illness (e.g., cancer) when paired with individual psychotherapy. This study assessed the safety and feasibility of psilocybin-assisted group therapy for demoralization in older long-term AIDS survivor (OLTAS) men, a population with a high degree of demoralization and traumatic loss.

Methods: Self-identified gay men OLTAS with moderate-to-severe demoralization (Demoralization Scale-II ≥8) were recruited from the community of a major US city for a single-site open-label study of psilocybin-assisted group therapy comprising 8-10 group therapy visits and one psilocybin administration visit (0·3-0·36 mg/kg po). Primary outcomes were rate and severity of adverse events, and participant recruitment and retention. The primary clinical outcome was change in mean demoralization from baseline to end-of-treatment and to 3-month follow-up assessed with a two-way repeated measures ANOVA. Trial registration: Clinicaltrials.gov (NCT02950467).

Findings: From 17 July 2017 to 16 January 2019, 18 participants (mean age 59·2 years (SD 4·4)) were enrolled, administered group therapy and psilocybin, and included in intent-to-treat analyses. We detected zero serious adverse reactions and two unexpected adverse reactions to psilocybin; seven participants experienced self-limited, severe expected adverse reactions. We detected a clinically meaningful change in demoralization from baseline to 3-month follow-up (mean difference -5·78 [SD 6·01], ηp 2 = 0·47, 90% CI 0·21-0·60).

Interpretation: We demonstrated the feasibility, relative safety, and potential efficacy of psilocybin-assisted group therapy for demoralization in OLTAS. Groups may be an effective and efficient means of delivering psychotherapy pre- and post-psilocybin to patients with complex medical and psychiatric needs.

Anderson, B. T., Danforth, A., Daroff, P. R., Stauffer, C., Ekman, E., Agin-Liebes, G., Trope, A., Boden, M. T., Dilley, P. J., Mitchell, J., & Woolley, J. (2020). Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study. EClinicalMedicine, 27, 100538. https://doi.org/10.1016/j.eclinm.2020.100538

Link to full text

Treating drug addiction with psychedelics looks promising

Although controversial only a few years ago, there is ample evidence that psychedelics can help in the fight against addictions (use disorders). Over the past decades, there have been multiple studies looking into the workings of psychedelics in the field of addiction. Multiple trials have concluded that there are indeed possibilities to develop psychedelic-assisted treatments towards treating multiple drug addictions. Below we list just a few promising areas which include LSD for alcoholism, psilocybin for smoking cessation and alcoholism, and ibogaine for opioid addiction.
Back at ICPR2012, researchers from Norway presented a meta-analysis of randomized controlled trials using lysergic acid diethylamide (LSD) for alcoholism. Researchers Krebs and Johansen had found six trials done in the 1960s and 1970s that included a total of 536 participants. The researchers concluded that “A single dose of LSD, in the context of various alcoholism treatment programs, is associated with a decrease in alcohol misuse.” The results of the meta-analysis were published in the Journal of Psychopharmacology that same year and made it to mainstream media.
Contemporary addiction research has focused on using two compounds in particular: psilocybin and ibogaine. LSD is less researched, perhaps because of stigma or the long active duration of the psychedelic effects of LSD. Ketamine and MDMA are also researched and covered in this year’s online conference. Preliminary studies suggest that these compounds may help with the treatment of drug-related disorders. However, it is still not completely clear how their mechanism of action results in the observed outcomes.
At Johns Hopkins School of Medicine, Professor Matthew Johnson conducted a study with psilocybin and tobacco smokers. Twelve of the 15 participants managed to quit tobacco smoking, and importantly: maintained their decision to quit. Although it was a small sample group, a success rate of 80% was enough to warrant studies with larger groups.

Image
Johnson, who is currently the President-Elect of the International Society for Research on Psychedelics, will give a talk at our Psychedelics in Psychiatry and Psychotherapy Symposium on the working mechanisms of psychedelics used in clinical research.

What could be the mechanism of action that helps people kick their addiction when treated with psychedelics? I an interview we did with Prof. Johnson in 2015 he stated that: “evidence suggests that there are psychological mechanisms of action at play. For example, people endorse that after the psilocybin sessions, it was easier for them to make decisions that were in their long-term best interest, and they were less likely to make decisions based on short-term, hedonistic desires.” They also seemed to feel more in control of decisions about their behavior, and Johnson says “they also reported an increase in their self-efficacy, their confidence in their ability to remain quit.”
Another area where psilocybin seems promising is in treating alcoholism. Addiction researcher Michael Bogenschutz at New York University has been interested in alcohol-related treatments and is now conducting studies using psilocybin: “I’m interested in addiction in general but for me alcohol, which is a very common, devastating addiction throughout the world, was a logical place to start. As I learned when I started investigating the topic, a considerable amount of research on the use of psychedelic treatment (mainly LSD) and alcohol had already been conducted in the late 1950s.”

Elizabeth M. Nielson, PhD, CASAC - Psychedelic.Support
At ICPR2020 Dr. Elisabeth Nielson will present the historical context and current clinical research on Psilocybin-Assisted Treatment of Alcohol Use Disorder.
In addition, at the upcoming International Symposium on Psychedelics in Psychiatry and Psychotherapy (ISPPP) there are several presentations about clinical application for psychedelics in alcoholism, including the Bristol Imperial MDMA in Alcoholism Study (BIMA) which is an open label within-subject feasibility study in 20 patients with Alcohol Use Disorder who have recently undergone detoxification. The study is conducted by Ben Sessa, MD, one of the ICPR2020 speakers, and its principal investigator is Professor David Nutt.

A less known psychedelic compared to psilocybin and MDMA is ibogaine, which is derived from the African plant Tabernanthe iboga. Ibogaine was a hot topic at this year’s World Economic Forum which included positive reports on ibogaine’s potential role as an addiction interrupter for opioid addiction.
In the Netherlands, researchers at the Radboud University have been investigating the use of ibogaine for addiction. During ICPR2016, researchers from Radboud shared some promising pre-clinical evidence for the efficacy of ibogaine in treating addiction and shared some of the challenges of conducting psychedelic research in the Netherlands.
Currently there are several clinical research projects recruiting participants for psychedelic research in the Netherlands and Europe.
Luís Fernando Tófoli, who is a Professor of Psychiatry at the Faculty of Medical Sciences of the University of Campinas, Brazil, gave a fascinating review at ICPR2016 about brain imaging studies on psychedelics and their relation to addiction studies. Reviewed results point to effects in the medial prefrontal cortex, the anterior and posterior cingulate cortex and the precuneus. Psychedelics also seem to affect limbic structures (e.g. amygdala), insula, occipital lobe and, less frequently, thalamus and they have been associated with a deactivation of the default mode network. Psychedelics have a relatively modest impact on dopaminergic circuits associated with addiction, but they affect structures implicated in cue processing and decision-making in drug-seeking behavior.
At ICPR2020, Prof. Tófoli is returning, this time discussing the role of integration in psychedelic experiences, including in the treatment of addiction with ibogaine in biomedical clinics.

Een van de weinige Nederlandse psychiaters die werkt met psychedelica

Psychiater Tijmen Bostoen werkt als trauma-expert in Centrum ‘45, waar binnenkort een gerandomiseerd gecontroleerd onderzoek (of RCT) van start gaat met MDMA in de behandeling van PTSS. Daarnaast behandelt Bostoen sinds dit jaar patiënten die zowel een psychotrauma als een depressie hebben met ketamine, aan het LUMC. Daarmee is hij één van de weinige psychiaters in Nederland die zich bezig houden met psychedelica. We spraken hem over zijn ervaringen.

Waar is je interesse in psychedelica begonnen?

Dat begon voor mij op ICPR 2016. Tijdens het congres werd me duidelijk dat psychedelica-onderzoek interessant is en dat ik er meer van wilde weten. Het onderwerp intrigeerde me heel erg omdat de onderzoeksresultaten zo veelbelovend zijn. Wat me tijdens het congres opviel, was dat er echt goed opgezet onderzoek is gedaan met RCTs. Dat maakte voor mij duidelijk dat ik het onderwerp serieus moest nemen.
Ik had al wel eens iets gehoord over behandelingen met psychedelica, met name omdat Bastiaans daar in de jaren ’70 mee bezig is geweest. Soms had hij opvallende resultaten met LSD-behandelingen bij de ernstigst getraumatiseerde concentratiekamp-overlevers. [Bastiaans was hoogleraar psychiatrie en net als Tijmen verbonden aan Centrum ‘45 in Oegstgeest, red.]
Maar als je er dan induikt, dan blijkt dat er best al veel onderzoek gedaan is in de vorige eeuw en dat er veel al is uitgezocht. Met hele interessante resultaten. Niet echt volgens de wetenschappelijke standaarden van nu, maar toch. Dat was echt een eye-opener voor me.

Vier jaar later ben je één van de weinige psychiaters in Nederland die met deze middelen werken. Dat is best snel gegaan.

Ja, inderdaad. Toen Rick Doblin (de directeur van MAPS) in Nederland was voor ICPR’16, werd ik uitgenodigd voor een etentje. De directeur van Stichting OPEN en mijn collega Eric Vermetten waren daar ook bij aanwezig. Tijdens dat etentje is onze interesse gewekt om zelf een studie op te zetten naar MDMA, met ondersteuning van MAPS.
Toen een paar maanden later bleek dat de MDMA-assisted psychotherapy for PTSD studie in Amerika zó voorspoedig ging dat MAPS eerder dan gepland in Europa onderzoek wilde gaan doen, wisten Eric en ik meteen dat we daarbij wilden aanhaken.
Binnenkort gaat de pilot van start bij ons in Centrum ‘45. Dit is een opmaat naar de fase 3 klinische studie waarmee MAPS MDMA wil registreren als medicijn voor PTSS. Met die registratiestudie hopen we over een jaar te starten. De voorbereidingen zijn volop aan de gang.

Daarnaast werk je sinds begin dit jaar ook met ketamine, aan het LUMC. In welke context doe je dat?

Ik behandel patiënten die zowel een psychotrauma als een depressie hebben. We behandelen die patiënten volgens een depressieprotocol met ketamine. Dat zijn zes ketaminesessies in twee weken. Dat is een heel intense behandeling.
Het is voor ons ook een beetje pionieren, omdat we nog niet zo goed weten hoe ketamine nou bij PTSS werkt. We willen toewerken naar een gespecificeerde PTSS-behandeling met ketamine. Deze pilot is vooral bedoeld om ervaring op te doen met ketaminebehandelingen en om te kijken of dit depressieprotocol ook aanslaat bij patiënten die naast depressieve klachten ook last hebben van een psychotrauma / PTSS.
Het is heel mooi dat we hierin kunnen samenwerken met het LUMC en ervaring op kunnen doen met deze behandeling.

Hoe kan het dat je PTSS-patiënten al mag behandelen met ketamine, terwijl er nog geen klinisch onderzoek naar is gedaan?

Het is een off-label behandeling. Ketamine is een geregistreerd geneesmiddel, dat eerder al uitgebreid onderzocht werd en inmiddels al vele tientallen jaren gebruikt wordt door anesthesisten: we weten wat het doet en wat de bijwerkingen zijn. De laatste jaren wordt gekeken wat de effecten bij psychiatrische aandoeningen zijn en dan vooral bij depressie. Als je een medicijn off-label gebruikt dan komen er wel extra criteria bij. Je moet bijvoorbeeld heel goed overleggen met de patiënt en goed duidelijk maken dat je iets voorschrijft voor een aandoening waarvoor dat middel niet bedoeld is. Je moet uiterst zorgvuldig te werk gaan. Maar dan mag het wel, binnen de geneeskunde.

Hoe reageren patiënten, slaat de behandeling aan?

Ik vind het in ieder geval opvallend hoe goed en snel ketamine werkt op de depressieve symptomen. Of het ook specifiek effect heeft op alle PTSS-symptomen, dat moet ik nog zien. Ik kan me er wel iets bij voorstellen dat ketamine de gangbare traumabehandelingen beter werkzaam maakt. Maar ik weet het nog niet zeker, daar is het te vroeg voor. Ik wil er meer van zien en er op een gegeven moment ook klinisch onderzoek naar gaan doen.

Wat voor dosis geef je patiënten en krijgen ze daar een psychedelische ervaring van?

We gebruiken 0,5 mg s-ketamine per kilogram lichaamsgewicht. Of het echt geestverruimend is zoals je bij de klassieke psychedelica of MDMA ziet dat weet ik niet, maar het geeft zeker veranderde bewustzijnseffecten. Je ziet echt wel dat mensen heel fors onder invloed zijn en moeite hebben de intense ervaring onder woorden te brengen. Maar vaak kost het deze getraumatiseerde mensen moeite zich over te geven aan de ervaring.

Zijn die psychedelische effecten onderdeel van het werkingsmechanisme, of eerder een bijwerking?

Sommige onderzoekers zien het inderdaad eerder als een bijwerking. Zoals ketamine nu vooral wordt toegepast, is als een biologische behandeling. Dus: je geeft een geneesmiddel dat processen in het brein op gang brengt, wat maakt dat er minder klachten zijn. Maar wat ik vaak zie: als de ketamine aan het uitwerken is, gaan mensen toch reflecteren op de ketamine-ervaring zelf, en vaak hebben zij daarin elementen van hun traumageschiedenis beleefd. En mijn indruk is dat dat wel belangrijk is, in ieder geval bij PTSS.

MDMA behaalt indrukwekkende resultaten in de MAPS-studies – er is zelfs een breakthrough therapy status aan gegeven door de FDA. Wat maakt ketamine dan nog interessant voor jou als behandelaar en onderzoeker?

Ketamine wordt vooral bij depressie ingezet en zorgt ook bij heel hardnekkige vormen van depressie voor opvallende resultaten. Dat is echt heel bijzonder. MDMA is eigenlijk nog niet bij depressie ingezet maar vooral bij PTSS. Dus dat is een beetje appels met peren vergelijken in die zin.
Ik wil heel graag weten of de ketamine-behandeling langduriger werkt voor depressie als je de setting verandert en meer gaat werken vanuit het kader waarin MDMA wordt gegeven. Want dat is bij ketamine het geval: het verlicht de symptomen heel goed, maar dat effect is na een aantal weken vaak weer uitwerkt. Misschien dat je dat wel kan veranderen als je veel meer doet aan de set en setting en de psychotherapeutische follow-up. Momenteel is er beperkt onderzoek naar de effecten van ketamine op PTSS. Daar ben ik heel benieuwd naar: heeft ketamine vergelijkbare resultaten bij PTSS zoals we bij depressie zien? En wat voegt een specifieke set en setting toe? Als we wat beter zicht hebben op wat bij PTSS zou kunnen werken, dan willen we dat verder onderzoeken in een goed onderzoeksontwerp.

Waarin verschillen de kaders waarin met MDMA en ketamine wordt gewerkt het meest?

De MDMA wordt op een hele andere manier gegeven: in drie sessies van acht uur met twee therapeuten. De ruimte zelf wordt mooi aangekleed, zodat mensen niet het gevoel hebben dat ze in een ziekenhuis liggen. Er wordt veel psychotherapie gegeven voor en na elke sessie. Dat is echt een totaal andere manier van werken dan wat nu met ketamine gebeurt.
Ik denk dat het best zou kunnen dat ketamine net als andere psychedelica werkt en dat de ervaring zelf heilzaam kan zijn. Dat dit nog niet zo uit de verf is gekomen, ligt misschien toch aan de dosering die gebruikt wordt en aan de setting. Nu krijgen patiënten de ketamine echt in een ziekenhuissetting: ze liggen aan een infuus in een ziekenhuiskamer. Als je het vergelijkt met de MDMA-behandelingen voor PTSS, dan is er erg weinig tijd voor voorbereiding op en integratie van de andere bewustzijnsstaat. Ik denk dat als je ketamine op dezelfde manier zou inzetten als psilocybine of MDMA, dat het best zou kunnen dat je ongeveer dezelfde veelbelovende effecten ziet: een grote en blijvende afname in symptomen. Maar dat moet nog blijken.

Waarin verschilt het effect van ketamine met dat van MDMA, zoals je dat in patiënten waarneemt?

Met ketamine zijn mensen veel minder in staat om hun gedachten te ordenen en in gesprek te gaan. Dat maakt ketamine echt anders dan MDMA. De effecten treden ook veel sneller op en werken veel sneller weer uit. Bij MDMA zie je het effect langzaam opkomen en patiënten zijn juist heel goed in staat om hun gevoelens te beleven, te duiden en erover te vertellen – vaak beter dan in de normale bewustzijnsstaat. Bij MDMA gebeurt dat al tijdens de sessie zelf.

Ben je ooit bang geweest dat de stap naar psychedelisch onderzoek negatieve consequenties zou hebben voor je carrière?

Dat valt wel mee. De meeste collega’s en peers zijn echt geïnteresseerd. Mensen stellen soms wel gezond kritische vragen en dat is logisch. Maar ik heb niet het idee dat het een soort taboe is of dat het meteen van tafel geveegd wordt ofzo.
Toen ik zag dat er echt methodologisch goede studies zijn gedaan, heeft dat mij over de streep getrokken. Maar ik blijf ook kritisch. Ik ben redelijk onder de indruk van de psychedelica. Maar een wetenschappelijke houding, goed meten van de effecten en mogelijkheden goed in kaart brengen is voor mij de enige manier om goed met dit onderwerp om te gaan.

Welke uitdagingen kom je tegen als psychedelica-onderzoeker?

Het is heel lastig om aan te geven wat psychedelica nou precies doen. Dat onderzoek is ingewikkeld. We weten wel veel, maar wat nou precies de werkende elementen zijn… dat is nog steeds lastig te zeggen. Psychedelica doen veel op het niveau van neurotransmitters en hormonen en met fMRI kan je processen in het brein in kaart brengen die door psychedelica beïnvloed worden. Maar psychedelica geven ook hele krachtige subjectieve effecten. En het lijkt soms wel of dat twee parallelle werelden zijn. Want dat van die subjectieve effecten, dat zou meer passen binnen een psychotherapeutisch kader: je werkrelatie verdiept, er is meer ruimte voor reflectie en voor catharsis. Dat is heel psychotherapeutisch beschreven. Maar tegelijkertijd hebben psychedelica ook echt een heel krachtige biologische werking… en dan zit je weer in dat straatje van hoe we met medicijnen omgaan. Je licht iemand voor, je geeft een bepaalde dosis van een middel en vervolgens laat je dat middel als het ware zelf z’n werk doen.

Zoals dus nu bij ketamine gebeurt.

In het geval van ketamine zie je die parallelle werelden heel duidelijk. Het wordt heel biologisch benaderd door een aantal mensen. Er zijn ook mensen die zeggen dat je het juist psychotherapeutisch moet kaderen. Vervolgens moet je het ook hebben over wat nou de werkzame elementen zijn: of je bijvoorbeeld optimaal moet doseren op basis van een bepaalde bloedspiegel die bepaalde neurotransmitters in gang zet. Of dat je juist een subjectieve psychologische staat beoogt waarin je kan werken. Wie weet zijn die twee werelden ook wel nauw met elkaar verbonden… dat zijn echt dingen die uitgezocht moeten worden.
Dan heb je ook nog verschillende aandoeningen. We hadden het net al over PTSS en depressie. Daar is zeker overlap, maar het zijn wel echt andere stoornissen. En er zijn ook ideeën over de toepasbaarheid van psychedelica bij andere aandoeningen. Denk aan OCD, verslaving, persoonlijkheidsstoornissen… Er is zich echt een heel nieuw onderzoeksveld aan het openen. Heel interessant. Ik ben echt heel benieuwd waar we over tien jaar staan.

Om aan het MAPS MDMA-onderzoek mee te mogen werken, moest je eerst een speciale training ondergaan. Welke extra vaardigheden heb je daar geleerd?

Er werd sterk gehamerd op een hele open therapeutische houding, waarin je vooral het proces ondersteunt waar iemand zelf, onder invloed van MDMA, inkomt. Je doet zeker interventies, maar die zijn allemaal in dienst van het proces waar de patiënt in komt. Je werkt samen met de patiënt met wat er dan ook maar naar boven komt tijdens de sessie. In de gangbare traumatherapie ben je juist heel vaak erg sturend, in de zin van dat echt over de trauma’s zelf moet gaan en over de gevoelens die daar omheen hangen. Dat is echt een heel andere houding.
Pas je die open therapeutische houding ook toe als je patiënten met ketamine behandelt?
Ketaminebehandelingen zijn veel korter dan MDMA-sessies, waardoor ik dan toch geneigd ben om iets meer te sturen. En van wat ik tot nu toe bij ketamine zie, hebben mensen meer hulp nodig om te begrijpen wat er op dat moment gebeurt. Bij MDMA hebben mensen vaak een heel goed overzicht, maar bij ketamine zijn mensen meer los van wat ze normaal kennen. De ketamine-ervaring is meer vervreemdend, in die zin. Mensen hebben dan toch iets meer structuur van buiten nodig om daar mee om te gaan.

Als onderdeel van de MAPS-training tot MDMA-therapeut, onderging je zelf ook een MDMA-sessie – in een zelfde soort setting als je toekomstige patiënten.

Ja. Ik denk dat het echt van meerwaarde is dat als je met psychedelica werkt, je zelf ook weet wat die middelen met je doen. Want die veranderde bewustzijnsstaat is zo enorm uitgesproken, dat het wel heel moeilijk voor te stellen is hoe dat voor iemand is, als je het niet zelf hebt meegemaakt. Als iemand wil begeleiden in zo’n bewustzijnsstaat helpt het echt dat je een idee hebt wat iemand op dat moment doormaakt.
Voordat ik meedeed aan de MAPS-training had ik er eerlijk gezegd wel m’n twijfels bij. Ik dacht dat ik wel ongeveer zou weten hoe de ervaring met MDMA zou zijn. Maar nu ik het eenmaal zelf heb meegemaakt en de intensiteit en de diepgang van zo’n proces heb ervaren denk ik: dit is echt met niets te vergelijken. En dat is niet alleen mijn ervaring. Ik heb het ook aan anderen gevraagd die in dezelfde context een eigen ervaring opdeden met MDMA en bijna iedereen vindt het zelf ondergaan van een MDMA-sessie een meerwaarde.

Dus je pleit ervoor dat alle behandelaren die met deze middelen (gaan) werken in ieder geval een keer zelf ervaren wat het inhoudt?

ls het in het kader is van een psychedelics-assisted psychotherapy, dan wel. Als je met een patiënt in gesprek wil over zijn ervaringen, en zeker als je dit gesprek voert terwijl de patiënt onder invloed is, dan vind ik zéker dat eigen ervaring met deze middelen er toe doet. Als je psychedelica voorschrijft vanuit een meer biologisch kader (zoals bij ketamine) dan weet ik niet of het echt zoveel meerwaarde heeft.

What is the future of legal MDMA?

There has been a renaissance in the research of psychedelics, and much of it has been led by promising studies over the past two or three decades. Aside from the discussion of whether MDMA is a true ‘psychedelic’, it is clear that recent studies have created momentum to reconsider these substances as medication for severe mental health problems such as depression, anxiety or addiction.
MDMA’s application to trauma therapy has become one of the central priorities of psychedelic researchers. So what is the current state of knowledge and where do we stand in the regulatory process? According to MAPS-founder Rick Doblin, MDMA will be legal soon if the hard work continues. “I keep saying it’s going to be 2035”.
MDMA Treatment
Victims of war or sexual assault are prone to develop anxiety and avoidance behaviors as a result of these tragic experiences. Some of them may be diagnosed with Post-Traumatic Stress Disorder (PTSD), a condition characterized by severe feelings of fear and distress in response to trauma-related details. The increasing prevalence of PTSD is aggravated by the lack of treatment options.
Current trauma-focused psychotherapies, such as exposure and cognitive-behavioral therapy, have important problems of access for certain high-risk populations, as well as high dropout rates. In regard to efficacy, some reviews have found that up to 70% of patients retain their PTSD diagnosis after treatment.
The only two pharmaceuticals with FDA approval also seem to be inefficient for many. One third of all PTSD patients are estimated to be treatment-resistant. This diagnosis is given when several different treatments fail to improve symptoms.

MDMA trials have focused on this specific population because of strategic reasons. It is easier to get permission to test a new drug on patients for whom everything else has failed. Psilocybin trials have taken a similar approach by focusing on treatment-resistant depression or anxiety related to the end of life.
Current clinical research employs a hybrid treatment model that combines the administration of 75 to 125mg of MDMA with therapeutic support provided in preparation and integration sessions. During the drug sessions, therapists monitor the patient and adopt a non-directive approach that allows the person under the effects of MDMA to dive into the experience with minimal interruptions. This model of psychedelic-assisted psychotherapy entails a groundbreaking paradigm in psychiatry that goes beyond mere medications and talk therapy.
A long path
It has taken a while before these modern trials were set up. MDMA is an amphetamine derivative first synthesized by Merck Laboratories in 1912 and later rediscovered by chemist Sasha Shulgin in the 1970s. At the time, psycholytic therapy was being developed with LSD and psychiatrists saw a new potential tool for psychotherapy in MDMA and its empathogenic properties.
Unfortunately, the increasing popularity of “Ecstasy” in recreational contexts and the ensuing anti-drug propaganda soon led to the classification of MDMA as a Schedule 1 substance in 1986, which introduced immense obstacles to scientists investigating its medicinal application.
Ever since, the Multidisciplinary Association for Psychedelic Studies has been working for the approval of MDMA as a therapeutic treatment in mental health and to remove the immense barriers that were thrown up for the potential medication.
Although preliminary investigations by Charles Grob had successfully proved the safety of administration of MDMA to healthy subjects in the 1990s, the first MAPS-sponsored trial for PTSD conducted in Spain by José Carlos Bouso was shut down because of political pressure from the Spanish authorities.
Placebo challenges
So far, six phase-2 clinical trials have been completed, and despite the small samples and the methodological limitations, the results are very promising. The first randomized controlled trials with PTSD patients began to take place in the late 2000s, and resulted in a landmark paper from 2011 by Michael Mithoefer, Mark Wagner, Ann Mithoefer, Lisa Jerome, and Rick Doblin. It concluded that ‘the rate of clinical response was 10/12 (83%) in the active treatment group versus 2/8 (25%) in the placebo group’.
One year later, most of these patients for whom all other treatments had failed still showed a persistent and significant improvement. More importantly, the lack of serious adverse effects pointed at the safety of MDMA in a clinical context and paved the way for more trials.

Skeptics pointed at the methodological weaknesses of this first trial. They criticized the use of lactose as placebo and the difficulties to blind the effects of MDMA to patients and investigators, a common problem in psychedelic therapy trials. An attempt of replication in Switzerland by Peter Oehen which circumvented the blinding problem with an active placebo group (25mg MDMA) showed good results, but were not statistically significant.
Researchers suspected that differences in the work and style of the Swiss therapists might have been behind these suboptimal results, which raised the question of how to standardize the psychotherapeutic part of the treatment. In subsequent trials, MAPS developed an adherence rating system in order to ensure that therapists stick to the standard guidelines of their therapeutic model.
In 2018, Michael Mithoefer published the first dose-response study, which compared the efficacy of three different doses of MDMA: 30mg, 75mg and 125mg. The groups with middle and high doses showed significant remission of PTSD with respectively 86% and 58% of each group’s sample not meeting the diagnostic criteria anymore after treatment, improvements which persisted in the one year follow-up. Shortly after, a similar study by Marcela Ot’alora replicated the results with 76% of patients not meeting the diagnostic criteria for PTSD one year after the treatment.
A Path Towards Regulation
Given these promising results, the FDA accelerated the approval process of MDMA with the Breakthrough Therapy designation in 2017 and allowed the early compassionate use of MDMA-assisted psychotherapy for treatment-resistant patients in 2020.
Two ongoing multi-site phase-3 trials sponsored by MAPS are currently assessing the efficacy of MDMA in around 200 participants from the US, Canada and Israel. Recently, MAPS’ interim analysis of the first phase-3 trial suggested that their results will probably reach statistical significance, and if nothing goes wrong, MDMA could be approved for the treatment of PTSD by mid-2022.
In the meantime, more phase-2 trials are starting to take place in Europe for PTSD and other conditions such as alcoholism. With the first psychedelic substance on the verge of approval, many questions remain in the air:

All these questions will require years of additional research, which needs to be done by current and future doctors, researchers and policy makers. But the direction and ambition of all this research is clear: to turn the hard facts of well-researched trials into a regulatory model, so that MDMA will be a legal future medication to help many.

Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis

Abstract

Background: Ketamine appears to have a therapeutic role in certain mental disorders, most notably depression. However, the comparative performance of different formulations of ketamine is less clear.

Objectives: This study aimed to assess the comparative efficacy and tolerability of racemic and esketamine for the treatment of unipolar and bipolar major depression.

Design: Systematic review and meta-analysis.

Data sources: We searched PubMed, MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Clinical Trials, and the Cochrane Database of Systematic Reviews for relevant studies published since database inception and December 17, 2019.

Study eligibility criteria: We considered randomized controlled trials examining racemic or esketamine for the treatment of unipolar or bipolar major depression.

Outcomes: Primary outcomes were response and remission from depression, change in depression severity, suicidality, retention in treatment, drop-outs, and drop-outs due to adverse events.

Analysis: Evidence from randomized controlled trials was synthesized as rate ratios (RRs) for treatment response, disorder remission, adverse events, and withdrawals and as standardized mean differences (SMDs) for change in symptoms, via random-effects meta-analyses.

Findings: 24 trials representing 1877 participants were pooled. Racemic ketamine relative to esketamine demonstrated greater overall response (RR = 3.01 vs. RR = 1.38) and remission rates (RR = 3.70 vs. RR = 1.47), as well as lower dropouts (RR = 0.76 vs. RR = 1.37).

Conclusions: Intravenous ketamine appears to be more efficacious than intranasal esketamine for the treatment of depression.

Bahji, A., Vazquez, G. H., & Zarate, C. A., Jr (2021). Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. Journal of affective disorders, 278, 542–555. https://doi.org/10.1016/j.jad.2020.09.071

Link to full text

DMT and near-death experiences

Being one of the most powerful psychedelics we know, it is not strange that DMT has become the subject of numerous speculations over the years. Theories linking this molecule to near-death experiences have circulated persistently among users and researchers – yet the scientific evidence just doesn’t seem to be there. 
Enzo Tagliazucchi is a neuroscientist and professor at the University of Buenos Aires. He will be speaking at ICPR 2020 about his research and the first neuroimagery study of DMT in naturalistic settings.
This is the final part of a three-part interview series with Prof. Enzo Tagliazucchi
Part one: The Science and Folklore of DMT
Part two: Psychedelics: key to consciousness
Part three: DMT and near-death experiences
Enzo, you have experience researching NDEs. How is this phenomenon approached from a scientific perspective?
NDEs are really fun to investigate because they are simultaneously a very strange phenomenon, and something that does indeed happen to people in robust and reproducible ways.
There are several things that are common features to most reported NDEs, such as the feeling of floating around, feelings of extreme bliss and transcendence, life review, and the sensation that you are about to cross a visible or invisible threshold, among others. It seems that different cultural backgrounds are not a huge factor determining the specific contents of NDEs. This is somewhat controversial, but apparently at least some of these features could be, in a certain sense, universal.
Then comes the question of why this is happening, and this has been the source of a lot of bullshit, unfortunately. Some insist that everything that happens during NDEs is the manifestation of your soul leaving your body and entering into the afterlife or other realms of existence, which is something that many people would love to believe. Researchers have tested this experimentally: for instance, they have hidden an object in a room and then have somebody experience an out-of-body experience (a defining feature of NDEs) and float around. Needless to say, they never find the object, and they don’t find it simply because they are not floating around in any meaningful interpretation of those words.
People do not even know whether some NDEs happen in the moment someone flatlines, or before or after the event. It could happen moments before you wake up: there is simply no known way of proving that NDEs take place when you are sort of dead for a moment. Even worse than that, people can report NDEs when they think they are going to die but they aren’t really at risk. For example, if you fall from a chair, you might report a flash experience that is indistinguishable from a NDE, but you weren’t even unconscious for a moment.
What are the main explanatory theories of NDEs and how would you assess Strassman’s DMT hypothesis?
Nobody knows for certain why NDEs occur. And maybe there is not simply just one answer, it could be several different factors. But as scientists like to have simple explanations, they have tried to come up with one factor underlying all the different aspects of NDEs.
Perhaps the most attractive one-factor theories are related to the potential presence of endogenous chemicals. Some came to believe that there is a kind of chemical imbalance during NDEs that can lead to the experience, and here Strassman proposed that a massive release of DMT when you are close to death is what is behind the strange phenomenology of NDEs.
As an alternative, Karl Jansen proposed that there is some ketamine-like compound in the brain that blocks NMDA receptors in a similar way to ketamine, a substance whose acute effects can lead to NDE-like phenomenology. At some point in the last couple years, I started to read Jansen and Strassman, became interested in this discussion, and eventually published a paper in which I tried to put their hypotheses to test for the first time.
Using computational semantic analysis, we compared drug reports from Erowid to the narratives of patients who had NDEs, and we confirmed that ketamine was actually way above in similarity to those experiences compared to DMT. Actually, if you think of what the DMT experience is like, it is not this solemn-going-to-the-light-in-bliss but rather a confusing but festive colourful state. People do not really report these things in NDEs at all. And if you have been in the K-hole you already know that it is probably the closest to feeling dead, whatever that means. But that is not the point… this is science and I try to be scientific about it, haha!
In the last paper I read by Strassman, he conceded that there might be some release of a ketamine-like substance when you are close to dying, but the question remains: Why does this substance lead to this strange state of consciousness? Whatever the function of this molecule, why can’t it just shut off your consciousness instead of giving rise to NDEs?
The answer given by Jansen is that a ketamine-like compound could have neuroprotective effects. If there is a massive release of glutamate, an excitatory neurotransmitter that makes neurons fire at a high rate, neurons might die because they are basically too activated, a phenomenon known as excitotoxicity. So if ketamine or a related compound blocks that process, it can extend the life of neurons and increase the likelihood of survival. It sounds reasonable that you have that kind of process built into your brain as a mechanism to cope when you are close to death.
But at this point, Strassman argued something like: OK, but why has evolution given us this very strange experience that happens when we block the glutamate receptor? Why can’t the brain just block the glutamate receptors and protect itself with no experience at all? He concluded that maybe it is not that these receptors get blocked and then you have this experience. It is something different, something like you have a soul and the moment your soul starts to leave your body, the receptors get blocked.
For me that is very difficult to swallow. I am a physicist, and I cling to a scientific worldview. At some point I think Strassman lost that worldview and I actually haven’t read much of his theories since then. I respect him nevertheless, he is a pioneer in this field of research.
So what happened in the search of an endogenous chemical behind these experiences? Again, not conclusive. My guess is that it is a combination of several factors, and that people are really misled when they believe something related to the proximity of death is behind all these experiences.
What about other non-ordinary phenomena such as mystical experiences?
Mystical-type experiences, on the other hand, you can investigate more easily, because you can induce these experiences in safe and reproducible ways. That is what the Johns Hopkins group has been showing over the last years, focusing on psilocybin as an induction agent.
Griffiths’ group repeated the famous Good Friday experiment by Panhke, but under more controlled and rigorous conditions, and they showed that you can induce these experiences with psilocybin combined with the proper set and setting in 60% of the participants. The likelihood of induction is dose-dependent, so the higher the dose the higher the chances of having this kind of experience. They also showed that if you are undergoing treatment for tobacco cessation or if you are an oncological patient with anxiety related to the end of life and you are treated with psilocybin, the likelihood that you are going to get better increases if you have a mystical-type experience. In other words, the potential therapeutic properties of the psychedelic experience are apparently tied to mystical-type experiences. I believe these findings are really interesting from a clinical perspective and, again, in contrast to NDEs this is something that you can induce reliably in a controlled setting.

Psychedelics: key to consciousness

Even if psychedelics have long been regarded as tools to explore or expand one’s consciousness, they have only been picked up by consciousness researchers rather recently. Experiments with LSD, Psilocybin or DMT are starting to offer helpful insights to scientists about the nature of consciousness, mind and brain. We asked Enzo Tagliazucchi to give us his perspective on how psychedelics can be used in consciousness research.
Enzo Tagliazucchi is a neuroscientist and a professor at the University of Buenos Aires. He will be speaking at ICPR2020 about the first electroencephalography (EEG) research project of DMT in naturalistic settings.
This is part two of a three-part interview series with Prof. Enzo Tagliazucchi
Part one: The Science and Folklore of DMT
Part two: Psychedelics: key to consciousness
Part three: DMT and near-death experiences
You came to psychedelics from consciousness research with the conviction that altered states can be used as helpful tools in the cognitive neuroscience of consciousness. What do you think psychedelics tell us about the relation between mind and brain?
Studying consciousness is difficult for many reasons, for example, how can you know that somebody is having a certain conscious experience?
Now, answering this question with human subjects is not as difficult as with animal models, because I can assume a lot of things about your behavior that I cannot assume in a monkey’s or a rat’s behavior. And this is because I am a human, like you are.
But the cognitive neuroscience of consciousness advances by doing experiments in which we have to assume that there is something like the “normal mind”, so that we can interpret the answers for participants and draw conclusions about their subjective experience. This is to say, we interpret the behavior of our research participants in experiments about consciousness by mentally putting ourselves in their shows and asking what our rational core would do in that circumstance. That is, we idealize our subjects as rational agents, adopting what Daniel Dennett calls the intentional stance.
Following this line of thought, cognitive neuroscience builds up a computational analysis of the mind in which you have to assume some standard functions like attention, language, memory, decision-making, etc. And it does a good job investigating standard human functioning, especially in situations where humans do not deviate from rational behavior.
However, if you go to Google Scholar and type “cognitive neuroscience of schizophrenia”, you are going to find very few papers on that topic, precisely because you can no longer adopt so easily the intentional stance towards these patients. It is as if they had a different kind of mind, and you just do not have a common ground anymore to apply the methodological perspective of classic cognitive neuroscience.
Here is where I think psychedelics enter. They can be useful to establish that common ground. Again, you won’t be able to do normal cognitive neuroscience experiments on somebody on a high psychedelic dose,  because whatever function you are trying to probe is not going to work the way you expect it to work. It is a bit like the case of schizophrenic patients and also that of animal models, in that we lack the proper perspective.
But the thing with psychedelics is that you can increase the dose very slowly. So you can start from a very low-level dose and then you can get a mind that is almost like yours, you can disarrange it a little bit. You have this parametric way of moving away from what is the “normal human mind”. You can see how these functions slowly become disarranged as you increase the dose, and I believe this is invaluable. Most neuroscientists haven’t yet realized this, but when they do there won’t be a coming back to the old ways of doing things.
I believe that researchers do not really realize this yet because they are really focused on studying the acute effects of psychedelics (I myself am, too), a state in which it will be very difficult to adapt the very successful program of cognitive neuroscience. But if you focus on microdosing and start climbing up from there, you could build a map of how the mind gets changed parametrically into something different. This is really the huge promise of psychedelics to understanding the healthy human mind.
Psychedelic users have been greatly influenced by Aldous Huxley’s ideas about consciousness. In the sixties, he popularized the theory of the brain as a “reducing valve” that could be opened by the use of psychedelics in order to let a greater degree of awareness or “Mind at large” enter individual consciousness. How would you assess this theory in the light of current neuroscientific knowledge?
There is something to what Huxley said. Something that psychedelics are showing us is that you cannot think of the brain as a machine that you can turn on and off. The brain is always undergoing some storm of electrical activity, a flurry of spontaneous activity. That never stops.
So if I put you in an fMRI machine and you close your eyes, I will still find strong brain activity signals within your visual cortex. Since there are a lot of things going on in the visual cortex even with your eyes closed, it seems that you should be seeing something but, as a matter of fact, you just don’t.
Why are you not conscious of this activity? What is stopping you from seeing all that spontaneous storm of activity in the brain?
A popular theory is that alpha rhythms have something to do with the inhibition of all that activity which is irrelevant to whatever task you are doing at the moment, which is very convenient. So if you ask a subject to perform certain activity you will find alpha rhythms increasing in the brain regions that are not relevant for the task at hand.
But then, one of the most robust signatures of the psychedelic state is that the alpha rhythm is blocked. Jack Cowan’s theory is that all the patterns and fractals you see under psychedelics are precisely what the spontaneous activity of your brain would look like if you could see it – which you can, under the right dose of a psychedelic compound. In fact, the visual cortex is organized following geometric patterns, so no wonder that you are seeing geometric patterns when this activity enters your stream of consciousness.
You could compare the brain with an artificial neural network. These days neural networks can do pretty sophisticated visual processing by representing images in successive layers of artificial neurons. The first thing they do is exactly the first thing the visual cortex does: extract geometric primitives, like all the edges and all the corners of the image. Starting from that, they begin to combine these primitives to build progressively more complex representations, until you get the complete image.
Visual percepts are sort of created in layers, as in artificial neural networks, but in your conscious experience you are never aware of the intermediate layers, you only get the end result. From an evolutionary perspective, you do not need the intermediate representations. They are just part of your internal computational machinery. What you really want to know is what the final object is like.
I think that when someone is under psychedelics, representations enter consciousness too early. You are getting the half-cooked images so to speak. And this is precisely because psychedelics tamper with the inhibition of spontaneous activity. Actually, this hypothesis could be tested using a method from computational cognitive neuroscience known as representation similarity analysis.
Whatever Huxley was thinking with his “reducing valve” wasn’t this, but still there is something that is stopping all this activity from entering consciousness, and whatever that is my conjecture is that psychedelics are good at removing that block.
Strangely enough, contemporary philosophers like Peter Sjöstedt or Thomas Metzinger find in the psychedelic experience arguments for theories as disparate as panpsychism (i.e. everything has mental properties) and eliminative materialism (i.e. consciousness is an illusion). You seem to see the potential of psychedelics for consciousness research from a rather materialist perspective. But why do you think that there is a push for rather the opposite panpsychist views among people interested in psychedelics and the study of consciousness?
Because of the mystical experience, I suppose. One of its major components is the unitive experience, the feeling of not having boundaries, of being part of everything. I think this experience can lead some people to believe in their consciousness as a whole united with everything.
I certainly don’t have anything against this perspective, understood as a philosophical argument. So panpsychism might be fun for philosophers to discuss, but is not very interesting for scientists because you can’t work on that hypothesis. I haven’t seen any serious proposal to apply the scientific method to the question of panpsychism, and I seriously doubt it can be done.
Anyways, scientists aren’t as detached from these philosophical issues as they wished they would be. Actually, they tend to be divided in their positions, even if they cannot state them clearly and explicitly. Some scientists will say that consciousness is only an informational processing procedure in the brain, that it doesn’t really have anything in terms of first person perspective and therefore, that all phenomenal properties are illusory. Philosophers like Keith Frankish or Dan Dennet argue that you cannot really have qualia, at least not qualia with the properties we usually assign to them.  This is the core of functionalism, the philosophical perspective that is informing research in cognitive neuroscience.
There is of course the other side of this debate, with people who argue that phenomenology or the first person perspective is the single most important thing that has to be explained about consciousness, and that it cannot be dismissed as illusory. You will find papers of very influential neuroscientists seriously taking their own introspection as grounds to formulate theories about consciousness. And then again, you will find others who only look at third-person data, and dismiss whatever their inner mental life is suggesting about the nature of consciousness.
As opposed to many psychedelic scientists who have extensive experience with these substances themselves, I am in the field of those who believe there is nothing except third person data to be explained. I suppose this position isn’t very common for someone with my research interests and with a long and rich history of personal experience with psychedelics. So what is going on?
I ended up thinking very often, how could one use psychedelics to actually discern a solution in this divide? How can you interpret the psychedelic state not as a panpsychist revelation, but as the way in which the illusion of your qualia starts to disarm, to finally realize that there is nothing at all to realize? For those claiming that qualia are illusory, like Dennett of Frankish, I tend to believe the burden is on them to unravel this illusion. I’d expect that most of them would consider psychedelics (and other altered states) as invaluable tools to achieve this purpose, but for some reason this isn’t a frequently adopted perspective. And I wonder why.
I often have talks with hardcore functionalists who defend that consciousness is just computation and, to my surprise, several of them are ready to claim that psychedelics will “fry your brain” (I got this from Daniel Dennett once, and he made his position public in a recent interview given to ALIUS). I guess there are very academic types who think: “there is my private life, and then there is my life as a scientist, and if I start messing around, mixing one with the other, then I am going to lose my objectivity”.
But I have had my fair share of experimentation and that never happened to me. I am even more convinced after taking psychedelics, that they are somehow disarming this sort of qualia illusion.
Perhaps altered states of consciousness are so interesting because they transform consciousness into something that is easier to dispel as an illusion. They are a tool to show to the brain that the brain itself is no more than a bunch of neurons connected together doing computations. That is my grand picture of how I see psychedelic fit into the scheme of consciousness research.

The Science and Folklore of DMT

Being one of the most powerful psychedelics we know, it is not strange that DMT has become the subject of numerous speculations over the years. Theories linking this molecule to the pineal gland, to dreams or near-death experiences have circulated persistently among users and researchers – yet the scientific evidence just doesn’t seem to be there. 

It has been established that DMT occurs in many organisms endogenously, like plants, animals and humans. Besides that, much has yet to become established science in the academic world. Is DMT synthesized in the pineal gland? If so, what is its function? Is it involved in generating dreams or normal consciousness? Is it behind so-called near-death experiences?

We approached researcher Enzo Tagliazucchi to help us bring some clarity and a scientific perspective to these questions. Tagliazucchi is a neuroscientist and professor at the University of Buenos Aires. He will be speaking about his research and the first Electroencephalography (EEG) study of DMT in naturalistic settings at ICPR 2020.

This is the first part of a three-part interview series with Prof. Enzo Tagliazucchi

OPEN Foundation: Twenty years ago, Rick Strassman popularized DMT as the “Spirit Molecule”. In his popular book, he made the claim that this psychedelic compound is endogenously synthesized in the human pineal gland. What led him to this hypothesis?

Enzo Tagliazucchi: It would not be strange if DMT would actually be synthesized in the pineal gland because melatonin, a molecule that is pretty similar in its structure compared to DMT, is released there. All the necessary enzymes in the corresponding metabolic pathway are present in the pineal gland. You have all these coincidences that seem to suggest that it is a natural process that is creating the molecule, and that this process can take place in the pineal gland.

Strassman was, in fact,  interested in melatonin research at first and then came across DMT. From there, he started to convince himself that it was synthesized in the pineal gland and started wondering about its function. People have been trying to find a role for DMT from the moment it became obvious that it is an endogenous molecule, for instance, some have the hypothesis that DMT is actually a neurotransmitter still without a known receptor (the sigma receptor was considered as a candidate for some time but eventually it was abandoned). Of course, whatever the function was, they conjectured, it had to be something related to the phenomenology of the psychedelic state.

In his investigations, Strassman came across these really strange experiences reported by his research participants, which he actually describes as a kind of shock for him. Confronted with this bizarre information, he hypothesized that DMT is present in the brain to signal certain important moments in life, and that these moments are experienced as strange DMT-like experiences, such as birth and death. This is why he coined the popular phrase “the spirit molecule” in reference to DMT.

Last year, a research team from the University of Michigan led by Jimo Borjigin reported concentrations of DMT in rats’ brains to be similar to that of other neurotransmitters like serotonin during induced experimental cardiac arrest. What are the implications of these findings and what do we know about the endogenous levels of DMT in the human brain?

Recently there was some controversy because of this paper, in which Strassman was actually co-author, showing in an animal model that you can find large amounts of DMT produced near the moment of death.

David Nichols tried to refute this hypothesis years ago arguing that even if DMT is actually synthesized in the pineal gland, you will never get sufficiently high concentrations of endogenous DMT to ever produce a psychedelic-like experience. That was the end for a while, and then came this article which Strassman and others took as evidence to support his theory.

David Nichols again published a rebuttal arguing that the finding of high amounts of DMT is not really conclusive because at that critical moment you get a massive release of several neurotransmitters. If you have twice the usual concentration of DMT, then you also have twice the usual concentration of serotonin. And since serotonin is competing with DMT and it has a higher affinity for all serotonin receptor sub-types, then why would you get an endogenous DMT trip considering these difficulties in binding to serotonin receptors?

I think if I had to bet money, I would say that there is DMT in the pineal gland. It is a very simple tryptamine and you have a lot of different possible pathways to get it. All the chemicals you need for the synthesis of DMT can be found in the pineal gland. I would even bet that when you have hypoxia or if there is a critical injury in the brain, there is a spike in DMT concentration. But at such a moment, you have spikes of several neurotransmitters. However, if somebody finds a high spike of DMT alone, that would be a remarkable finding.

I think that more research is needed because it is really strange that DMT is in the brain. People should keep doing this research and should keep asking: Why is DMT there? What does it do? What receptors does it bind to? What is its role? These questions are important, even if the findings so far have been, for the most part, negative.

We don’t really have any proof at all that Strassman’s theories are more than attractive hypotheses. Something valuable about Strassman’s work is that it made a lot of people think for the first time about the possibility of endogenously triggered altered states of consciousness. Unfortunately, I think there is yet nothing to the claim that DMT is behind these experiences.

It seems that Borjigin’s research has been welcomed by DMT enthusiasts who link this molecule to dreams and normal consciousness. If it is present in the human brain at significant levels, could DMT be considered a neurotransmitter playing a role in generating ordinary consciousness or in dreaming, as it has been claimed?

The challenge is to find DMT in a sufficiently high concentration to produce such effects. You would need around 25 mg of DMT being produced in a short period of time for something like that to happen in your consciousness and, apparently, there is no way that can happen. The endogenous concentrations are in the microgram range, below the active levels by orders of magnitude. The reason why it can’t happen is not only because researchers have not found such high levels, it is because essentially the metabolic pathways do not seem to be able to support that massive biosynthesis.

Similarly, it does not seem that DMT is produced with a sufficiently high concentration to be involved in dreaming, and so on. I do not think it is even needed to explain the phenomenology of dreaming. We understand more or less the neurochemistry of dreaming and serotonin, in fact, tends to be blocked during REM sleep. So the neurochemistry does not seem to suggest at all that 5-HT2A receptor activation by any molecule, let alone one in such small quantities, is responsible for dreaming. This does not preclude, of course, that the phenomenology of dreaming and psychedelic states are very similar. You might get to the same effect following different routes.

If it is in the concentrations it is suspected to be in, there is no way it can influence consciousness. That is the current state of knowledge.

See Enzo’s talk titled The neural and psychological correlates of inhaled N,N-dimethyltryptamine (DMT) in natural and ceremonial settings at ICPR2020.

interested in becoming a trained psychedelic-assisted therapist?

Indigenous Talk: Fulni-ô Culture & Jurema - Online Event - Dec 12th