RESEARCH | +80 articles

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Samoon Ahmad M.D.

Magic mushrooms and the future of psychology

by Samoon Ahmad M.D. | Psychology Today | 22 Jul 2020

A conversation with Stephen Ross about the frontiers of psychological research.

The following is an abridged version of Dr. Ahmad’s recent interview with Stephen Ross, M.D. Dr. Ross is the Director of Addictive Disorders and Experimental Therapeutics Research Laboratory at NYU and an Associate Professor in the Department of Psychiatry at the NYU Grossman School of Medicine.

Dr. Ross has conducted extensive research into the effects of psychedelics, for example psilocybin on addiction and cancer-related existential distress.

Dr. Samoon Ahmad: To start, could you give me a little bit of an overview about what drew you to psilocybin?

Dr. Stephen Ross: I had just taken over the leadership of the Substance Abuse Division and I was being supervised by Jeff Guss, who’s a longtime faculty member. One day in supervision he starts talking to me about some conference he’s going to in Switzerland commemorating the discovery of LSD. I was like, "What are you talking about? Why would anybody commemorate the discovery of LSD?" And he said, "Well, actually, psychedelics were a big part of psychiatry."

So, I started looking, and you don't have to look very far because it's all kind of hidden in plain sight. There’s this enormous body of research in psychiatry spanning 30 years. There were APA conferences dedicated to LSD; it was hailed to be a wonder drug, and it was used in all these clinical indications. What really got my attention was that the most studied indication with LSD was the treatment of alcoholism.

There were thousands of people in clinical trials. What they found was that a single dose of LSD led to improvements in drinking compared to placebo even after six months. I just thought that was fascinating. The other most studied indication for LSD was for the treatment of terminal cancer—specifically psychiatric and existential distress.

I just thought all this was so fascinating that we decided to form a reading group. We called ourselves the Psychedelic Reading Group at NYU. About a month after we formed the group, I heard that psychedelic research had resumed in the US in the late 90s and that one of the sites was UCLA. Now, I had gone to UCLA for medical school, and my favorite rotation was at Harbor-UCLA, which is kind of like Bellevue. And though I never met him at the time, there was a guy, Charlie Grob, doing psilocybin research for terminal cancer—studying people who had anxiety, depression, and existential distress—at UCLA.

I was introduced to him when I went to visit my family in late 2006. I went to Harbor and we had like a three-hour lunch. He was Division Chief like me, running their child division, and he's just this amazing guy who said, ‘This is a really promising part of psychiatry and it's starting to come back and I'm doing this trial.’ And then he said, ‘Why don't you do a bigger trial at NYU? My daughter is an NYU student. I love NYU.’

You know how much I love Bellevue, but they would not let me do it. I thought that was the end of it, but the NYU College of Dentistry reached out to me, and they said they were interested in part because the head of their clinical research center was dying of lung cancer. So we did this study, this psilocybin and cancer study at the Bluestone Center for Clinical Research at the Dental School.

At the end of that trial, we designed this psilocybin for alcoholism trial, but the dental school said, "We can't have drunk people running around the dental school. You have to do that at Bellevue." And I said, "But Bellevue doesn't allow us to do that." Turns out after several years and positive media portrayals, Bellevue has accepted me back, and so we now have our psychedelic lab at Bellevue. We have several full-time studies. We're finishing up psilocybin for alcoholism. That's going into a Phase 3. We're just starting psilocybin and for major depression. That's a Phase 2. I'm hoping to restart the psilocybin and cancer work soon. We're finishing up use of psilocybin and religious professionals.

Interestingly, in the age of COVID-19, we’re hoping to move in that direction, as well. I designed a trial using psilocybin to treat frontline healthcare workers—you know, ICU docs, ER docs, nurses, and so on—who have COVID-related anxiety, depression, and existential distress. Depending on getting funding, we may be doing something COVID-related.

Dr. Ahmad: In your opinion, are these the kinds of conditions that psilocybin has the most potential to treat?

Dr. Ross: Well, there are three main areas that are likely going to get psilocybin rescheduled in the next three to five years: Cancer-related existential distress, alcoholism, major depression. I mean, the trials could fail, but I would doubt it at this point—certainly for cancer and alcohol. We know that there’s a very strong efficacy signal.

We're finishing up the trial on psilocybin and alcoholism in about 100 people, and we’ll analyze the data in a month or so. My sense is that it’s going to be a positive trial. It's going to be helpful compared to placebo. Psilocybin is [also] being studied for tobacco addiction at Johns Hopkins, and they're finishing up a controlled trial of psilocybin versus nicotine replacement, and we'll know more there soon, too. Their pilot trial, you know, was like in 12 people, and it’s astonishing. Like 80 percent of people after two doses of psilocybin were not smoking at six months—but, again, that was open label. It was very small. We have to see what the control trial shows.

There’s also a trial at the University of Alabama finishing up with the use of psilocybin to treat crack cocaine addiction. We should know in a year or so about that. There's now a trial starting up using psilocybin to treat opiate addiction, but that's in the very early stages.

I think psychedelics can be very helpful for addiction. Certainly, that was the most promising area historically, but we'll have to see the results of all these trials to see how helpful they are for these other disorders. If they are, then they’ll have a huge public health impact.

Dr. Ahmad: I’m sort of thinking of the path of marijuana and how long that took to become accepted. Do you think a similar amount of cultural or societal change needs to happen in terms of educating people about psychedelics like psilocybin?

Dr. Ross: I think it's going to be vital to educate the public. Otherwise, history will repeat itself. When psychedelics escaped from the lab and started to be used by the general public, people realized that these drugs were dangerous. Because of that, they were demonized and thoroughly repressed.

Now they're coming back and it’s like the echoes of history. There's this exuberance phase and the public is hearing about it through the Pollan book and other sources, and they're thinking, “My God! This is going to cure me. One or two doses of psilocybin will cure me." And then they realize it's not legal, so then they find it in the underground.

And now you get into dangerous territory. I think if we're not careful, we can have a cultural backlash again. I think what we need to do is be very cautious. Continue to do the research, to do good research to see what the data shows and how good or not the effects are, and then educate the public that, yeah, these are new treatments, but they have risks associated with them and they should only be used in these kinds of ways.

I think the right model is that this is medication-assisted psychotherapy. All our treatments are done with two dyad therapy teams, and there is an enormous amount of preparation before the dosing session.

On the dosing day, you know, it's very controlled. There's a kind of living room in the Clinical Translational Science Institute. We make sure they're ready. We then give them the pill. We turn on preselected music that we play for the whole time. We have them lying supine on the couch. They put eye shades on, they listen to the music, and the default is to focus internally while the two therapists are there to support them.

With psilocybin, it’s a six-hour experience. It comes on gradually, it peaks for about two or three hours, and it comes down gradually. Following the dosing session with the psilocybin, there's a lot of integrative psychotherapy. I really think that the arc is at the heart of the therapeutic experience. The drug is part of it, but the drug facilitates the psychotherapy as opposed to the model of ketamine for depression, which is that it's a biological effect that is changing glutamate or BDNF [brain-derived neurotrophic factor].

Our cancer patients—and this is throughout the study—75 percent said the experience was the single or top-five most meaningful most spiritual experience of their lives. I think these are highly memorable, difficult, transformative experiences that kind of get people thinking in a different way, and then it's what happens after that's key. So, again, I think it’s drugs plus psychotherapy and not just drugs alone.

Months, sometimes years, later we ask them to reflect on the experience, and they're often able to say, precisely, "I had this experience. I remember this thing happening and that's stuck with me to this day. It had a profound effect on me at the time and it still has a profound effect on me. I can remember very clearly when I had that confrontation with cancer" or "When I experienced my death" or "When I came to another insight." And that's why these are so memorable. They have this kind of spiritual content to them.

Dr. Ahmad: You recently published your long-term follow-up study on the treatment of existential distress in patients with life-threatening cancer. Could you share some of your key findings?

Dr. Ross: Yes. The original sample was about 30 and we were able to follow up with about half of them, about 15 or 16, because the other half had died. It was pretty astonishing. Four and a half years after a single dose, we found pretty much what we found one day after giving them the dose. It was that 80 percent of people were in remission from their depression or anxiety symptoms.

But... you have to be very skeptical of that. To really demonstrate that you need a much bigger study. It needs to be a parallel design. But the idea that people with cancer who have a very bad reaction with it, who feel anxious and depressed and wish they were dead already or that life has no meaning, it appears that psilocybin really works for those people. In the majority of them, it can rapidly transform them out of that state and into a much better orientation to cancer and life, and that it can last for a long time.

Dr. Ahmad: Have you found that these spiritual experiences are any more or less pronounced in people who are not struggling with the issue of personal mortality?

Dr. Ross: Well Hopkins did a study they published in 2006. They gave psilocybin to normal volunteers. They didn't have any psychiatric problems, but these were spiritually oriented people. In that study, they found that three out of four said the psilocybin experience was the singular or among the top-five most spiritual or most meaningful experiences of their lives.

Our religious professional trial that we're doing with Hopkins, these are, again, “normal” volunteers, but they’re rabbis, priests, imams. We're still analyzing the data, but, just anecdotally, they've been some of the most profound experiences I've seen. These religious professionals are having really intense spiritual and mystical experiences and they are having, for the most part, a positive impact on their religious practice, and sort of deepening their religion or giving them new insights into the nature of reality and God. So I think that the use in “normal” volunteers is interesting to consider and how it may help people that don't necessarily have a psychiatric illness, but want to have some kind of spiritual growth.

Dr. Ahmad: For patients who have a negative experience, what do you do to manage them?

Dr. Ross: We have a whole algorithm to deal with somebody having a difficult psychological experience. Interestingly, psilocybin is extremely safe medically. It's not associated with organ damage or overdose death. It can cause a mild increase in blood pressure and we measure that a lot, but the main thing is that people can have anxiety reactions or psychotic-like experiences. That's why we carefully rule out people with psychotic illnesses or a family history of these illnesses. We rule out people with severe personality disorders. We also rule out people where there is not a good rapport.

We're very careful to only go into a dosing session if we feel comfortable. If somebody does have a difficult experience, we’ve rehearsed it ahead of time. 'If you feel like you're going crazy and you're never going to come back, that's common. If that happens, this is what you should do: Dive into the experience, don't run away from it. Try to go with it and be curious as the first step.' If they're still having a hard time, we will then sit them up and we might provide therapeutic touch to them. Somebody may hold their hand or their shoulder and reassure them that they’re under the influence of a drug and that they are going to be okay.

And those are often the therapeutic moments. If someone is having a really hard time and they're resisting, and we remind them, 'Go back into it. Don't be scared. We’ve got you.' It's typically those moments that people have these kinds of psychological breakthroughs.

If someone is really having a hard time though, we can give them Valium, but we rarely have to do that—maybe two or three times in 150 patients. If we need to abort the experience, there is an anti-psychotic you can give them. Psilocybin is a 5-HT2A agonist, and we have Zyprexa, which is a 5-HT2A antagonist. If we give them that, it will essentially stop the experience. I think we've done that once.

Dr. Ahmad: Are there any directions that you hope the research will take in the future?

Dr. Ross: We're getting close to forming a Center for Psychedelic Medicine at NYU, and the novel direction we want to go is to use psychedelic therapeutics within medicine and neurology—or at the intersection between psychiatry and medicine. This is an area that is completely new, and this would be for pain disorders. There's evidence that psychedelics have potent anti-inflammatory properties, so we're going to be looking at inflammatory conditions like rheumatoid arthritis and some of these kinds of conditions, too. There's also some evidence that psilocybin is associated with neural regeneration, and there are some people now thinking of using it for neurodegenerative disorders like Alzheimer's or Parkinson's.

The anti-inflammation stuff is interesting. It comes from studies of a psychedelic drug called DOI down at LSU by guy named Chuck Nichols. He took rats that had asthma. When you biopsy them before they get the drug, there’s all this inflammation and all these inflammatory cells. When they gave them DOI, one dose of it, a day later they did the biopsies again of the pulmonary tissue, and what they found was remarkable: There was no more inflammation. All the inflammatory cells were gone. The entire inflammatory process was not there.

Psychedelics exert their psychological effects by activating the serotonin 2A receptor, but how they work as anti-inflammatories is actively being worked on. It definitely appears that they have rapid and sustained anti-inflammatory properties, but there's a lot more research to be done there to see if that's true effect, how universal it is, and then what the exact mechanism is.

It’s wild to think of utilizing them not for their psychological effects, but for their biological effects. And I think the area that, to me, encapsulates putting all this together would be this use of LSD in metastatic cancer pain. There, LSD may have direct analgesic effects, but it also may indirectly help pain by making depression and anxiety better.

So, yeah, the interface with medicine and neurology, I think, is the newest thing. There’s also this concept of microdosing. Rather than these big macro-doses that cause mystical experiences, how can you leverage things and use them daily? There's a lot of hype about LSD and psilocybin microdosing, but there's no data. Those trials are starting.

I was invited by the Journal of Psychopharmacology because they did a review article on microdosing. I think my title was like ‘All Hype, No Data, and the Implications of Microdosing Within Psychiatry.’ It's funny. My mom, who’s in her seventies, asked me, ‘Do you think I should microdose with LSD?’ And I was like, ‘Mom! What are you talking about?’ And she goes, ‘I hear it's great. It's been proven to be great!’

So it just goes to show you that there’s so much out there, and that people think that it's going to help their creativity and their energy and their sex lives and their sleep and on and on. The reality is we know nothing about microdosing. We don't know anything about its potential benefits or its potential harms. If you give a psychedelic a lot, it may be harmful. The serotonin 2B receptor that psilocybin also activates is associated with valvulopathy [disease or disorder of the valves of the heart]. That’s associated with, like, the Fen-phen drug; that was a [serotonin] 2B agonist.[ii] So it may that we find out that microdosing causes cardiac problems, but we just don't know.

People are now just beginning to look at microdosing in human populations, number one, to take normal volunteers and see what are the psychological effects; and then, right around the corner from that group, there are those starting to design trials for microdosing to see if it can help treat psychiatric disorders like major depression, ADHD, addiction.

With microdosing, we just don't know. It's one of these examples of the over-exuberance among the public. People think that something is a real thing, they want to try it, and then they get into trouble.

I have another research program with CBD (cannabidiol), and we're using that daily to treat pain disorders. There's psychedelics, like bromo-LSD as an example, that don't cause any psychological effects, but appear to be helpful for cluster headaches.

Dr. Ahmad: Could psychedelics be used to reduce levels of anxiety and stress?

Dr. Ross: I think so. There's the whole inflammatory hypothesis of depression—that depression is associated with hyper-activation of cytokines and increased inflammation. People with depression have shorter rates of survival compared to people without depression.

We looked at this in cancer. We actually looked at inflammatory and immune markers because cancer-related distress, whether anxiety or depression, is associated with decreased rates of survival, so the implication is that there's something going on We know that depression, in particular, drives this hyper-inflammatory response and decreases immuno-response, but unfortunately we never got to analyze those samples because of Hurricane Sandy. When Sandy hit Bellevue, our samples were in the Bellevue CTSI (Clinical & Transitional Science Institute) and because all the generators are in the basement, and, as you remember, the lights went out, so we lost our samples. We never we never got to analyze them. It would be really interesting to…and, again, this is, like, you have to be very careful here because there really is no data yet, but some people get really excited that psilocybin will cure cancer—not just cancer anxiety, but that it'll make their anxiety and depression so much better that their immune system will get better and they'll fight off the cancer.

That's a real stretch, but you could look at that. You could properly design a trial to actually look at that, and if that were the case, it would be pretty big. But I would think that just improving someone’s state of mind that has cancer is going to have some positive effect on the rate of survival.

Dr. Ahmad: I want to thank you for enlightening us. I really appreciate it. I also want to thank you again for the very kind words about my marijuana book, which is now scheduled to come out September 9.

The full interview was published on Dr. Ahmad’s site, samoonmd.com. You can read it here.

Magic Mushrooms and the Future of Psychology

A conversation with Stephen Ross about the frontiers of psychological research.

www.psychologytoday.com

 

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The mystical experience is critical for the therapeutic effects of psilocybin

by Alex Criddle, MA | Psychedelic Science Review | 14 Aug 2020

Two studies indicate that higher doses of psilocybin are necessary for sustained reductions in depression and anxiety.

Research indicates that a mystical experience is a mediator between the therapeutic effects of psilocybin and the patient. Two studies conducted in 2016 found that in end-of-life cancer patients, those who reported having a mystical experience were more likely to have decreased depression and anxiety in addition to an increased sense of well-being.

What is a mystical experience?

A mystical experience is an altered state of consciousness that exhibits a few key features. These features can include a sense of internal or external unity, a transcendence of time and space, feelings of ineffability and paradoxicality, a sense of awe or sacredness, a noetic quality of direct knowledge of an ultimate or higher reality, and a deeply felt positive mood. The exact characterization of the experience varies from person to person, but these features are common among most mystical experiences.

Griffiths, et al., 2016

The first study was a randomized, double-blind, cross-over trial conducted by Roland Griffiths and colleagues. 51 patients were given low (placebo-like) doses of 1 or 3 mg/70kg or a high dose of 22 or 30 mg/70kg of psilocybin in conjunction with psychotherapy. The doses were in a counterbalanced sequence with 5 weeks between sessions with a 6-month follow-up afterward.

Prior to each session participants scored their depression, anxiety, and other negative emotions on clinical questionnaires. After each session, participants were given a series of questionnaires to assess the experience and outcomes. These included the 5-Dimension Altered States of Consciousness (5D-ASC), Hallucinogen Rating Scale (HRS), and the Mystical Experience Questionnaire (MEQ30).

What Griffiths et al. found was that high doses of psilocybin produced significant decreases in self- and clinician-rated scores of depression and anxiety. This was in addition to an increased rating of their quality of life, sense of meaning, and optimism, despite being end-of-life cancer patients immediately after the high-dose psilocybin sessions. This result was largely dependent on a high mystical experience score (rated on the MEQ30). These positive outcomes were sustained at the 6-month follow up, with 80% of participants showing clinically significant benefits.

Both clinicians and participants associated the benefits with the high-dose psilocybin sessions that contained a mystical experience rather than the low-dose, non-mystical experience sessions or the psychotherapy itself. This suggests that the mystical experience is key in mediating the positive outcomes.

This study’s limitations include pharmacological effects from the placebo dose (the authors suggest 0.01 mg/70 kg should be used instead), the nature of a crossover trial which inhibits the accuracy of interpretations of clinical benefits after the crossover has occurred, and the difficulty in using stringent exclusion criteria for these end-of-life cancer trials.

Ross et al., 2016

A second study, a double-blind, placebo-controlled, cross-over trial conducted by Stephen Ross and his colleagues, corroborated these findings. In this study, 29 patients were given either psilocybin or niacin (placebo) at a dose of 21 mg/70 kg in conjunction with psychotherapy. There were 7 weeks between sessions with a 6.5-month follow-up to assess continued outcomes.

The data indicated that psilocybin, but not niacin, produced immediate, clinically-significant reductions in depression and anxiety levels, even prior to the crossover. At the 6.5-month follow-up exam, patients who had had higher scores on the MEQ30 during their psilocybin session had higher sustained reductions in depression and anxiety levels long-term in addition to decreases in cancer-related demoralization and hopelessness. Patients experienced improved spiritual wellbeing, quality of life, and attitudes towards death. The researchers concluded that

"...the psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression."

There are, however, a few limitations to this study. This trial included a small sample size (29 patients), the majority of whom were white women. This crossover style of trials limits the accuracy of the interpretation of clinical benefits after the crossover has occurred.

Summary

Both Griffiths and Ross’s studies suggest that psilocybin produces sustained reductions in depression and anxiety levels in end-of-life cancer patients over at least 6 months. It does appear from these studies that the strength of the mystical experience, provided by a dose of psilocybin around 21 to 30 mg/70kg, is attributed to the sustained reductions in depression and anxiety providing direct and/or indirect benefits to the therapeutic potential of psilocybin.

It is important to note that these studies used pure psilocybin, not psilocybin-containing mushrooms. The dose required for a mystical experience using magic mushrooms may be very different from using pure psilocybin. The features of the two mystical experiences may differ as well. These differences may be due to the entourage effect that occurs with the compounds in cannabis and is hypothesized to occur with the compounds in magic mushrooms.

The Mystical Experience is Critical for the Therapeutic Effects of Psilocybin

Two studies indicate that higher doses of psilocybin are necessary for sustained reductions in depression and anxiety.

psychedelicreview.com

 

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Quipazine: A long-standing enigma in psychedelic research

by Mario de la Fuente Revenga, PharmD, PhD | Psychedelic Science Review | 8 Sep 2020

The “psychedelic drug” label appears to define a clear-cut category. However, there are lesser-known RCs that depict more diffuse boundaries in this classification.

The term psychedelic defines a drug class based on a distinct range of effects on the human psyche. However complex, these effects are intimately linked to the interaction between the drugs and a narrow range of subtype 2 serotonin receptors in the brain. It is precisely the activation of such receptors that ultimately manifests as “the trip.” This connection is well-established — to the point that blocking these serotonin receptors with the antagonist ketanserin can abolish the psychedelic experience.

Intuitively, one could argue that any synthetic or naturally-occurring chemical able to interact with serotonin receptors in a similar manner may as well be a psychedelic drug. However, the ways of pharmacology are often not as straightforward. While the argument probably holds true for a good number of chemicals, some might not produce a clear-cut psychedelic effect — or even one at all. Quipazine may be a good example of this grayer area in the classification of psychedelic drugs.

The not-so-straightforward link between pharmacology and the manifestation of effects

The best-known psychedelics can be grouped into two major families based on their core chemical structures: tryptamines (psilocybin, LSD) and phenethylamines (mescaline). Although Quipazine (Figure 1) does not belong in either lineage, it engages the serotonin receptors relevant to the effect of classic psychedelics. It also produces comparable effects in animal models such as drug discrimination3 and the rodent head-twitch response.

Quipazine checked all the boxes in the lab bench to earn the label “psychedelic,” but its effect on humans was unclear. In 1994, The National Institute of Drug Abuse (NIDA) published a monograph on psychedelics that discussed in great detail the different models employed to study psychedelics and the available data at the time. The monograph included the case of Quipazine within an “enigmatic agents” category.

Figure 1: The chemical structure of quipazine.

As discussed in the NIDA monograph, earlier reports in human subjects did not observe any effects of Quipazine on human volunteers that could resemble those of classic psychedelics. While it is tempting to settle the case here and tag Quipazine as “non-psychedelic,” this move presents important ramifications. As mentioned above, different experiments in vitro and in lab animals showed that Quipazine matched the effects of classic psychedelics. But, if Quipazine failed the ultimate test — eliciting the psychedelic effect in humans — the validity of models widely used in psychedelic research could be rightfully questioned.

The potential interference of secondary effects

Psychedelic effects manifest in a wide range of doses depending on the drug: LSD is active at just a fraction of a milligram, while hundreds of milligrams of mescaline are required to reach a psychedelic dose. If the potency of Quipazine is comparable to that of mescaline, it is then plausible that an active psychedelic dose was never attained.

What could have stopped testing higher doses of Quipazine? Likely the secondary effects of the drug: as the NIDA monograph summarizes, Quipazine was not easy on the research subjects’ stomachs. Even if Quipazine is a legitimate member of psychedelics, it appears to be a lot more efficacious at upsetting the stomach than eliciting colorful imagery.

The nausea and vomiting effects of Quipazine are likely due to an off-target effect on yet another serotonin receptor, the subtype 3. To test the hypothetical psychedelic effects of Quipazine, J.C. Winter in the NIDA monograph suggested “determining the hallucinogenic activity of Quipazine in humans pretreated with a drug such as ondansetron [a serotonin 3 antagonist].” Likely noting this suggestion, one anecdotal report echoed by Alexander and Ann Shulgin stated that combining Quipazine with ondansetron resulted in a “full psychedelic response.” However, no additional details were provided relative to dosage, duration, or quality of effects on this second-hand report.

Data in humans might simply be too limited to solve the case of Quipazine

No psychedelic-like effects were observed in a controlled study; on the other hand, anecdotal reports claimed otherwise. Only further research will allow us to finally establish whether Quipazine may or may not enter the exclusive club of psychedelic drugs. Until that happens, Quipazine’s case appears to maintain the same status declared in the 1994 NIDA monograph: enigmatic.

Be that as it may, the case of Quipazine demonstrates that there are lesser-known enigmatic chemical entities that challenge the structural conservatism of psychedelics and fuel the future of psychedelic research outside the best-known families of psychedelic drugs.

Quipazine: A Long-Standing Enigma in Psychedelic Research

The “psychedelic drug” label appears to define a clear-cut category. However, there are lesser-known research chemicals that depict more diffuse boundaries in this classification.

psychedelicreview.com

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UC Berkeley launches Berkeley Center for the Science of Psychedelics

Lucid News | 17 Sep 2020

UC Berkeley has launched a new psychedelic research center that includes spiritual and theological investigations alongside with scientific inquiry.

“The UC Berkeley Center for the Science of Psychedelics (BCSP) will explore psychedelics as tools for understanding the brain and mind, enhancing well-being, and deepening spirituality, in collaboration with faculty from UCSF and the Graduate Theological Union."

The fascination that many of us have with psychedelic medicine is how stakeholders in healthcare (insurance, hospitals, healthcare administration, etc.) will grapple with and interpret therapeutic agents that potentiate a mystical experience within the context of treatment for mental health conditions.

Part of the challenge is that words sometimes fail to capture the subjective experience of addressing depression, PTSD, anxiety, and addiction with psychedelic therapies. Historically, spiritual or religious practices and frameworks have been anchors for the psyche when encountering non-ordinary states of consciousness. This is less true today, as many people have moved away from more traditional religious practices and are seeking new ways to express their spirituality.

How does medical science, healthcare systems, and providers integrate such a fundamentally different framework into modern practice?

The team assembling the Berkeley center is trying to make sense of this challenge:

“…the center plans to collaborate with the Graduate Theological Union, an independent consortium of religious schools and theological institutes based in Berkeley and the larger San Francisco Bay Area, in the development of an immersive learning program on psychedelics and spirituality.”

I cannot wait to see what comes of this collaboration.

Two other notable aspects of this project include therapist training (in conjunction with the Theological Union) and a journalism/public education component headed up by non-other than Michael Pollan:

“The UC Berkeley Center for the Science of Psychedelics will host a public-facing website, overseen by Michael Pollan, with the goal of fostering a more well-informed and nuanced understanding of psychedelics. The website will host a broad palette of tools to help educate the public about pathbreaking psychedelic research.”

Berkeley Launches Psychedelic Science Center & COMPASS Prepares for IPO - Lucid News

In this week’s Trip Report, Berkeley’s new psychedelic research center will focus on spiritual and theological investigations alongside scientific research, and COMPASS files to be listed on the NASDAQ.

www.lucid.news

 

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LSD, music, and the Mysteries of Consciousness

by Joel Ng, MA | Psychedelic Science Review | 26 Sep 2020

Connectome-Specific Harmonic Waves: A new way of looking at the brain sheds light on the biological correlates of consciousness.

What is consciousness? A question asked by philosophers, theologians, and, more recently, neuroscientists. What does the brain do, to generate the thing called “I”? In a 2017 study, Atasoy and colleagues used psychedelics, math, and fMRI (functional magnetic resonance imaging) data to create a new method of examining neural activity, one that sheds light on the biological correlates of consciousness.

Methods

Twelve participants were administered LSD and a saline placebo and underwent fMRI scans 14 days apart in a counterbalanced, single-blind, within-study design. For the LSD condition, participants were administered 75µg LSD intravenously, while in the placebo condition, participants were administered saline intravenously. After the scan, participants were asked to rate the intensity of five facets of the LSD experience: ​

1. Complex Imagery (i.e., eyes-closed visions of objects)​
2. Simple Hallucinations (i.e., eyes-closed visions of geometric patterns)​
3. Emotional Arousal (i.e., the intensity of emotion)​
4. Positive Mood​
5. Ego-Dissolution​

Atasoy and colleagues then mathematically decomposed these fMRI scans, in a similar way to how a musical chord can be decomposed into individual notes. This allowed them to obtain a roadmap of neural connections in the brain. They compared the activity on these roadmaps between individuals who were sober with individuals who were tripping, along with their self-reported ratings on the five key facets of LSD experience. This roadmap is referred to by experts as the connectome.

The Connectome

The brain is constantly active, with many neural signals traveling around the brain at any given time. The route these signals take can be mapped out by looking at neuronal connections in the brain and examining the activation patterns that take place across this map. Atasoy et al. focused on harmonic waves in the connectome.

Harmonic waves are repeating signals, for example, sine waves. At their most basic, harmonic waves represent change over time. Oscillations in neuron activity (brainwaves) interact with each other in the brain to create harmonic patterns, similar to how individual notes on a piano when played together form a chord.

Atasoy and colleagues traced out neuronal activation patterns in the brain, with each activation pattern corresponding to a particular frequency of activation. At any point in time, several of these activation patterns are triggered and are contributing to the total activity in the brain. Some patterns are activated more frequently than others, and some signals oscillate across the brain faster than others. These networks of activation are building blocks of more complex patterns of brain activity.

Activation patterns and the ego

Atasoy et al. found that LSD makes the brain activate more neuronal patterns non-randomly. There was a reduction in lower frequency activation patterns, but an increase in higher frequency activation patterns. This was especially illuminating when the data were correlated with subjective reports of the participants. Certain neuronal activation patterns were found to correspond to certain subjective aspects of the psychedelic experience.

In low-frequency activation patterns, LSD reduced the energy of these patterns – analogous to hitting a key on the piano more gently. This reduction of energy in low-frequency activation patterns was found to correspond to the subjective experience of ego dissolution, where the less energy these patterns had, the stronger the subjective experience of ego dissolution.

Low-frequency waves travel further than high-frequency waves, losing less energy moving through a medium. An intuitive example of this is how the bass in a song is the first thing one hears when approaching a concert. Low-frequency waves would therefore be expected to be more global in nature compared to high-frequency waves, propagating further across the brain. Higher-level, global aspects of conscious experience like the ego, therefore, would be expected to be reflected in low-energy frequency states rather than more local high-frequency states, a prediction supported by the findings.

LSD also causes more neuronal activation patterns to trigger in tripping individuals compared to sober individuals, this is analogous to using more keys to play a chord on a piano. Biologically, this means that LSD causes interaction between areas of the brain that would not interact with each other in the sober state, a finding reflected in other studies. Further research into the correlation between activation patterns and aspects of subjective experience would provide more information on how consciousness is generated in the brain.

Criticality, set, and setting

Lastly, Atasoy et al. found that LSD shifts brain dynamics further towards criticality, a sweet spot between order and chaos. Sober mind-states tend further towards order than chaos, but still remain in the zone of criticality. Criticality enables the mechanics necessary for complex dynamics. A certain level of order is required for coherent functioning, and a certain degree of disorder is needed for flexibility and adaptability. Dynamic systems in the state of criticality exhibit certain traits, including optimal computational properties.

Examining network correlates of creativity reveal that brain dynamics at the edge of criticality might constitute the neural basis of creativity. Shifting towards criticality renders the brain more supple and flexible within its own intrinsic functioning but also more sensitive to incoming stimuli. A natural consequence of tuning the brain closer to criticality in an LSD trip is an increased sensitivity to both the external environment and internal states – referred to as ’setting’ and ’set’ respectively, in relation to psychedelics.

Mental health implications

Deviations from criticality could be symptomatic or even causative of certain psychiatric disorders. In particular, brain dynamics in depression, addiction, and obsessive-compulsive disorder (OCD) have been associated with the subcritical regime, whereas the super-critical regime has been found to govern brain dynamics during epileptic seizures, and in conditions such as autism. By studying mental illnesses through this lens, more effective treatments could be devised that target the hierarchical predictive coding infrastructure of the brain.

In conclusion, psychedelics allow for a greater understanding of the phenomenology behind the conscious experience and mental illnesses through the examination of connectome-specific harmonic waves. It also provides a potential biological correlate for other theories of consciousness, such as Tononi’s Integrated Information Theory, Carhart-Harris’ REBUS and the Anarchic Brain, and Friston’s Free Energy Minimization, allowing for future research to potentially unify these theories.

LSD, Music, and the Mysteries of Consciousness

Connectome-Specific Harmonic Waves: A new way of looking at the brain sheds light on the biological correlates of consciousness.

psychedelicreview.com

​

 

[mr peabody]

Merlin Sheldrake

The future is fungal: 'Megascience' of mycology on the rise

by Rachel Cooke | The Observer | 23 Aug 2020

The study of fungi has long been overshadowed by more glamorous scientific quests. But biologist Merlin Sheldrake is on a mission to change that.

As a boy, Merlin Sheldrake really loved the autumn. In the garden of his parents’ house – he grew up a few moments from Hampstead Heath, which is where he and I are walking right now, on an overcast summer morning – the leaves would fall from a big chestnut tree, forming gentle drifts into which he liked nothing more than to hurl himself. Wriggling around until he was fully submerged, Sheldrake would lie there, quite content, “buried in the rustle, lost in curious smells.” As he writes in his wondrous new book, Entangled Life, these autumnal piles were both places to hide and worlds to explore.

But as the months passed, they shrank: reaching into them, trying to find out why, he would pull out matter that looked more like soil than leaves. What was going on? Turning to his father for an answer (he is the son of Rupert Sheldrake, the controversial science writer best known for proposing the concept of “morphic resonance”) was how he first came to learn about decomposition, and thus it is to these rotting leaves that we may trace his original interest in the “neglected megascience” of mycology – the study of fungi – even if neglect is a relative term. “In east Asia, fungi have been loved and revered for thousands of years,” he says. “In China, there are temples to the man who worked out how to cultivate shiitake mushrooms. But yes, in the west it has been neglected.”

There are, he thinks, two reasons for this. The first is straightforward: only recently have technologies been available that allow scientists fully to investigate the fungal world; to open up the hidden realms that lie beneath us, invisible to the eye. The second is historical. “There is an entrenched disciplinary bias,” he says. “Fungi weren’t seen as their own kingdom of life until the 60s. Mycologists were put in a corner of the plant sciences department, rather than in their own fungal sciences department. This had a huge impact – if you’re not training researchers, it will be neglected.” Outside science, many people, if not most, associate fungi only with mushrooms. “And they are ephemeral,” he says. “It’s as if we could only see the flowers and fruit of a tree, and not the rest of it: its leaves, stems and roots.” He shakes his curls. “Fungal taxonomy has been a total mess for ages. Linnaeus described it as chaos, a scandal of art. Through the middle ages and into the 18th century, people had no grasp at all of it. They thought mushrooms came up where lightning struck – that you could tell which one was going to kill you by boiling it with a wooden spoon.”

Underground network: a wood-rotting fungal mycelium exploring and consuming a log.

Even now, the non-mycologist often experiences a strange ambivalence when it comes to fungi, one that can encompass both disgust and fear, and a powerful attraction; there’s a reason why Raymond Briggs called his smelliest character Fungus the Bogeyman. In Entangled Life, Sheldrake describes the horror stirred in Gwen Raverat’s Aunt Etty by the pungent and suggestively shaped stinkhorn mushroom, Phallus impudicus (Raverat, the engraver and memoirist, was the granddaughter of Charles Darwin). Etty would, Raverat recalled in 1952, “sniff her way” through her local wood, armed with a special stick with which she used to poke the stinkhorns into her basket. She would then take them home and burn them “in deepest secrecy on the drawing room fire with the door locked – because of the morals of the maids.” As Sheldrake notes, her exploits would have spread the stinkhorns’ spores far more effectively than any number of the flies that, attracted by their stench, usually do this work.

But Entangled Life, which arrives garlanded with praise from nature writers Robert Macfarlane and Helen Macdonald, is an astonishing book that could alter our perceptions of fungi for ever.It seems somehow to tip the natural world upside down. The science it relates is complex. For his work on underground fungal networks in Panamanian forests, Sheldrake received a PhD in tropical ecology from Cambridge University. His principal interest is in mycorrhizal fungi, which are the kind that live in symbiosis with plants. Such fungi send out gossamer-fine tubes called hyphae, which weave into the tips of plant roots at cellular level; in this way, individual plants are joined to one another by an underground network – a vast, highly intricate, collaborative structure that has been dubbed the Wood Wide Web. But he also has a gift for making difficult ideas easily comprehensible. His enthusiasm for mycology is not only passionate; it’s grounded in his conviction that, in the future, fungi will play an ever more crucial role in our understanding of the environment, in a range of new technologies from building materials to sustainable food, packaging products to alternative “leather,” and in our relationship with waste.

Mycorrhizal relationships matter because 90% of plants, the basis of everything that sustains us, depend on them. “Mechanised industrial farming has done huge damage to the microbial symbiosis of plants,” Sheldrake says. “These fungi don’t just feed plants, they protect it from disease, they hold the soil together, and they’re conduits for carbon into it [carbon, soil’s main component, helps it retain water and makes it fertile].” Scientists are already harnessing the power of such networks: in Japan, slime mould has been used to design transport networks: “It takes a long time for computers to cycle all the way through the possibilities, but an organism can quite quickly find an optimal path, and algorithms can then be developed from that.” And this is only the beginning. There is so much untapped potential. Only 6-8% of the world’s fungi have so far even been identified.

A laser scan of fungi living within plant roots, with the fungus rendered in red, and the plant in blue.

In his book, Sheldrake hunts for truffles in Italy (“they were … socketed like skulls,” he writes of those in Piedmont he saw for sale), and he pays due attention to those fungi that have mind-altering properties. “We still don’t know why some contain psilocybin,” he tells me. “It has been suggested that it was to befuddle insect pests, to take their minds off their next meal, but the problem with the deterrent theory is that it doesn’t seem to be very effective.” But it’s his wilder facts that induce a sense of wonderment: the feeling of “vertigo” that he experienced as a boy, when he first grasped that the world below ground was just as diverse, ingenious and infinitely vast as that above it.

Hyphae make mycelium, the mass of branching that comprises the vegetative part of a fungus. But they also make more specialised structures, such as mushrooms – organs that can perform astonishing feats. When some explosively discharge their spores, they accelerate 10,000 times faster than a space shuttle after launch. Others can push their way through asphalt and lift paving stones. One study estimated that if a single hypha was as wide as a human hand, it would be able to lift an 8 tonne bus. If you teased apart the mycelium found in a gram of soil and laid it end to end, it could stretch anywhere from 100 metres to 10 kilometres.

For some time now, Sheldrake and I have been sitting on a bench, close to some trees – a spot that, as dog walkers pass by, invites the question of how the public should best behave towards the fungal realm. “We need to stop spraying fungicide,” he says. “A few strokes of a pen could make that illegal. But for our own part? Well, there are citizen scientists who report on the presence of mushrooms at certain times of year, and show how they’re responding to climate change. That’s a good thing to do. Fungal conservation is in its infancy. In 2018, just 56 species were on the International Union for Conservation of Nature (IUCN) red list, compared to tens of thousands of plants and animals. Beyond that, if you’re picking mushrooms, don’t take them all: leave some behind, and try not to damage the networks by digging around in the ground.”

There are plenty of ways we might connect with fungi, not least by eating them. As he worked on Entangled Life, Sheldrake ate mushrooms every day: “It was a way of reminding myself that I was talking about living things; that I’m part of the metabolic cycles I was writing about.” Once he was in possession of a physical copy of the book, he then grew some mushrooms on it. “They were delicious,” he wrote, when he posted a film of himself cooking them on his Twitter account. “I couldn’t taste any off-notes, which suggests that the fungus has fully metabolised the text.” He particularly likes lion’s mane mushrooms, which taste a little like lobster or crab. He and his brother, Cosmo, are also into fermentation, and have a small lab in their parents’ garden, where they make sauerkraut, kimchee, pickles and beetroot kvass (an eastern European drink usually made from fermented rye bread). “It’s very life-giving,” he says.

Shiitake mushrooms (Lentinula edodes) being home cultivated.

Sheldrake isn’t currently affiliated with any institution. “I’ve got lots of scientific papers to publish,” he says, before we begin walking to the station. “And there are so many experiments to be done. I need some funding. But I’m reluctant to re-enter the academic world, that constant round of applying for grants.” Might he start his own company? “Yes, there’s that, too.” In his book, he writes almost as admiringly of Paul Stamets, a man who may have done more than anyone else to popularise fungal topics outside university departments (Stamets runs a multimillion-dollar fungal business, Fungi Perfecti; his TED talk, “Six Ways That Mushrooms Can Save the World,” has been watched millions of times), as he does of Sir David Read, an emeritus professor of plant science at Sheffield University, and the man who, in the 1980s, was the first scientist to show conclusively that carbon could pass between green plants through fungal connections. It seems wholly possible that Sheldrake may indeed remain outside academia; that part of his mission in the future may have to do as much with the communication of science as with science itself.

Explaining mycology to the lay person isn’t easy. While everyone knows what a bird is, or a tree, the language of the microbial realm is unfamiliar, and its elements largely invisible to the naked eye. But he seems, if not exactly to relish this challenge (he’s not about, I think, to become the new David Bellamy), then to understand the importance of rising to it. Either way, the shores of this far corner of biology seem to suit him. “At university, plant sciences were slightly marginalised,” he says, softly. “But that also meant that you had more space, and I always liked that.”

Entangled Life is published by Vintage (£20). To order a copy go to guardianbookshop.com.

The future is fungal: why the 'megascience' of mycology is on the rise

The study of fungi has long been overshadowed by more glamorous scientific quests. But biologist Merlin Sheldrake is on a mission to change that

www.theguardian.com

 

[mr peabody]

The legacy of Jordi Riba, pioneer of modern psychedelic research

by Mario de la Fuente Revenga, PharmD, PhD | Psychedelic Science Review | 5 Nov 2020

Jordi Riba Serrano PhD, a Spanish trailblazer in the resurgence of psychedelic science, passed away in August 2020 at the age of 51. His important contributions toward understanding the pharmacology of ayahuasca and other psychedelics will remain.

Some of the most paradigmatic examples of what we know as classic psychedelics come from natural sources that have been used by different groups of people since the dawn of time. The basis of our scientific knowledge on these psychoactive substances starts with the observation of the ritualistic use of plants and fungi in shamanistic societies, followed by the careful and systematic isolation and identification of the components responsible for their effects on the human psyche.

Jordi Riba, a turn of the millennium ethnopharmacologist, devoted most of his research career to the study of ayahuasca. With the support of his mentor, Manel Barbanoj, he conducted at the Sant Pau Institute for Biomedical Research (Barcelona, Spain), the first controlled clinical study featuring this Amazonian plant-based psychedelic brew in the late 90s一laying the foundation of our current knowledge of its clinical pharmacology.

The bumpy road of psychedelic research

An article published in a scientific journal is a very poor representation of the hurdles that one had to be overcome to make it possible. Jordi Riba’s initiation on the study of ayahuasca was not a smooth ride. He faced initial resistance from religious groups that considered his studies a desecration of their revered sacrament. After the initial setbacks, the same groups, later on, came to embrace his work, helped him out, and even participated in his studies as volunteers. However, this is not the only point where Riba found resistance to developing his research plans.

Often lacking in institutional support and under draconian funding constraints, Riba managed to move his research forward and achieved international recognition一all the while, he was virtually unknown in his home country.

Most of Jordi Riba’s scientific career took place at the Sant Pau Institute for Biomedical Research, where he surrounded himself with a small team of close collaborators who accompanied him during his scientific journey. However, his network expanded worldwide; at the moment of writing this piece, his extensive list of peer-reviewed publications accumulate thousands of citations and features as co-authors renowned researchers in psychedelic science from all over the world. At the end of his career, his ever-curious mind found a more stimulating environment at the University of Maastricht (Netherlands), where he continued his research over the last few years.

Very early on, Riba took the challenge of translating Jonathan Ott’s Pharmacotheon into Spanish, making it accessible to millions of Spanish speakers worldwide. Like Ott’s thorough analysis of psychoactive plants, Riba’s early works are rigorous, very systematic, and somewhat descriptive–making them a hard digest for the inexperienced reader. But it is this kind of groundwork that set the stage for his greater contributions.

In the last years of his career, Riba engaged in more application-oriented research, addressed more contentious topics, and even founded a small start-up (Blumentech S.L.) to seed the exploration of a therapeutic application for ayahuasca for neurological disorders. Jordi Riba was very connected to his hometown, Barcelona, to the point that he playfully flirted with the idea of registering a mixture of isolated alkaloids under the brand name of “Barnahuasca.”

The man behind the scientist

Riba was by no means someone with an aversion for risk一a certified scuba diver and pilot; he jumped into the water or climbed into the cockpit of a Cessna whenever he had the occasion. He was not blinded by the glittering promise that psychedelics would ever get an approved therapeutic indication for mental health but was up for the challenge. Riba embraced risk一scientifically and otherwise一as well as the uncertainties inherent to his main field of research and career, and yet he found the exploration of the mechanism through which psychedelics manifest their effects fascinating enough to justify every minute of his time at work.

His hard work did not go unnoticed. In 2017 Riba was listed among the top 25 crafters of tomorrow’s world by the Rolling Stone magazine一sharing the stage with tycoon Elon Musk and the United States Senator Kamala Harris. With a very optimistic outlook on the future of Riba stated, ​

"I don’t think it will be long before we see psychedelics incorporated into the therapeutic arsenal." ​

If such a prediction feels closer to being fulfilled than ever, it could be, in part, thanks to his contributions.

Some final thoughts

Jordi Riba’s life was cut down short at the age of 51. His extensive and seminal work should be a reminder that psychedelic science stands on the shoulder of giants who, like Jordi, managed to open the path in an unfavorable scientific and societal environment. Riba’s legacy stands alone for its scientific quality, but it is also a reminder that the seemingly dissipating stigma around psychedelic research was once very pervasive. On the bright side, his work is also an open invitation for newer generations to venture into a fascinating field that is taking its first steps into adulthood.

The author of this article, Mario de la Fuente Revenga, was a colleague and personal friend of Jordi Riba. Dr. de la Fuente Revenga writes this article from that perspective.

The Legacy of Jordi Riba, a Pioneer of Modern Psychedelic Research

Jordi Riba Serrano PhD, a Spanish trailblazer in the resurgence of psychedelic science, passed away in August 2020 at the age of 51. His important contributions toward understanding the pharmacology…

psychedelicreview.com

​

 

[mr peabody]

First-ever clinical trial combining MDMA and LSD

Psilocybin Alpha | 25 Aug 2020

Researchers will examine whether MDMA can offset some of the negative side effects of LSD in a therapeutic setting.

Mind Medicine, a neuro-pharmaceutical company for psychedelic inspired medicines, and the University Hospital Basel’s Liechti Lab, are now combining MDMA and LSD in a groundbreaking Phase 1 clinical trial. The Phase 1 MDMA-LSD trial is scheduled to start in Q4 of this year in Basel, Switzerland.

Combined MDMA-LSD treatments have the potential to create next-generation psychedelic assisted therapy paradigms. When added to a psychedelic assisted therapy session, MDMA has the potential to reduce some known rare negative side effects that may occur while using LSD or other classic psychedelics on their own. It has been shown that classic psychedelics such as psilocybin and LSD can sometimes induce short-term unpleasant effects for patients during a psychedelic assisted therapy session. These symptoms may include negative thoughts, rumination, panic and paranoia.

MDMA, an empathogen, is known to acutely induce feelings of increased well-being and trust. By combining LSD and MDMA within the same session, the Liechti Lab and MindMed are evaluating if the combination produces greater overall positive acute effects when compared to LSD or MDMA on their own. MDMA may reduce some of the negative mood effects of LSD and make the patient more comfortable during psychedelic-assisted therapy.

University Hospital Basel’s Liechti Lab’s Dr. Matthias Liechti stated: “The potential of MDMA-LSD is to create a psychological state that may have the benefits of both substances and have longer lasting effects than standalone psilocybin or LSD. Inducing an overall primarily positive acute response during psychedelic assisted therapy is critical because several studies showed that a more positive acute experience is linked to a greater therapeutic long-term effect in patients.”

MindMed is interested in understanding how to balance these compounds in a cohesive way to create better patient outcomes and develop more advanced psychedelic assisted therapies as it expands both its R&D and commercial drug development pipeline.

President of MindMed, Dr. Miri Halperin Wernli added, “A new treatment paradigm combining MDMA and LSD may enhance the positive effects of LSD by inducing a positive psychological state with MDMA which is an empathogen to help counteract some known negative or less positive aspects of LSD or psilocybin. With this innovative treatment paradigm, we are looking to bring the participants outside the bounds of their everyday perceptions, bringing their mind into a very flexible state of mind facilitating new states of consciousness. This will provide the opportunity to step outside their usual sense of self and experience themselves from a radically different and new perspective.”

The Phase 1 Clinical Trial is intended to take around one year to complete. If MindMed finds the results promising, the company may decide to undertake further studies with treatments combining MDMA and LSD, and prepare patient trials for various indications.

More details on the Phase 1 trial can be found here : https://clinicaltrials.gov/ct2/show/NCT04516902

MindMed Announces First-Ever Clinical Trial Combining MDMA and LSD - Psychedelic Alpha

MindMed is funding a Phase 1 Clinical Trial at University Hospital Basel Liechti Lab NEW YORK, Aug. 25, 2020 /CNW/ — Mind Medicine (MindMed) Inc. (NEO: MMED OTCQB: MMEDF)…

psilocybinalpha.com

 

[mr peabody]

Dose-response study of LSD confirms critical role of the Serotonin 2A Receptor

by Lily Aleksandrova, MSc, PhD | Psychedelic Science Review | 26 Nov 2020

Escalating LSD doses lead to more pronounced subjective and autonomic effects, while pre-administration of ketanserin prevents the effects of a high LSD dose.

The therapeutic potential of LSD for a variety of conditions, including addiction, anxiety, and depression, has been highlighted by several recent placebo-controlled trials. Although such studies support LSD’s safety over a wide range of therapeutically relevant doses, they generally only include a single high LSD dose. This underscores the need to develop optimal dosing protocols in order to maximize the therapeutic benefits against the potential risks of compounds such as LSD. Importantly, the first modern study to investigate the subjective and adverse effects of LSD over a range of well-defined doses in healthy subjects was published last month in the journal Neuropsychopharmacology.​

Holze et al. administered a range of pharmaceutically well-defined LSD doses to healthy subjects​

The small double-blind, randomized, placebo-controlled trial was conducted by Holze et al. at the Liechti lab, University of Basel, Switzerland. It included 16 healthy volunteers (8 male and 8 female, who underwent six 25 hour-long experimental test sessions, separated by at least 10 days. In each session (given in random order), subjects received either placebo, LSD (25, 50, 100, and 200µg), or 200µg LSD 1h after administration of ketanserin, a serotonin 2A (5-HT2A) receptor antagonist (blocker).

It is becoming increasingly important that psychedelic compounds used in clinical research are standardized and developed according to pharmaceutical standards. Importantly, unlike other groups, Holze et al. confirmed the LSD content and pharmaceutical stability of each dose. Specifically, LSD of >99% purity was obtained and prepared as oral solutions of 25 and 100µg according to a set of regulatory standards called “good manufacturing practice.” These doses were then analytically confirmed using techniques previously used at the Liechti lab.​

Dose-response relationships in terms of LSD’s subjective and physiological effects​

As expected, escalating doses administered to healthy subjects led to proportional increases in plasma LSD concentrations (Figure 1). The rate of LSD elimination was proportional to the amount of drug in the body.

Subjective effects over the first 24h after dosing were measured using numerous validated self-rating scales reported useful in predicting therapeutic long-term responses, particularly Oceanic Boundlessness and anxiety measures (Figure 1). LSD subjective effects were dose-dependent and started at the lowest 25µg dose, with a ceiling for “good drug effects” generally seen at 100µg (Figure 1). The 200µg dose did produce higher ratings of blissful state, insightfulness, and changed meaning, but also higher anxiety and ego dissolution.

The average duration of self-reported effects increased from 6.7h at 25µg to 11h at 200µg LSD, due to a faster onset and longer duration with the higher doses. Although participants were blinded to the treatment condition in each session, most of them retrospectively identified the LSD dose they had received correctly. Generally, the 100 and 200µg doses were indistinguishable, while 25µg was readily distinguished from the placebo. Holze et al. also evaluated the so-called autonomic effects of LSD, and found moderate increases in blood pressure and heart rate at the high doses, as previously seen.

In the current study, plasma levels of brain-derived neurotrophic factor (BDNF), a key biomarker for neuroplasticity, tended to be higher post-LSD compared to placebo. However, contrary to a recent Hutten et al. study,5 only the 200µg dose caused a significant increase in BDNF, reaching a peak at 6h. ​

The critical role of the Serotonin 5-HT2A Receptor in the positive and adverse effects of LSD​

Importantly, pre-administration of a 5-HT2A receptor antagonist effectively prevented the normal response of participants to high-dose LSD, as previously reported.6 Specifically, ketanserin (40 mg) reduced the subjective effects of the 200µg dose to levels observed following 25µg LSD. Consistent with this, the LSD + ketanserin combination was identified either correctly or as a low dose by participants after the test session. In addition, the 2A blocker appeared to prevent both the autonomic effects and the increases in plasma BDNF normally observed following 200µg LSD.

This pilot study confirms that LSD’s subjective and autonomic effects in healthy subjects seem to be primarily mediated by serotonin 5-HT2A receptor activation. Although encouraging, this study has several limitations, including the small number of healthy volunteers, which likely have positive expectations and some substance experiences, and the highly controlled research (and not therapeutic) setting. Finally, since ketanserin is a high-affinity but non-selective 5-HT2A antagonist, non-specific actions at other receptors cannot be excluded. Nonetheless, ketanserin effectively blocks the effects of high-dose LSD and maybe at the heart of the LSD “neutralizer technology” announced earlier this year.​

Published dose-response study may assist with dose-finding for future LSD research ​

Based on these results, Holze et al. propose that an analytically confirmed 100µg dose of LSD may optimize the positive drug effects against the risk of acute adverse reactions, making it most suitable for the treatment of depression and anxiety. Indeed, acutely higher Oceanic Boundlessness and lower anxiety ratings seem to predict a better psychedelic treatment response. Finally, Holze et al. hypothesize that although the 25µg “minidose” used here was clearly acutely psychoactive in most subjects, the authors state that LSD “microdoses” are unlikely to impair cognition or produce adverse effects.

After the completion of this study, the Liechti lab announced a research collaboration and licensing agreement with the psychedelic company MindMed. MindMed’s co-founder and co-CEO, J.R. Rahn, commented in a press release: “We see this now completed study as an important stepping stone with highly relevant data to support Project Lucy as the team identifies optimal dose levels of LSD to test in the intended Phase 2b trial of an anxiety disorder.”

First Modern Dose-Response Study of LSD Confirms the Critical Role of the Serotonin 2A Receptor

Escalating LSD doses lead to more pronounced subjective and autonomic effects, while pre-administration of ketanserin prevents the effects of a high LSD dose.

psychedelicreview.com

 

[mr peabody]

The Ayahuasca Afterglow Phenomenon*

by Emma F. Stone, MA, PhD | Psychedelic Science Review | 11 Nov 2020

The afterglow effect is commonly referenced in psychedelic literature. However, limited attention is being paid to several uncontrolled variables.

Those familiar with the expanding field of psychedelics research have likely encountered a phenomenon known as the afterglow. The afterglow can essentially be understood as a persisting feeling of elevated and invigorated mood, accompanied by liberation from past concerns such as guilt and anxiety. An individual’s willingness to enter into close relationships with others may increase during the afterglow, and the efficacy of psychotherapeutic interventions are often enhanced. According to the scientist and clinician Walter Pahnke, the afterglow phenomenon lasts for a period of two weeks to a month before gradually subsiding. Evidence points to the afterglow period as ushering in far-ranging benefits.

However, current understandings of what constitutes the afterglow are still far from concise. Psychedelic Science Review contacted Mario de la Fuente Revenga, PharmD, PhD, who has authored papers exploring the afterglow effect. He commented on the current state of understanding of the afterglow phenomenon. “It might be tempting to link it to the potential antidepressant effects of psilocybin, but there is no consensus as to what the after-glow exactly means, its duration, or if it really exists.” He added, ​

The fact that its existence has not been proven, however, does not preclude formulating interesting questions as to what the aftermath of psychedelics is like at the mental state and physiological levels.​

One psychedelic which is often connected with a marked afterglow effect is ayahuasca. A 2020 study found associations between the afterglow from ayahuasca and improved cognitive flexibility and more mindful behavior. However, little is outlined in this study about the impact of factors that may contribute to the afterglow such as dosage, ayahuasca preparation, or DMT concentration.​

Benefits of the afterglow​

In a study authored by Murphy-Beiner and Soar, survey results demonstrated that the 24-hour period following ayahuasca administration resulted in increased mindfulness, specifically observation, description, acting with awareness, and non-reactivity. Tests measuring cognitive flexibility also showed significantly improved results.

Other research into the benefits of the afterglow has correlated it with improvements in conditions as varied as OCD, substance addiction, and anxiety in terminally ill patients.

Factors that affect ayahuasca afterglow

The last few years have seen a number of studies and reviews exploring how the afterglow delivers benefits, without always unpacking the critical factors that likely influence the duration or nature of the afterglow experience.

For example, in their 2020 study, Murphy-Beiner and Soar acknowledge that the ayahuasca use data incorporated in the study was self-reported with no controls. This precludes critical factors such as DMT levels, dosage, preparation, and the presence of other active compounds that may contribute to the afterglow effect.

A 2020 brain ayahuasca brain imaging study by Sampedro et al. found that “…ayahuasca and potentially other psychedelics induce neural modifications beyond the time frame of the acute inebriation.” The study provides the alkaloid concentrations in the ayahuasca preparation ingested by study participants. However, other relevant details concerning the preparation of the brew, the plants used, or the presence of other active compounds were not provided.​

Dosage – How much DMT is in ayahuasca?​

The plant-based brew that comprises ayahuasca contains dimethyltryptamine, or DMT, a fast-acting and potent hallucinogen. Similar to the way THC potency affects the experience of cannabis users, DMT potency affects the experience of ayahuasca users and their experience in the days after their trip. DMT represents a key consideration in research exploring the occurrence and effects of the afterglow.

Another critical element of the afterglow experience is dosage. In the Murphy-Beiner and Soar study, the dose of ayahuasca taken by participants was unknown to the researchers and therefore not recorded. While there are obvious legal choices guiding this style of qualitative research, a lack of information regarding the dose administration renders it impossible to determine if a minimum dosage is required to kick the afterglow effect into action.

Dr. de la Fuente Revenga emphasized to Psychedelic Science Review that limitations related to dosage are inherent in naturalistic settings, where such details are simply not available. “While it is not an ideal situation, inferring that a sufficient dose of such preparation with known concentrations of alkaloids causes a psychedelic effect and subsequent after-glow –if there’s such a thing– is not a long stretch, though,” he reflects.

Recording the dosage may also help to determine whether biphasic effects occur at certain levels and the optimum dosage based on body weight to experience the range of benefits of afterglow so frequently described. Research into dosage will help to further illuminate understandings of the afterglow effect and perhaps help unveil the mechanisms at work.​

Preparation of the brew​

Finally, variations exist in the preparation of the ayahuasca brew itself that may significantly influence the length and strength of the afterglow that persists. There are numerous preparation factors that may have an impact on the brew. For starters, the ratio of Banisteriopsis caapi vine to that of Psychotria viridis could result in extracts with different concentrations of each compound. Psychotria viridis can also sometimes be swapped out for alternative plants containing DMT.

Another factor influencing the concentration of compounds is the number of “washes” or reductions the plant material undergoes during the brewing process. Washes ultimately increase the strength of the final brew by creating repeated reductions. In ritualistic shamanic ceremonies, the curandero determines the strength of the brew he or she requires, and the brewing process can take days. These elements of subjective decision-making may indirectly influence the afterglow phenomenon.​

The presence of other active compounds​

Some researchers assert that there are likely synergistic mechanisms at play in ayahuasca compounds that are not currently understood by present models.7 Much of this theory is based on the fact that ayahuasca contains a number of psychoactive compounds in varying concentrations, including DMT, harmine, harmaline, harmol, harmalol, and tetrahydroharmine. In a 2004 paper, psychedelic researcher Dennis McKenna stated,​

The synergistic interaction of these alkaloids is the basis of the psychotropic action of ayahuasca.​

Also, ayahuasca brews containing the datura plant as an alternative to Psychotria viridis also contain the compounds atropine and scopolamine that may cause unexpected side effects.9 The research suggests it is presently unclear whether the pharmacological interactions between these different compounds in ayahuasca act synergistically or additively to cause psychoactive drug effects. It follows that perhaps the synergy, or entourage effect of these compounds, may contribute to the afterglow experienced by users.

Some final thoughts

While it is apparent that the afterglow is associated with diverse benefits, current understanding of the mechanisms that influence this phenomenon, and indeed comprehension of the phenomenon itself, remain limited and lacking at present. Studies are required that go beyond self-reported data to create research designs that account for dosage, DMT potency, the presence of other active compounds, and brew preparation.

Dr. de la Fuente Revenga also pointed out that many limitations can be addressed by testing the different chemicals that comprise ayahuasca independently. ​

Except for DMT, the rest of the components of ayahuasca are pharmacologically active but conventionally non-psychedelic. It would be interesting to look into preparations of ayahuasca featuring only B. caapi, to discount the effect of DMT and better understand how the effects of both plants come together.​

More rigorous research will offer greater nuance about the afterglow experience, its benefits, and the duration of its action. Clearly, current legal and financial limitations inhibit the viability of such research in many locales–something that will hopefully change as the legal landscape guiding psychedelic use transforms.

*From the article here :

The Ayahuasca Afterglow Phenomenon: Exploring Its Significance and Limitations

The afterglow effect is commonly referenced in psychedelic literature. However, limited attention is being paid to several uncontrolled variables.

psychedelicreview.com

​

 

[mr peabody]

Scientists uncover molecular origins of the LSD experience*

Bryan Roth, MD, PhD | INVERSE | 18 Sep 2020

The psychedelic experience encompasses our entire experience of consciousness. But it begins with a tiny invisible process: LSD binding to a receptor in the brain.

After investigation, scientists now know how that binding happens and what it actually looks like, findings that help explain how the whole mind-altering process starts.

Previously, scientists suspected that LSD creates a powerful psychedelic experience by binding to serotonin receptors in the brain, specifically 5-HT2A receptors. When receptors at a specific layer in the cortex are activated they fire in an unorganized way, and become unable to take inputs from the outside world.

But scientists were still unsure of how LSD actually activates these receptors. Now, a research team has shown that there's actually a single amino acid (a building block) that's unique to the receptor protein. When LSD binds to that protein, the trip begins.

This finding was published Thursday in the journal Cell.

Bryan Roth is the paper's lead author and a pharmacologist and psychiatrist at The University of North Carolina School of Medicine. He says the paper caps off 30 years of work in the field of psychedelics.

"Now we know how psychedelic drugs work – finally!" he tells Inverse. "Now we can use this information to, hopefully, discover better medicines for many psychiatric illnesses."

Scientists have shown how LSD binds to the brain, and sets a trip in motion.

How LSD binds to the brain

LSD has a crystal structure, which means that scientists can track the way that x-ray beams reflect off of that structure to get a better sense of its shape. For instance, Roth's previous research demonstrated that LSD has a "lid," which makes it particularly sticky when it binds to a serotonin receptor. That's perhaps one reason, he suggested in 2017, that a trip can last hours.

In this study, Roth and colleagues used a technique called X-ray crystallography to examine how LSD binds to a protein on those serotonin receptors called Gαq, and even more specifically to one amino acid (a building block of that protein).

"This is the first time we see LSD bound to the protein in the brain which mediates the psychedelic actions of LSD," he says. "We actually found a single amino acid was essential for the actions of LSD and is found in only this particular receptor."

Ultimately, LSD settles into a "pocket" on the receptor and the looping helix shape of the protein begins to shift outwards (see the red arrows below).

A: The red arrows show how the structure of the serotonin receptor changes when LSD (pink) binds.
B: An external view of LSD bound to the serotonin receptor.

To figure out what happens in greater detail, the team also investigated how a designer psychedelic called 25CN-NBOH binds to serotonin receptors. Technically, LSD is only a partial agonist, which means it binds to the receptor but only partially activates it. That designer drug, 25CN-NBOH is a full agonist, which means it activates the receptor to its fullest extent.

In that designer drug's case, the team suggests that this pocket actually expands slightly (seen in green below), compared to when LSD is bound (seen in purple).

Green shows the expansion of the pocket that the scientist believe may be caused by LSD.

Eventually, those serotonin receptors end up activated, setting firing patterns in motion that block out the outside world, in the case of a trip.

"In a sense, we have a picture of the initial psychedelic event at the molecular level," Roth adds.

How can we use this information

After a drought of psychedelic research that began in the 1970s, there's a renewed interest in the potential therapeutic effects of hallucinogens, including LSD. Recent studies suggest that LSD has the potential to decrease the sensation of physical pain, or the severity of conditions such as cluster headache.

Some research suggests it can also help reset neurons, and ease the experience of anxiety or depression. For example, clinical trials have shown that it can alleviate anxiety related to terminal diseases.

That said, there are risks. LSD can raise heart rate and blood pressure, both potentially problematic for people with heart problems. And there's still the risk of having an unpleasant "bad" trip, though adverse effects are usually short-lived.

"Our ultimate goal is to see if we can discover medications which are effective for depression but do not have the intense psychedelic actions," said Roth.

The key is figuring out how to separate the psychedelic effects of these drugs might be separated from the therapeutic ones – if they can be separated at all. Roth adds that by taking apart them signaling processes involved with an LSD experience piece by piece, we might be able to switch some effects on while keeping others off.

*From the article here:

Scientists uncover the molecular origins of an LSD trip

Scientists discovered how LSD binds to the brain and activates receptors that underpin a trip. These findings could be used to create specific LSD therapies.

www.inverse.com

 

[mr peabody]

New psychedelic could treat depression without hallucinations*

by Tessa Koumoundouros | Science Alert | 10 Dec 2020

Recently advances have shown that psychedelics like ketamine have powerful potential for treating mental health conditions such as addiction, anxiety, and depression. But psychedelics can come with serious side effects, like cardiac toxicity and their infamous hallucinations.

"Psychedelics are some of the most powerful drugs we know of that affect the brain," said chemist David Olson from University of California. "It's unbelievable how little we know about them."

So University of California neuroscientist Lindsay Cameron, Olsen and colleagues decided to take a closer look and see if they could mess with a psychedelic compound in a way that allows them to keep its useful features, but do away with the more dangerous parts.

After extracting the psychedelic compound ibogaine from the African rainforest shrub Tabernanthe iboga, the researchers used a drug-designing technique called function-orientated synthesis to identify which part of the ibogaine molecule induces structural changes in brain cells in laboratory cultures and animals.

They named their resulting synthetic molecule tabernanthalog (TBG).

Cameron and team then treated alcohol-addicted mice and heroin-addicted rats with TBG. Not only did a single dose allow the mice to stop drinking, the compound had a long-lasting effect on rats trained to self-administer doses of heroin, reducing their tendency to seek out the drug. Even when presented with cues that reminded them of their addiction, the rats generally avoided relapsing.

Experiments in zebrafish also showed TBG has a lower toxicity level than the original ibogaine compound. It also doesn't cause mice to twitch their heads in a way that indicates they're hallucinating, and it appears to be increasing connectivity between nerve cells.

When mice were handled and forced to swim for a stretch of six minutes - activities known to stress them out without causing harm - a dose of TBG helped chill them out again, giving it an antidepressant quality similar to ketamine.

"Not only does TBG potently promote neuronal growth, it also produces antidepressant-like behavioural responses and reduces alcohol - but not sucrose - consumption in mice," the team wrote in their paper.

While current antidepressants are certainly helpful, figuring out which one works for you involves a horrifying game of trial and error with your brain. This can be a nauseating nightmare that makes you feel far worse before a turn for the better, and can go on for up to eight weeks before it can finally be established if the drug is even working.

After that, ongoing side-effects of antidepressants include insomnia, dizziness, weight gain, and, in some people, the drug's positive effect can wear out over time.

Unlike those medications, psychedelics are thought to change underlying brain circuitry rather than just masking symptoms. A 2018 study found they promote structural and functional neural changes in the prefrontal cortex of rats.

"However, a causal link between psychedelic-induced neuronal growth and behaviour has yet to be established in either humans or rodents," the team cautions in their paper.

A day after rats were treated with TBG, their brain cells were observed to develop more connecting branches (dendritic spines) - but Cameron and team still have to work out if this change in structure is linked to the observed changes in the animals' behaviour.

"With the exception of 18-methoxycoronaridine, which is currently in phase II clinical trials, very few ibogaine analogues have demonstrated this level of safety while also producing therapeutic effects," the team wrote.

There is still much to work out, but these structural changes may be helpful for treating more than one problem.

"We've been focused on treating one psychiatric disease at a time, but we know that these illnesses overlap," Olson said. "It might be possible to treat multiple diseases with the same drug."

With almost 800 million people with mental health disorders worldwide, those of us relying on external help with our brain chemistry would sorely love another, potentially safer option.

This research was published in Nature.

*From the article here :

Researchers Synthesise a Psychedelic That Could Treat Depression Without Hallucinations

Recently advances have shown that psychedelics like ketamine have powerful potential for treating mental health conditions such as addiction, anxiety, and depression. But psychedelics can come with serious side effects, like cardiac toxicity and thei

www.sciencealert.com

 

[mr peabody]

Psychotria viridis

Neuroscientists believe deep neural networks could help illustrate how psychedelics alter consciousness

by Eric Dolan | PsyPost | 5 Jan 2021

Substance use disorders have a debilitating impact on the wellbeing of individuals and their families. Like many other mental health disorders, these conditions have proved stubbornly resistant to treatment. The potential of psychedelic compounds to treat substance use disorders has led Canadian R&D company Entheon Biomedical to investigate the therapeutic use of the psychedelic dimethyltryptamine (DMT). The company has commissioned a clinical trial investigating the safety and efficacy of intravenous DMT. Technology Networks spoke to Entheon’s CEO, Timothy Ko, to find out more.

Ruairi Mackenzie (RM): What will be involved in the first stage of your DMT clinical trial?

Timothy Ko (TK): We have a clinical study agreement in place with a contract research organization, the Centre for Human Drug Research (CHDR) located in Leiden, Netherlands, to conduct an early phase clinical trial with DMT on humans. The objective of the study is to evaluate the safety of DMT in humans and, specifically, we’re looking to better understand the pharmacodynamics and pharmacokinetics of DMT when administered intravenously.

This will be a data-centric clinical trial, gathering vital information on the biochemical and physiological changes that occur when DMT is administered. This trial will give us further insight into the drug’s effects on the central nervous system and its impact on subjective experience, providing not only pharmacokinetic/pharmacodynamic but also a host of other valuable biometric data. All of this is critical to properly understand DMT’s potential as part of a therapeutic protocol to treat substance use disorders.

RM: What do you see as the unique challenges in treating substance abuse disorders in comparison to other mental health disorders?

TK: The success rates of current treatments and interventions are dismal, and as a society, we have become conditioned to accept these low rates of success as a foregone conclusion. We want to turn those assumptions upside down - to invert the addiction-recovery ratio and we believe we can do it through the development of a DMT-based therapeutic protocol.

Substance-use disorder is obviously a very complicated situation for both the individual grappling with it and for a society and public health system that is tasked with addressing and remedying the devastating effects and widespread damage that stems from unchecked substance-use disorder. With no straightforward solution present, our belief is that a medicalized, psychedelic-assisted therapy model provide a powerful tool for substance-use sufferers to gain the clarity and support required to reclaim their lives.

RM: How is DMT well placed to meet those challenges?

TK: Through extensive talks with our scientific advisors, a review of the literature and historical studies, DMT emerged as our ideal candidate for addiction treatment. DMT belongs to a class of psychedelic compounds, including psilocybin and LSD, which have shown high therapeutic value, and it is the psychoactive ingredient in ayahuasca. Being endogenous to the human body, DMT can be found in many plant species, and throughout its research history DMT has demonstrated a strong safety and toxicology profile. In addition, DMT is rapidly metabolized, so it is well-suited for a shorter, more tailored therapy experience, which has the added benefit of decreased costs and increased scalability. The ability to maintain a flexible and short therapy duration provides an element of control that cannot presently be achieved with other longer-lasting psychedelics. DMT is short-acting, powerful and has demonstrated safety in humans. These are the core reasons why we chose to focus our efforts on DMT.

RM: Do you believe that DMT will prove efficacious for all substance use disorders, or will it treat certain disorders more effectively?

TK: Our initial target indications will be nicotine addiction, alcohol-dependency and opioid use disorder. That being said, our DMT-assisted therapeutic protocol is being designed to address the core mechanisms underlying drug-seeking and using behaviour. Understanding that these drug-seeking behaviours are generated from a complex psychological and emotional place, DMT holds promise to directly address this base state, from which all manner of substance-use disorders are thought to originate from. From this standpoint, our aim is to prove efficacy for the initial target indication and then expand to focus on additional indications and substance-use disorders.

RM: What is the timeline for your DMT trial? How soon do you believe psychedelic-based therapeutics could be widely available?

TK: Recognizing the potential constraints of the ongoing coronavirus pandemic, we currently anticipate that our clinical trial at CHDR will commence in Q3 of 2021. We are doing everything we need logistically to ensure our trial remains on track.

Recently we announced our DMT drug-supply agreement with Psygen Labs, and that they have successfully completed production of our DMT research batch. This represents a major step in our clinical pathway, as the commencement of clinical trials and preparation hinges on having a consistent and high-quality drug supply. Once all necessary permits and licenses are in place, our drug-supply will be shipped to CHDR for requisite testing and formulation.

We are proving the safety and efficacy of our treatment protocol through standard regulatory channels that traditional drug developers go through - the FDA, EMA, and Health Canada. We expect that given our current trajectory, we would like to be in the final stages of clinical development and ready to seek final approvals and pursue commercialization in 4-5 years. But really, given the pressing need for effective treatments, paired with the growing loss of life from overdose, and the significant social and economic impact of substance-use disorders, an effective and scientifically validated solution cannot come quickly enough.

Timothy Ko was speaking to Ruairi J Mackenzie, Science Writer for Technology Networks.

New Clinical Trial Explores Safety of DMT for Substance Use Disorders

Substance use disorders have a debilitating impact on the wellbeing of individuals and their families. Like many other mental health disorders, these conditions have proved stubbornly resistant to treatment. New clinical trials are exploring the safety of the psychedelic DMT for the treatment of...

www.technologynetworks.com

​

 

[mr peabody]

Are the subjective effects of psychedelics necessary for their therapeutic benefits?

by Justin R. Kulchycki, MS | Psychedelic Science Review | 4 Jan 2021

Researchers at the forefront of psychedelic science put forth their arguments in this important debate.

It is generally believed that peak mystical experiences induced by psychedelic compounds are necessary for their remedial advantages. Historically speaking, the cultural and religious use of naturally occurring psychedelics was centered around their subjective effects. However, as scientific study continues to reveal the clinical applications of these compounds, it is worth asking: are the subjective effects essential to their therapeutic properties?

It is likely that the availability of these therapies would increase if the subjective effects were not required to treat depression, anxiety, and addiction. Two prominent researchers in psychedelic science, Dr. Roland Griffiths and Dr. David Olson, are currently debating if the therapeutic benefits produced by psychedelic compounds are dependent on their subjective effects.

Griffiths’s argument

David Yaden and Roland Griffiths of Johns Hopkins University School of Medicine make the case that the subjective effects produced by psychedelics impart their full and enduring beneficial effects. Their argument relies primarily on self-report data provided by the Mystical Experience Questionnaire (MEQ), which allows for the empirical measurement of the first-person experience. Fundamentally, the scores derived from the MEQ can predict beneficial outcomes from experiments where psychedelics were administered. Subsequent statistical analyses of these data have suggested that mystical-type experience is a mediator in positive therapeutic response (anti-depressive, anxiolytic, and anti-addictive).

It is worth noting that the participants in these studies commonly rate their psychedelic experiences among the most meaningful experiences of their lives. Interestingly, the statistical analyses carried out revealed that the high ratings of personal meaning assessed at 14 months after the study could be predicted by the occurrence of a mystical experience on session day. The authors suggest that the subjective effects experienced under psychedelics may provide the impetus for modifying pathological thoughts and behaviors.

Olson’s argument

While it is appealing to attribute the therapeutic benefits of psychedelics to their subjective effects, one researcher is suggesting that a specific pharmacological mechanism is responsible. David Olson from the University of California Davis makes the point that the evidence supporting the necessity of subjective effects is largely correlational. And, of course, it is imperative for scientists to adhere to the perennial scientific axiom “correlation does not imply causation.” Olson maintains that enhanced neural plasticity in key circuits is the root of psychedelic-induced changes in behavior. Therefore, a mystical experience, per se, may not be required to produce the anti-depressive, anxiolytic, and anti-addictive effects that have brought these compounds to clinical attention.

To his point, Olson emphasizes that the psychedelic compounds are psychoplastogens, compounds with the capacity to engage neural plasticity mechanisms in the brain and therefore rewire neural circuitry. He claims that the relevant pharmacological feature of psychedelics is their psychoplastogenic capacity. Olson goes on to point out that the antidepressant response of ketamine increases for several days following treatment despite the subjective effects vanishing after a few hours. Mechanistically, this is due to the fact that psychoplastogens only require a short stimulation period (<1 hr) to initiate a neuronal growth response that can last for several days. Additionally, Olson mentions that MDMA, another psychoplastogen, has mild subjective effects relative to classical psychedelics, but still shows tremendous clinical potential for treating neuropsychiatric diseases such as PTSD.

Future directions

Both Griffiths and Olson recognize that neither view can be established as the paradigm without further studies. Each group has suggested a study that would provide useful information regarding the necessity of subjective effects. This hypothetical study would involve psychedelics being administered to individuals who were rendered fully unconscious under anesthesia. It would be crucial that the participants in the study report no recollection of a psychedelic-like experience. Such a study would help sort out some of the psychological and neurobiological effects of psychedelic compounds.

Are the Subjective Effects of Psychedelics Necessary for Their Therapeutic Benefits?

Researchers at the forefront of psychedelic science put forth their arguments in this important debate.

psychedelicreview.com

​

 

[mr peabody]

Unique magic mushroom microdosing study to begin in Australia

by Rich Haridy | NEW ATLAS | 20 Jan 2021

A novel Australian trial is set to investigate the popular yet still deeply unproven practice of microdosing psychedelics. The research promises to be the first exploration of naturalistic psilocybin microdosing in a lab-setting using a cutting-edge neuroimaging technique and a unique kind of trial protocol.

The idea underpinning the phenomenon of psychedelic microdosing is that tiny doses of psychoactive drugs, such as psilocybin or LSD, can deliver subtle enhancements to productivity, creativity, mental well-being and energy. The key to microdosing is that doses must be so small that the user feels no acute hallucinogenic effects. Basically, if you feel something acute after taking a dose you have had too much.

While the practice is not particularly new, it has risen in popularity dramatically over the past decade, inspired by highly active internet communities and large volumes of positive anecdotal reports. Despite the flurry of popular reporting there is still a dearth of robust empirical data on the true efficacy of microdosing. Only in the last few years have scientists been able to begin exploring the subject through clinical trials, so the jury is still out over whether this practice is an effective phenomenon or simply a glorified placebo effect.

Vince Polito, from Macquarie University, has been researching naturalistic microdosing behaviors for several years. In 2019 he published a compelling, and unique, longitudinal study that tracked the experiences of nearly 100 microdosing subjects over six weeks. His latest project, sponsored by life sciences company Mydecine Innovations Group, is another novel investigation of "real-world" microdosers.

“Our focus of the study is exploring whether microdosing leads to changes in novelty perception or pattern recognition,” says Polito. “In exploring the experiences of genuine microdosers from multiple angles, looking at behavioral, neuroimaging and biomarker data, we want to discover what actually happens when people microdose ‘in the wild’ and whether we can find objective indicators of some of the benefits that microdosers claim."

Instead of using a traditional study protocol, where researchers themselves would administer doses of a drug to participants in controlled environments, this new research is deploying a very unique method to investigate the acute effects of a mushroom microdose.

“We are going to ask people already microdosing to come into the lab on two occasions,” Polito explains to New Atlas in an email. “We will be using a simplified version of the self-blinding protocol developed by researchers at ICL [Imperial College London], meaning that participants will prepare a placebo and a genuine microdose. They will take one of these on each testing day (but will not know which one they have taken). So the study will use a within-subjects design, comparing the performance of people on days when they are and are not microdosing.”

The self-blinding microdose protocol Polito is referring to was developed by a team of UK researchers and involves the participant placing either microdoses or placebos into envelopes that are only marked with QR codes. The participant shuffles the envelopes, losing track of which ones contain microdoses and which contain placebos. This essentially serves to blind the participant from what they are taking, and then at the end of the study the researchers can track, via the QR codes, when each participant was taking either a microdose or placebo.

The UK study employing this novel protocol hopes to have the first phase of its results published very soon. A second phase is set to commence later in 2021 and it will potentially look at incorporating lab-based measurements into the data it is gathering.

The upcoming Australian study is a little simpler and more focused than its UK counterpart. While it will look at subjects who self-report ongoing microdosing practices, it is primarily interested in the immediate after-effects of taking a microdose.

“The study will be open to people microdosing with psilocybin only,” says Polito. “We don't require people to follow a specific dosing regime. We don't want to influence people's microdosing behaviors in any way, we want to explore the experiences of people microdosing according to their existing practices. We are mainly interested in the immediate or state-based effects of microdosing so our measures will focus on markers of any psychological or physiological changes that occur while a person is microdosing (rather than cumulative or longterm effects).”

Alongside a variety of cognitive and biometric measures, the study will be the first to explore the microdosing brain using a cutting-edge neuroimaging method called magnetoencephalography (MEG). While the idea of MEG has been around for decades, recent technological advances have allowed this novel form of neuroimaging to be optimized.

MEG scans allow researchers incredibly detailed insights into real-time electrical activity in the brain. Unlike fMRI, which tracks neuronal activation by imaging blood flow changes, MEG tracks electrical activity in ways similar to an EEG but with profoundly greater resolution.

“There have been very few imaging studies of microdosing so far and I think that this will be the first MEG investigation,” says Polito. “This will allow to explore more precisely changes that occur in neural networks on dosing days, and to identify very subtle changes that may occur in response to our experimental stimuli.”

The study is currently recruiting subjects and Polito asks any interested volunteers in the Sydney area to contact his research team at this email address.

Unique magic mushroom microdosing study to begin in Australia

A novel Australian trial is set to investigate the popular yet still deeply unproven practice of microdosing psychedelics. The research promises to be the first exploration of naturalistic psilocybin microdosing in a lab-setting using a cutting-edge neuroimaging technique and a unique kind of trial…

newatlas.com

 

[mr peabody]

Psychedelic research center launched at New York’s Mount Sinai

by Rich Haridy | NEW ATLAS | 7 Jan 2021

Dedicated psychedelic research center will initially focus on furthering work on MDMA-assisted psychotherapy for PTSD.

Surfing the wave of novel research into medical uses for psychedelic compounds, the Icahn School of Medicine at Mount Sinai has launched a dedicated psychedelic center focusing initially on the study of MDMA and psilocybin for PTSD and other stress-related conditions.

Named the Center for Psychedelic Psychotherapy and Trauma Research the institution is first focusing on MDMA-assisted psychotherapy for post-traumatic stress disorder (PTSD), a promising treatment currently in advanced stages of Phase 3 trials with FDA approval expected over the next one to two years. The Center will be led by professor of psychiatry and neuroscience Rachel Yehuda whose field of expertise encompasses traumatic stress and the neurobiology of PTSD.

“People taking MDMA report feelings of introspection, connectedness, compassion towards self and others, empathy, and increased interpersonal trust, which are optimal conditions for engaging in the processing of difficult or traumatic material,” says Yehuda. “It is important that we listen to people’s subjective experiences with these compounds and then study therapeutic possibilities through rigorous clinical trials.”

Alongside MDMA the Center will also investigate psychedelic-assisted psychotherapy with compounds such as psilocybin. As evidenced in the Center’s name the research will primarily focus on psychedelics as adjunct to psychotherapy for trauma-related disturbances.

The Mount Sinai Center is among the first formal research facilities in the world dedicated to the study of psychedelic medicine. In April 2019 Imperial College London launched its Centre for Psychedelics Research becoming the first academic institution to create this kind of focused psychedelic science facility. Later in 2019 Johns Hopkins University launched the Center for Psychedelic and Consciousness Research, the first research hub of its kind in the United States.

Unlike the Imperial College and John Hopkins centers, Mount Sinai’s Center for Psychedelic Psychotherapy and Trauma Research seems initially to have a much more narrow research focus. However, despite the primary focus on PTSD and psychotherapy its activity encompasses more than mere clinical trial and research. The Center will also train clinicians in psychedelic-assisted psychotherapy and serve as an education facility to help inform the public as these new treatment modalities begin to be clinically deployed over the coming years.

Psychedelic research center launched at New York’s Mount Sinai

Surfing the wave of novel research into medical uses for psychedelic compounds, the Icahn School of Medicine at Mount Sinai has launched a dedicated psychedelic center focusing initially on the study of MDMA and psilocybin for PTSD and other stress-related conditions.

newatlas.com

 

[mr peabody]

Ergot: A Look at LSD’s Precursor

by Sean Lea | Truffle Report | 20 Mar 2021

First synthesized by Albert Hofmann in 1938 before its turbulent history as a countercultural drug and a controlled substance, LSD is a fairly recent addition to mankind’s pharmaceutical repertoire. Hofmann did not just synthesize LSD out of thin air, however — it is actually the product of his years-long research on a very old fungus called C. Purpurea, otherwise known as ergot. Like LSD, the consumption of ergot may cause hallucinations along with a variety of more dangerous symptoms.

What is Ergot?

Ergot is a fungus that is best-known for infecting rye crops, but it also contaminates other cereals like sorghum and millet. When these crops become infected with ergot, dark violet sclerotia appear among the ordinary grains and the plants’ reproductive organs are damaged. Unless they are harvested, these poisonous purple “grain kernels” fall to the ground and sprout fungi throughout winter that produce spores and perpetuate crop infection the following spring. For this reason, ergot was common enough to be considered an ordinary part of rye plants and ended up being consumed frequently throughout European history.​

Symptoms of Ergotism​

Ergot fungus contains a cocktail of poisonous alkaloids that can give rise to a wide berth of unpleasant symptoms, depending on the individual. These infections are known as ergotism and cases are classified as either convulsive or gangrenous.

Gangrenous ergotism was originally known as “holy fire” or “St. Anthony’s fire”. Due to the unknown cause of the infection when it was first observed, it was considered by many to be a form of divine punishment. Gangrenous ergotism is characterized by a painful burning sensation in the victim’s extremities, followed by a “mummification” of the afflicted limb before it eventually falls off. This is the most deadly presentation of ergotism.

Convulsive ergotism, from the perspective of psychedelics and hallucinogens, is the precursor to the effects sought after by LSD users. Having said that, this infection is far less pleasant than an LSD trip. Along with nightmarish hallucinations, sufferers of this infection may find their bodies undergoing painful contortions. Due to the extreme muscle contractions that convulsive ergotism causes, it can also cause pregnant women to miscarry.​

Research and medical uses for Ergot​

As dangerous as ergot can be, it has medical applications. Among the many hazardous alkaloids that occur within ergot sclerotia, there are also the compounds ergotamine and ergonovine —used in the treatment of migraines and postpartum hemorrhaging respectively. Other, less supported, medical uses for ergot include the treatment of excessive menstrual bleeding because of its tendency to narrow blood vessels. From the 16th century onward, midwives had used ergot to induce labor, but this practice stopped because of the severe side effects and bleeding it was known to cause.

Ergot in rye was not suspected as a cause for ergotism until around 1670, when a French physician noticed several discrepancies between ergotism and ordinary contagious infections:​

• Infections were common among the poor, for whom rye bread was a dietary staple, while the rich —who consumed mostly white bread— appeared immune​
• Infections occurred more frequently in rural regions rather than crowded urban areas​
• People who lived in relative isolation could still contract the disease​
• The condition did not necessarily spread between people who lived in the same household​

He noticed the ergot in the rye plants while he was investigating and treating the infections, but farmers did not believe his theory that the purple grains were harmful. In 1853, Louis Talasne finally identified ergot as a fungus that did not occur naturally in rye plants.

In the 1930s, lysergic acid was isolated as the common active agent between ergot alkaloids and Albert Hofmann started his research into its potential medicinal uses. He experimented with many lysergic acid derivatives before synthesizing LSD-25 as a potential respiratory and circulatory stimulant. Although its effects appeared to be fairly benign during animal testing, Hofmann would try it five years later and experience its hallucinogenic effects himself. Luckily, in spite of the fact that Hofmann briefly imagined that his neighbour was a witch, these hallucinations tended to be far less “hellish” than those caused by convulsive ergotism.​

Ergotism and history​

Ergot has existed for as long as rye plants and rye cultivation have been widespread. The first known outbreak occurred in 857 CE within Germany’s Rhine Valley. A 1039 CE outbreak in France resulted in a hospital for victims being erected and dedicated to St. Anthony — hence the name “Saint Anthony’s fire.”

Since the cause of ergot poisoning was not understood until fairly recently, and infection was so common, theories abound on the role ergotism may have played in many historical events. These include:​

• Many ergotism outbreaks contributing to the viking conquests which led to the split of the Holy Roman Empire​
• Since ergotism afflicts animals, it might have accelerated the spread of the bubonic plague by killing rats —forcing fleas that carried that pathogens to find human hosts more quickly​
• Misunderstood symptoms of convulsive ergotism may have led the masses to consider the the infected to be either possessed by demons or attacked by witchcraft​

In fact, one of the more well-known theories concerning ergot outbreaks concerns the 1692 witch trials of Salem, Massachusetts. In 1976, Linnda Caporael suggested that the rainy conditions of the year prior to the trials might have facilitated widespread ergot growth among Salem’s rye crops. The young girls who were thought to have been attacked by witchcraft may actually have eaten contaminated bread and experienced the demonic hallucinations commonly attributed to convulsive ergotism. This theory has been disputed since it does not explain why the victims were only young women or why they only experienced convulsions and hallucinations.

Since the cause of ergot poisoning was unknown for so long and records are spotty, it’s difficult to prove or disprove any of these theories. Thankfully, recent agricultural developments have made ergotism infections uncommon —but it’s still difficult to say how they may have influenced the events of the past.

Ergot: A Look at LSD’s Precursor - Truffle Report

Ergot: A Look at LSD’s Precursor - Truffle Report The grain fungus that preceded and led to the synthesis of LSD by Albert Hofmann

www.truffle.report

 

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Psychedelic drug DMT to be trialled in UK for depression

by Linda Geddes | The Guardian | 9 Dec 2020

UK regulators have given the go-ahead for the first clinical trial of the use of the psychedelic drug dimethyltriptamine (DMT) to treat depression.

The trial will initially give the drug – known as the “spirit molecule” for the powerful hallucinogenic trips it induces – to healthy individuals, but it is expected to be followed by a second trial in patients with depression, where DMT will be given alongside psychotherapy.

Taking the drug before therapy is akin to shaking up a snow globe and letting the flakes settle, said Carol Routledge, chief scientific and medical officer at Small Pharma, the company running the trial in collaboration with Imperial College London.

“The psychedelic drug breaks up all of the ruminative thought processes in your brain – it literally undoes what has been done by either the stress you’ve been through or the depressive thoughts you have – and hugely increases the making of new connections."

“Then the [psychotherapy] session afterwards is the letting-things-settle piece of things – it helps you to make sense of those thoughts and puts you back on the right track. We think this could be a treatment for a number of depressive disorders besides major depression, including PTSD, treatment-resistant depression, obsessive-compulsive disorder, and possibly some types of substance abuse.”

DMT is found in several plants and is one of the active ingredients in ayahuasca, a bitter drink consumed during shamanistic rituals in South America and elsewhere. DMT is also available as a street drug in the UK, where it classified as a class A substance, carrying a maximum penalty of seven years in jail for possession and life imprisonment for supply.

The Medicines and Healthcare products Regulatory Agency (MHRA) approved the trial on Monday, and Small Pharma is currently involved in discussions with the Home Office, which must also give permission because DMT is a controlled substance.

The hope is that the initial trial, which aims to establish the lowest dose of DMT that elicits a psychedelic experience, could begin in January. It will involve 32 healthy volunteers, who have never previously taken a psychedelic drug, including ecstasy or ketamine. This will be followed by trial in 36 patients with clinical depression.

The treatment will be modelled on studies of psilocybin – the psychedelic ingredient in magic mushrooms – in depression. Here patients are brought into a clinic, where they undergo a “setting” session, during which the clinician primes them to open their mind to the drug, and ensures that they are comfortable and relaxed. Next, they are administered the drug, and once the psychedelic experience ends, the patient immediately undergo a session of psychotherapy.

The difference with DMT is that the psychedelic experience comes on faster and more intensely, but is over more quickly. “Whereas a psilocybin session takes all day – and if you’re doing two or even more of those, that’s a large time commitment – a DMT session, all in, will probably take under two hours,” said Peter Rands, Small Pharma’s CEO.

“We expect DMT to be rapid-acting, equivalent or perhaps even better than psilocybin, so within hours of a session you will get rapid relief [from your depression]. We also expect the effect to be sustained over a similar time period.”

One recent trial of psilocybin and psychotherapy found a continued reduction in patients’ depressive symptoms four weeks after taking the drug.

Previous studies of ayahuasca have also suggested that it might have an antidepressant effect, said Amanda Feilding, founder and director of the Oxfordshire-based Beckley Foundation, which designs and develops psychedelic drug research to inform global drugs policy.

“I myself don’t find DMT to be a very lovable compound, but it is definitely an interesting study to do,” she said. “It is a harsher compound than other psychedelics like psilocybin or LSD, where the experience is more like a flower opening and receiving what’s already inside you.

“DMT triggers a strong psychedelic trip, where people experience what they call ‘the entities’ – they meet beings who seem to be real, like being in a dream. But it can rather take one over.”

*From the article here:

Psychedelic drug DMT to be trialled in UK to treat depression

Exclusive: UK regulators give go-ahead for drug to be trialled ahead of possible treatment alongside psychotherapy

www.theguardian.com

 

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Pharmacological testing in psychedelic research

by Alaina M. Jaster, BS | Psychedelic Science Review | 2 Feb 2021

Receptor testing of the affinity and potency of compounds is a critical component of psychedelic research.

The way that psychoactive drugs work in the brain is through interaction with different receptors, transporters, or enzymes that, in turn, alter regular functioning. Receptors are the main targets for psychedelics, usually G-protein coupled receptors (GPCRs) or sometimes ion channels. Measuring things like receptor activation and biological responses can give key insights into signaling mechanisms and the effects of psychedelic compounds. But, sometimes these tests can be hard to understand. This article breaks down the basics of two receptor assays.

Radioligand binding assays

Common types of binding assays utilize a radioligand that is unique to the receptor class to study the interactions of a drug with a target receptor. Three major types are used:​

• Saturation binding: This assay reveals the equilibrium dissociation constant Kd, which is reflective of the affinity a drug has for a receptor. A low Kd value means a high affinity of the drug to activate the receptor.​
• Competition binding: This test uses a radiolabeled ligand with a non-labeled competing ligand to determine the binding affinity and selectivity of a drug for its given receptor target. This binding data is sometimes referred to as the inhibition constant, or Ki.​
• Kinetic binding assays measure the dissociation and association rates of a drug through specific binding of a radioligand. This information can be used to determine if there are cooperative binding interactions occurring between multiple compounds.​

All of these assays can be done using homogenized tissue, cells, or tissue slices, and are typically measured using a scintillation counter.

It is important to note that receptor affinity is not the same thing as potency. The potency of a drug is basically how much is needed to produce a particular effect. Affinity refers to how well a drug binds to a receptor. In order to calculate the potency of a drug (the EC50), the efficacy (Emax), or maximum effect expected from the drug, must also be determined. This can be accomplished through functional assays.

Functional assays

Functional assays refer to measuring the change in a biological response, and in the context of psychedelics, it is usually an agonist response. These assays can be behavioral-based animal studies, cell-based experiments, and enzymatic reactions, and can all reveal potencies of psychedelic compounds. Functional assays should reflect the drug’s mode of action, be reproducible, accurate, robust, stability-indicating, and practical.

An example of a behavioral functional assay is the head twitch response (HTR) assay, a rodent model for serotonin 5-HT2A receptor activation. Typically, the number of recorded HTRs following drug administration is analyzed as a response vs. time. The potencies of each compound can be calculated by finding the dose required to induce a half-maximal response, the effective dose (ED50). This allows for comparisons between compounds or across different concentrations. A recent study led by Dr. Adam Halberstadt provides a new framework for comparing the potencies of hallucinogenic compounds obtained via HTR testing to subjective and behavioral effects across species.

An example of a cell-based function assay is the calcium mobilization assay used to evaluate the potency of psychedelics. Most classic hallucinogens activate the 5HT2A receptor, a Gq-coupled receptor that causes downstream calcium influx into cells.7 This assay measures the movement of calcium following the treatment of cells with different concentrations of a psychedelic. This method utilizes a calcium-sensitive fluorescent dye that is taken up by the cell. Fluorescence is measured following an incubation period, or in real-time, and is quantified to reveal the ED50 to compare between compounds or different concentrations.

Conclusion

Drug effects depend on the occupation of receptors, how they modulate that receptor’s activity, and the experimental measure used to quantify the effects. Radioligand binding assays and functional assays are two tests that researchers use to understand how psychedelic compounds work together at the receptor level in the brain. These assays are fundamental tests that are used well before a drug (especially potent ones like psychedelics) heads down the path to clinical trials. Understanding the complex interplay, and perhaps synergy, between psychedelic compounds and receptor proteins is an essential step for advancing psychedelic research.

Testing Psychedelics and Their Receptors

How do scientists know which psychedelics activate which receptors? Find out how we know which receptors are activated by LSD, psilocybin, and more.

psychedelicreview.com

 

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‘Pharmacopeia’ season finale features cutting edge psychedelic research

by Barbara Bauer, MS | Psychedelic Science Review | 9 Feb 2021

“We have some compounds now that are unlike anything you’ve ever seen before.”

The last episode of season three of Hamilton Morris’s show Hamilton’s Pharmacopeia aired last night on Vice TV. Titled ULTRA-LSD, the show features some of the biggest names in psychedelic research, talking about how they got started in the field. And, of perhaps greater interest, Morris gives exciting peeks inside some of the latest work in psychedelic research.

The show begins with a review of the research on the rye grain fungus known as ergot, which produces the alkaloid compound lysergic acid, among many others. Lysergic acid (a lysergamide) from the fungus is the starting material from which Albert Hofmann first synthesized LSD. Morris talks to Dr. Daniel Panaccione, a biochemist at West Virginia University, who has spent his career studying the life cycle of ergot to understand how and why it produces alkaloid compounds, particularly lysergic acid.

Psychedelic cheese?

Morris poses a thought-provoking question to Panaccione regarding making ergot alkaloids, which are quite difficult to synthesize in the lab: “How does the fungus accomplish what is so difficult for human chemists?”

Panaccione explains that the mystery lies within the complex genetics of the fungus. “There are things you can do genetically to wake a fungus up to make them produce chemicals,” he says. Often researchers find they can activate all manner of unknown biosynthetic pathways that produce compounds that haven’t been chemically characterized yet.

He gives the example of the fungus that gives Camembert cheese (sometimes called brie) its unique aromas and flavors, Penicillium camemberti. He says he was surprised to find from his research that P. camemberti has all the genes needed to synthesize an ergot alkaloid. And yes, Panaccione says, “it wouldn’t be that difficult” to genetically engineer Camembert that contains psychedelic lysergamides.

So, why does ergot go to the trouble of making these alkaloids? It’s symbiosis. Panaccione theorizes that the fungus uses the rye as a food source in exchange for protecting the grain from insects. He has demonstrated the latter in his research by injecting insect larvae with ergot alkaloids and finding that it is lethal to them.

At the forefront of psychedelic research

Morris also presents fascinating interviews with Amanda Feilding, Executive Director of the Beckley Foundation, and Drs. David Nichols and Bryan Roth of the University of North Carolina (UNC)-Chapel Hill.

Feilding spoke about her background in psychedelics (including her experience with trepanation) and the research work of The Beckley Foundation, which spans a wide range of studies on compounds such as LSD, psilocybin, ayahuasca, and cannabis.

Last year, Psychedelic Science Review published a 2-part series on a study that solved the crystal structure of LSD bound to the human 5-HT2A receptor. Roth and Nichols were both co-authors of the paper, and the testing was conducted at Roth Labs. This crystal structure has swung the door wide open not just for studying the binding of compounds to 5-HT2A and their resulting effects but also for identifying new therapeutic compounds. As Roth puts it,​

The Holy Grail of hallucinogen action right here. We have caught the hallucinogen in this stage of activating the receptor.​

Morris visited David Nichols at his lab at UNC-Chapel Hill, where he learned about his current research focus dubbed CELAD (Nichols also made the LSD that Roth used in his crystal structure work). It’s unclear from the episode what the acronym stands for, but chemically, it is described as a nitrogen mustard derivative of nor-LSD.

In his quintessential Pharmacopeia manner, Morris relates how Nichols plans to apply CELAD to his psychedelic research. Nichols’ psychedelic nitrogen mustard would form an electrophilic aziridinium ion that he hopes would alkylate a mutant 5-HT2A receptor forming an irreversible bond that could facilitate study of the drug-receptor complex.

Nichols commented from his perspective on the rapid and revolutionary discoveries being made in psychedelics science:​

I’ve spent my whole life in this field and never thought we’d get to the point we are now.​

Bryan Roth is working with what he calls ULTRA-LSD, or Ultra Large Scale Docking. His lab uses in silico methods, among other computer tools, to screen compounds and identify those that are likely drug candidates. Roth is working from a virtual library of over 34 billion small, drug-like molecules, or as he describes it, “This huge universe of chemical scaffolds.” From this universe, Roth’s goal is to identify 100,000 novel scaffolds for the 5-HT2A receptor. He says, “We can do it. We’re doing it.”

Morris adds, “Should Roth succeed, the product will be countless novel psychedelic scaffolds that may be more potent than the lysergamides.” Roth can’t reveal what he’s learned so far in the project. But what he does say sounds like the beginnings of a whole new world of psychedelic study.​

We have some now that are nothing like anything you’ve ever seen before.​

Pharmacopeia Season Finale Recap

On Hamilton’s Pharmacopeia, Hamilton Morris explores new psychedelics unlike anything you’ve ever seen before.

psychedelicreview.com