The Impact of Psychedelics on the Brain

Psych Congress Steering Committee Members, Charles Raison, MD, Mary Sue and Mike Shannon Chair for Healthy Minds, Children, and Families, Madison, Wisconsin, presented a session at the 2021 Sana Symposium, entitled "A Primer on Psychedelics: Understanding How They Impact the Brain." In this presentation, Dr Raison discusses the history, pharmacology, and clinical potential of the lesser-known psychedelics, including Ibogain, 5-MeO-DMT, LSD, and DMT.

Currently, Dr Raison is working on a Phase 1 clinical trial, the PILOT RECAP Study, which "will investigate the effect of co-administering the amnestic agent midazolam with a single 25 mg dose of psilocybin on the induction of a psychedelic experience and subsequent memory for the experience with the goal of identifying an optimal dosing regimen of midazolam that will allow a psychedelic experience to occur while also inducing amnesia for the experience."

Read the Transcript:

Dr Charles Raison:  Howdy, folks. Our topic today is a primer on psychedelics, with the focus on how they impact the brain but also on their metabolism and some of their relevant clinical effects. I'm going to focus on some of the psychedelics that are not as well understood, and certainly not as well known, in this segment of the session.

In particular, I'm going to focus on ibogaine, 5‑MeO‑DMT, LSD, and DMT. Of course, LSD is very well known, but we know less about it, as you'll see, in terms of modern studies. Here's my faculty disclosure. Here's the general disclosure. Here's the learning objectives. I'm not going to read them.

Let's start here with a picture of Sasha Shulgin, of course, the chemist who synthesized so many psychedelic compounds in the back half of the 20th century. To give you a flavor for how large a domain there are of agents that show psychedelic properties, here's a shortlist of the tryptamines. That's one class of psychedelic agent.

Here is a list of some of the phenylethylamines. These are all things that Shulgin synthesized and tested. Obviously, we have a huge array of potential agents that we could look at.

In addition to having an academic position, I serve as the Director of Clinical and Translational Research for Usona Institute. We're a nonprofit medical research organization that is focusing on the development of psilocybin as a treatment for major depression. I know a lot about psilocybin. I know a fair amount about MDMA from hanging out with the MAPS folks.

One of the things I enjoyed about getting ready for this lecture is it somewhere between encouraged and forced me to read up on some of these other agents. Not only did I enjoy it but it actually shifted my thinking.

That's why I want to start out with ibogaine, something that I felt less positively about until I actually did the research and had a recent experience with some folks from Texas, which I'll tell you about in a second.

Ibogaine. One of the first things to say about ibogaine is that it's not a tryptamine or a phenylethylamine. It's not a classic psychedelic. What is it? It is a natural constituent of the root bark of the iboga tree, which comes from West Africa.

It looks like it was originally discovered by pygmy tribes who then transmitted this knowledge to a religion called Bwiti ‑‑ I'm probably not pronouncing it right ‑‑ in Gabon, which is in West Africa, widely used there for initiation ceremonies and visionary purposes.

The international interest in ibogaine has put the iboga tree on the endangered tree list. There's a real problem there.

French explorers brought it to Europe at the turn of the 20th century. Interestingly, it was marketed in France as Lambarene from the 1930s until 1970 as a stimulant because the molecule has some things in common with psychostimulants and at lower doses, it does have stimulant‑like properties.

Full synthesis was 1956. The structural elucidation of the molecule came in 1960. There are various root mixtures. There's a lot of details there, but fortunately, the molecule can also be synthesized so it's not reliant on wiping out the iboga tree to make it available for clinical purposes.

Its anti‑addictive properties, which is what people are really interested in with this molecule, were discovered by accident in early 1960s by a group of heroin addicts, young gents who were fooling around with drugs. They found that when they did ibogaine, they were protected from cravings and didn't need to use opiates. Some of them got sober.

Those folks, one in particular, went on to file several patents for addictive conditions in the 1980s. Nothing ever came of it, partly because there was enough interest in the 1990s that NIH funded some testing. It did show some preliminary anti‑addictive promise, but the challenge with ibogaine is that it has effects on cardiac conduction channels and it can be fairly lethal.

In nonclinical studies, I've seen estimates that 1 out of every 300 persons who uses this agent will die. This killed the research of it for the 1990s, but ‑‑ and this is really interesting ‑‑ there was something going on with this molecule because ibogaine clinics in various countries really began proliferating in the 1990s.

ATAI Life Sciences is developing ibogaine and noribogaine for opioid use disorder. ATAI Life Sciences, of course, being one of the companies associated with COMPASS Pathways, which of course is working on the psilocybin space.

Let me make a caveat I should've made upfront. For each of these compounds, I'm going to give an example of a company or two that is taking them into commercial development. This is by no means an exclusive list. I cannot keep up on all the people and all the companies that are popping up in this space.

I'm just giving you examples of companies that are undertaking the development of these agents.

What about ibogaine pharmacology? Here's interesting. Not only is it not a tryptamine or phenylethylamine ‑‑ it's not a classic psychedelic, as I said ‑‑ it is a kappa opioid agonist. Remember that the kappa opioid receptor is implicated in depression.

Blocking this receptor was looked at as anti‑depressant property. Those agents didn't make it to market. Blocking the kappa‑opioid receptor is now on the market in combination with olanzapine as a way to protect against the weight gain associated with that anti‑psychotic. It's also a weak mu‑opioid agonist. This may be why it helps with withdrawal and craving from opiates.

It's an NMDA receptor antagonist. Of course, ketamine is an NMDA receptor antagonist. It's also a serotonin reuptake inhibitor. It's a very dirty drug that way. Again, quote dirty. Sometimes these drugs are more powerful than very, very targeted agents.

Again, no effects on the serotonin 5‑HT2A receptor, which is the receptor that mediates most of the psychedelic experiences with agents that are classic psychedelics. In animal studies, it induces something called glial‑derived neurotrophic factor, which is a little bit like BDNF.

In animal models, again it suggests that the induction of that factor is associated with enhancements of dopaminergic tone in the striatum. Of course, dopamine in striatum is a key player in mediating addictive behaviors. It is metabolized primarily by into noribogaine by cytochrome P450 2D6. Also by 2C9‑384. 2D6 is the big player.

This means that 2D6 polymorphisms are likely to impact the effects of this drug, both its therapeutic effects and probably its adverse effects and risks. The ibogaine experience is not an easy thing by all accounts. Dosage, 15 to 20 milligrams per kilogram.

The first thing is the experience lasts a long time, from 12 to 36 hours. Thirty six hours is a long time. It tends to occur, this experience, in two interdigitating phases. Initially, there's a dream‑like, there's a fancy word, oneiric phase, where people feel not so much like they're having a simple psychedelic experience, but a little bit like a waking dream.

They get a lot of visionary stuff. They can get auditory hallucinations. That fades with the passage of time over hours. Typically, a very introspective life review phase will follow. Often characterized by a great deal of regret, sorrow, and guilt, especially in folks whose lives have been damaged by substance abuse.

I use the word darker here. You hear this over and over again, that this agent is hard. Nobody, very few people take it and don't really have a rough experience.

This rough experience, very often, as you can see over on the graph on the right, leads to a reviewing of one's life. Eventually, often, the sense of transformation of feeling that although in the case of substance abuse, a lot of life may have been wasted, you're still alive. There's a future. You can change. Really interesting.

What are the clinical effects? As I said, these young heroin addicts in the '60s discovered that if they did ibogaine, it tended to squelch their cravings and reduce their opioid use. Observational studies did indicate that it has, initially, protection against opioid withdrawal.

One of the hard things about quitting opioid is how sick you get. You do this agent and it provides a window protection of a couple of weeks from withdrawal symptoms, almost as if you're tapering off. It seems to also reduce craving and reduce desire to use the agent.

There have been a couple of survey‑type studies worked up by my colleague, Alan Davis, who's now at Ohio State. There's a survey, for instance, of 88 patients, who received ibogaine treatment in Mexico, down in Baja, between 2012 and 2015.

Most of them, 80 percent, indicated that ibogaine treatment had eliminated or drastically reduced their withdrawal symptoms. 25 percent reported reduction in craving that lasted at least three months. 41 percent of all participants reported abstinence after six months.

After that, 70 percent of the sample relapsed at least once. These are not easy disorders to treat. What's interesting is about half of them reported decreased use, even if they relapsed. Eleven percent went totally long‑term abstinent.

We talked about those acute effects, the life review. It turns out that the ones that rated their treatment experience as more spiritually meaningful were also more likely to achieve abstinence. That becomes important in our next couple of slides.

Then, more recently, there's been this retrospective survey. This is asking people after the fact what they thought. Of 51 US Special Operations Forces veterans, so Navy Seals, and people like that. In that population, ibogaine treatment was associated with a big reduction in retrospective reports of suicidal ideation, of cognitive impairment, and symptoms of PTSD, these are massive effect sides. There's no placebo here, it's just a pre to post measurement. These are huge. Very interesting.

The other thing that I think is really interesting about ibogaine is it really illustrates this dialectic that is going to be hugely important in the development of psychedelic agents, in my opinion.

Let's think about the first part of that dialectic, which is that ibogaine is an example of a drug for which people are working to develop non‑hallucinogenic analogs, agents that might have exactly the same clinical benefit, but without the psychedelic experience.

Obviously, if somebody could find that type of magic bullet, you wouldn't need therapy. You wouldn't need supervision. You could maybe take it at home. It would fit a pharmacological model. Our system is so set up for that model that there's a lot of pressure and potential if somebody could find it.

Back in 1996, researchers developed something called 18‑MC. I'm not going to try to get through Methoxycoronaridine, which is a nicotinic antagonist. Unlike ibogaine, there's no NMDA effects. It doesn't affect the serotonin transporter.

This is really important. It had reduced affinity for sodium channels. Hence, less risk for the heart. It also didn't have the signal receptor effects that ibogaine has, but it has the mu‑opioid receptor effects and it had the kappa‑opioid receptor effects.

In rodent models, it's been shown to reduce the self‑administration for a variety of addictive agents. It seems to have the anti‑addictive effect, but probably not as much the psychedelic effect. Phase I studies are being commenced by MindMed for the development of program opiate use disorder.

There's another analog called Tabernanthalog, which was just recently developed. Water‑soluble, non‑hallucinogenic, not toxic. It's another analogue of ibogaine. In rodents, same thing. It looks like it has potential as an anti‑addictive treatment without the psychedelic effects probably. Under development by Delix Therapeutics.

That's one arm of this dialectic. The other is the arm that maybe these agents are not simple pharmacologic agents, but are more like neuroplastic agents that make people very open to context in the right kind of context produce psychotherapeutic change, doubling down on set and setting.

An example of that is that ibogaine is being widely used, still in Mexico, to help people with PTSD and substance abuse. This is a picture of folks that run a fascinating non‑profit called VETS.

The gentleman, he's quite open about this, was himself a Navy SEAL who had severe PTSD that was ruining his life. He went down to Mexico, got Ibogaine treatment, and had remarkable recovery. These folks raise money and they send Special Ops vets down, offshore, down to Mexico, usually, for post‑traumatic stress disorder and substance abuse treatment.

As I said in the slide of efficacy, it looks like it has a big effect on people. These activities all have a very strong emphasis on the spiritual effects of these agents on the experiential effected seeing these agents as a catalyst to self‑awareness and psycho‑therapeutic change, really.

The other thing that's interesting is that this approach is on the cutting edge of something else that's going to be really important in the field going forward, which is how do we combine agents? It is now become very common to combine an initial treatment with ibogaine followed by another agent we're going to talk about, 5‑methoxy DMT, or 5‑MeO.

This agent has its detractors, but man, it has its fans. There's a book called "The God Molecule." People in the underground that talk about their experiences describe this as being very different than other psychedelics.

Why the toad? Well, let's do some quick history, 5‑MeO is found in a number of plants, but in high concentrations, and most famously, a component of the parotid gland secretion in the Sonoran Desert Toad.

Unlike psilocybin or peyote, the indigenous use of this compound is less clear. It may contribute to the psychedelic effects of snuff used in Central and South America. People fight about that. It was first synthesized in 1936. Underground use began in the '70s. It's currently illegal in the United States.

Popularization of it as a treatment began in Northern Mexico, where the Desert Toad's endemic. Interestingly, one of my graduate students was probably the woman most responsible for starting this.

She realized that ibogaine was so dark that maybe if you added 5‑MeO afterwards, it could give people an emotional lift. Turned out to probably be true. Clinical use began for the treatment of substance abuse disorders in combination with ibogaine based on those findings.

The last five years have seen a slowly growing database of open‑label, survey‑based type studies suggesting that, like other psychedelics, 5‑MeO may hold promise for treating a number of mental health disorders.

Like with other psychedelics, the acute effect is associated with outcomes, in this case, mystical experience, ego dissolution. The more that happens, the more people claim that long‑term they have a reduction in symptoms.

It is in commercial development by my institution, Usona Institute. It's also being developed by Beckley PsyTech, GH Research in a variety of forms, both inhaled, intramuscular.

What about the pharmacology? If you block 5‑HT1 receptors in animals, you block the behavioral effects of this medicine. It may be acting more through the 5‑HT1A receptor than a 2A receptor, although it does have agonism at 2A and 2C.

It also has agonism at the orphan receptor sigma one. When that is activated, it produces anti‑inflammatory effects that people are interested in at this compound. It's metabolized by O‑demethylation.

2D6 is the biggest player. 2D6 metabolizes to bufotenine, which is a psychedelic in its own right, very powerful, and a more potent agonist at 5‑HT2A. As this compound is metabolized, you get increasing 5‑HT2A agonism. 2D6 rapid metabolizers get more of the bufotenine and probably have a different psychedelic experience than people that are not rapid metabolizers.

It is rapidly cleared from the body by deamination by monoamine oxidase A. You can combine it with a monoamine oxidase inhibitor. It gives you a longer effect, but people have died doing that, as with other very powerful serotonergic agents.

Metabolism follows a non‑linear pattern. It's not the case that every little bit of an increased dose produces an increased acute effect. It's non‑linear, so sometimes little bitty increases in doses can produce remarkably more intense effects.

What are those effects? It can be smoked, insufflated, injected. It comes on, kaboom, when you smoke it, it comes on in a few seconds, or if you insufflate it. The experience is short. It lasts about 30 minutes.

This is a thing that interests a lot of people. It's a qualitatively different acute experience than other psychedelics. It's more frequently characterized by ego dissolution. People sometimes call it a whiteout. They're gone.

Mystical experiences are common at higher doses. People often don't remember the acute experience, which makes it very different from something like MDMA or psilocybin, where people tend to remember everything.

The acute experience has fewer visual effects than other psychedelics. It has intense, feeling, tactile experiences. People move around sometimes. They can be ataxic. They can have memory loss. The body may also feel heavier. It's an interesting effect.

Intense emotions are typical. Some people have euphoric experiences. I have known people in the underground who've had really intense fear, anxiety, panic‑type experiences.

It appears to have powerful neurogenic effects in animals. A single injection into the intracerebroventriculars produces rapid neurogenesis in the subgranular zone of the dentate gyrus of the hippocampus.

It also blocks EEG effects. If you give rodents salicylate, they develop an anxiety symptom or syndrome. You can block the brain effects and the anxiety symptom if you give them 5‑MeO.

Now you know we have these little organelles, brains in a vac. 5‑MeO, when you do that and you look at what those brain cells put out in terms of proteins. 5‑MeO stimulates a lot of proteins associated with long‑term potentiation, which is a key for memory formation, dendritic spines, so basically neurogenic effects.

What about LSD, the most famous of all psychedelics, by far? I'm going to talk about it a little bit less, perhaps, because it is so famous. It was marketed before as Delysid by Sandoz in the 1950s. The dosage, it is incredibly potent.

Effects start at about 25 micrograms for most people, typical dose is somewhere between 100 and 500 milligrams. This dose is one‑tenth the mass of a grain of sand. This is how people could give a whole room of people an LSD experience back in the 1960s.

It's in commercial development by MindMed. It had a half‑life of three to five hours. Like ibogaine, it's a long‑acting agent. 12 hours would be typical, but sometimes people could go for 20 hours.

Pharmacodynamics, it is a serotonin agent. It has powerful effects at 5‑HT2A, 2C, 1A, 1B, and it also has dopamine effects of the graph, the lower the bar, the more potent the effect, counterintuitive.

It is metabolized by a number of the P450 isoenzymes in the liver. One of the metabolites is active, one is not. 2D6 poor metabolizers have been shown to have longer, more intense experiences. Down the road, with this agency's approval of 2D6, genetic testing may become very relevant.

In studies conducted prior to 1970 ‑‑ and there were many of them ‑‑ it showed benefit for alcohol use disorder, less data for depression anxiety, more data for helping people cope with end‑of‑life anxiety and despair.

Homestretch, mescaline. Mescaline was actually the first psychedelic probably identified in the West, synthesized a long time ago. It's the active psychedelic compound in peyote, San Pedro cacti, and many other cacti. I've got a picture over on the right. No doubt there's been a continuous indigenous use in the Americas dating back thousands of years, at least.

It's currently under development by an interesting company called Journey Colab for substance use disorder in group setting. It can be taken by mouth, smoked, or insufflated. Oral dosages, 200 to 300 is average, 300 to 500 strong, above 500 ‑‑ buckle your seat belt ‑‑ very strong.

Acute effects take a while, like psilocybin, 45 to 90 minutes, peaks to four to five hours. Like LSD, it's a long ride, 10 to 12 hours, which of course is very relevant for it's commercial development because it means people probably have to spend the night in the unit if they were to use this agent.

It's not a tryptamine. It's a phenylethylamine. Its primary mechanism of action is through 5‑HT2A receptor. It has very modest dopamine activity. It is metabolized by oxidated deamination. Not much is known. I did a lit search on the role of genetic polymorphisms in the P450 enzymes.

Survey data ‑‑ of which now there are several surveys ‑‑ suggest that people with psychiatric symptoms report improvements when it's used in naturalistic setting. Again, as with 5‑MeO, there are some suggestions from survey data that it may hold promise as a novel treatment for psychiatric symptoms.

Then there's N,N‑dimethyltryptamine, which is better known as DMT, fascinating compound. It is a tryptamine, obviously. Very rapid‑acting, with an immediate onset and rapid effect if it's smoked or injected like 5 to 15 minutes. It's why they used to call it the "businessman's lunch." People back in the day used to do DMT, and then they'd be back to work in an hour.

On the other hand, remarkably, if you combine it with an MAOI, you can prolong the effect for hours. As we’ll talk about, the DMT is rapidly broken down. If you swallow this pill, it doesn't get into your head unless you block MAOs, monoamine oxidase. That blocks its metabolism, and it can get up into your brain.

It's under commercial development by MindMed and by Sacred Medicines as ayahuasca. DMT is the primary active hallucinogen in ayahuasca. It binds to a bunch of serotonin receptors. You can see them there, some of the standard players plus 6 and 7, 7, of course, is a target for some standard psychiatric medications.

There's some evidence that DMT may be an endogenous neurotransmitter. There's a lot of debate about this. It also has activity in the sigma‑1 receptor, and so it may have anti‑inflammatory effects.

As I said, it's rapidly metabolized by monoamine oxidation A when inhaled and injected. The MAOIs, the monoamine oxidase inhibitors in ayahuasca prolong the metabolism, allowing central nervous system effects, which maybe you can take by mouth. That experience can last for hours.

There are several small randomized trials suggesting that ayahuasca does have the types of antidepressant effects you see with other psychedelic agents, such as psilocybin.

Interestingly, let me go back for a second, and say there has not been any studies yet of DMT itself, smoked or injected, just pure, boom, fast effect DMT. There really aren't any data on what its potential is as a mental health treatment, but a lot of people are interested in it.

There are some weird things about DMT, just as there are with 5‑MeO DMT. It's been shown by researchers at Imperial College London, the acute experience shares many things in common with reported near‑death experiences.

More than other psychedelics, Roland Griffiths had some proof showing that it tends to make people think they've seen entities. There's this, in the popular age, purple aliens.

If you're interested in this, just google it. There's a massive online discussion about this. It does seem like there's something about this agent that makes people have the conviction that they've been contacted by alien beings.

Depending on how you feel or your belief about alien beings, that could be problematic, but it's definitely a feature of this agent.

That's it. I've run through them. I'm out of time. I'm going to stop, and let's do some live Q&A.

We're back with ourselves, meaning that I'm going to ask myself the question. I'm looking at the chat, these are good questions. Let's see if we can get through a couple of them in about four minutes we've got.

What are your thoughts about using these medicines, psychedelics, in personality disordered people, specifically borderline? It's interesting. I sit as Director of Research for Usona Institute, which is a non‑profit.

One of the things we've been doing is providing psilocybin to appropriate academic research sites around the world, and this is one of the questions people are interested in looking at. Somebody is going to do that study. At some point in the next few years, we'll actually have an answer. The short answer is we don't know.

On the one hand, folks with severe personality disorders are incredibly difficult to treat. They do respond to medications, including serotonergic medications, but it's hard and not so well.

You think, "Well, maybe they wouldn't be as appropriate for treatment." Then, on the other hand, psychedelics may have shorter‑term direct mood effects, but when they work on people, they often seem to change their perspective on the world.

It's that change of perspective in the world that would be hugely useful for folks with something like borderline personality disorder because to some degree, in addition to emotional volatility and some of these more lower brain type struggles, there are cognitive distortions that sometimes it's something psychedelic could address.

I think that this is one of the most…to see whether or not these agents might be, in fact, differentially beneficial for folks with borderline personality disorder. Again, short answer, don't know yet. It hasn't been done.

Next question. What are your thoughts on treatments using simple molecules like more specific action or whole‑plant natural medicines? The idea of entourage effects that if you take the whole plant in the case of something like ayahuasca or ibogaine, that you're getting a very complex mixture of chemicals as opposed to a single agent like we put it in the pills.

The first thing to say about it is that from an FDA perspective, almost certainly, it will be those single‑molecule agents that make it to market because to be GMP, to be good manufacturing grade of something like psilocybin, you've got to be precise, and it's got to be pure to like 99.99 percent.

Extracts and whole products require a major change in how the government thinks about it. Now they've been changing, so keep an eye on that. I know in the case of psilocybin, my colleague at Usona, Alex Sherwood, he just broke those mushrooms down and looked at everything.

It turned out that as far as we can tell, it is just primarily psilocybin, which is a pro‑drug for psilocin that's doing the deed. Whether there are these beneficial effects from whole‑plant extracts versus single molecules, first off, we don't know.

Second off, nobody's done direct studies. Third off, it may differ by agent. Some agents are maybe entourage effects, other natural products maybe not so much. Then, finally, have there been any long‑term comparison studies between psychedelic agents and SSRIs, SNRIs? No.

Robin, in the talk before mine, gave you the world's knowledge on the direct comparison of the SSRI with a psychedelic, and there was a short study. Now, he'll follow these people up longitudinally, so we will know more.

They are very different agents. You take an SSRI every day, often in perpetuity, how that stacks up with a single or a double psilocybin session where the effects might fade in time is unknown.

Whether there are optimal long‑term psychedelic dosing strategies that would outcompete chronic SSRI exposure is a huge question, one of the main questions in the field, and we don't know.

With that, I'm out of time. Let me thank you all for hanging in there with us. Thanks for sticking with me. This has been a marathon of a session. Although, I must say really interesting. I hope you learned a lot from our experts.