New Frontiers in Addiction and Depression Rx w/ psychedelics

Zeus gave Sisyphus the eternal punishment of forever rolling a boulder up a hill in the depths of Hades for his crimes of being a trickster and twice cheating death.

“Then I witnessed the torture of Sisyphus, as he wrestled with a huge rock with both hands. Bracing himself and thrusting with hands and feet he pushed the boulder uphill to the top. But every time, as he was about to send it toppling over the crest, its sheer weight turned it back, and once again towards the plain the pitiless rock rolled down. So once more he had to wrestle with the thing and push it up, while the sweat poured from his limbs and the dust rose high above his head. (Odyssey, Book 11:593)”

His tale sounds woefully close to the trials of addiction and depression. Just when you see the light, just when the journey appears as though it will end in success and the completion of a herculean task, life turns that boulder right around and sends you back to the foot of the mountain – only to start the task all over again with nothing more than your corporeal toolkit.

But what if Sisyphus had real tools? Not just his hands and brute strength, but genuine tools like levers and pulleys? What if he had a partner to help him brace the boulder while he lassoed it with the rope that could be manipulated to make the work of one man equal to two? and to mitigate the back-roll?

Depression and addiction, much like PTSD from episode seven, have benefitted little from new discoveries. The tool kits haven’t changed much lately while the rates of incidence climb without check. Is there a way that psychedelics can offer a good old fashioned Craftsman-style revolution? We talk with Celia Morgan (https://psychology.exeter.ac.uk/staff/profile/index.php?web_id=Celia_Morgan), Laurie Higbed (https://theorg.com/org/awakn-life-sciences/org-chart/laurie-higbed )and others about where the research stands. We’ll walk through the history of psychedlics in addiction and depression, and we’ll hear from people like Mary Ann Dimond with a poignant reminder that these are not problems, not boulders, not numbers, but people who are struggling, people who are loved, and all to often, people who are gone.

Transcript

SUMMARY KEYWORDS

ketamine, mdma, patients, psychedelics, therapy, alcohol, study, psilocybin, depression, drug, experience, feel, drinking, psychotherapy, trial, explored, group, treatment, alcohol use disorder, detox

SPEAKERS

JoJo, MaryAnn, Celia Morgan, Laurie Higbed, Arun Sridhar

JoJo 00:03

The 1971 ban and war on drugs put a gradual chokehold on how research and clinical studies with psychedelic molecules can be conducted. The legislation place these psychedelic molecules like LSD and psilocybin, in the same category as highly addictive drugs. MDMA joined the list in the early 1980s. In Episode Six, we saw how the gradual restarting of research came about the efforts to restart the research took a long time and did not involve the traditional group of scientists, pharmaceutical companies, or drug discovery researchers. It came about due to a realisation that mistakes were made in the past mistakes that wrongfully placed these plant based substances and compounds into the DEA schedule one classification. Mistakes were also made by the very people who acted as proponents of the psychedelic therapies. Rather than choosing drafted protocols and conducting studies of the highest scientific quality. These researchers of the time conducted only observational studies, they forge data and more importantly, because they enjoyed the altered state of mind became evangelists with zero consideration for how careful science must be conducted. This has since changed. Our sixth episode in the series explore the stories of how people who wanted to change the system, decided to work with the system and chose the path taken by most traditional medicines. It’s crucial to mention and stress one point. Just because these are plant based substances, and that growing mushrooms or other plants are not illegal. It doesn’t make it right to administer this to patients who seek help. The history of psychedelic plants and chemical discoveries is rife with self administration and self discovery, but so is medicine. Just because early researchers many years ago self administered medicines or plant extracts, who do not see clinical trials conducted without adequate safety studies, dose ranging considerations, or investigators or chemists administering these drugs to themselves. While the political and legal framework and decisions in the era of the war on drugs was wrong, it does not make it right for underground therapists to administer these plants or plant based substances widely, or even synthesise these substances and make the recipe available to underground chemists, while still consulting for the DEA, as some chemists did at the time. Granted that many underground practitioners trained in various Mesoamerican methods to help patients with mental health disorders, or in the case of the chemist, who became one of the most influential figures in psychoactive advancements influenced many positively with his helpful chemistry underpinnings. But in today’s society, if one wants to legitimise a therapy, it has to be done within the realms of what is deemed illegally right. And none of those people did anything towards legitimising these drugs. Now we seek to explore how this tide is being turned. In Episode Seven, we explored PTSD and the impact of psychedelics in treating PTSD both via personal experiences of veterans who explored it in countries where psychedelics are legal, as well as an interviews with the lead trial of the trial that explores MDMA as treatment for PTSD. It’s time now to see how the tide is turning for other disorders. This is psychedelics. A scraps original podcast exploring the therapeutic potential of psychedelics. An enthralling story of an improbable drug class, as old as humankind itself, banished into exile, yet comes back soaring like a phoenix from the ashes to save mankind’s affliction with mental health disorders.

Arun Sridhar 04:32

Okay, so we have established that any drug development for a new therapeutic opportunity and widespread use must have carefully considered clinical studies to be performed. But let’s explore how this thinking came to be and what evidence is available to change our view that psychedelics can indeed help patients with depression and substance abuse. Remember Episode Three, when we talked about LSD and its use in the hands of psychologists, how Humphry Osmond, Abraham Hoffer, and john Smithies. When LSD was first explored for clinical studies, Osman had started an experiment where the intention was that he would use LSD as a way to give his alcohol addicted patients a bad experience and to use psychotherapy to see the merits of his patients giving up alcohol. But what happened was something that blew up in his mind. He found that the psychedelic experience with LSD, which was legal back then made us patients see themselves as an out of body experience, and tell their own story to their psyche, about how their habits came to be and how it was affecting them and the people around themselves. This in turn made them quit abusing alcohol, Stan grof, despite his philosophical and psychological treatises, he equated LSD to a microscope and the telescope and fell short by doing only observational study. One could argue that this is the only thing that was possible at the time. But this is far from the case. clinical trials were conducted for many drug approvals and indication expansions just because the drug and that synthesis was legal. A new application and used by a clinician requires careful clinical trials. So the real evidence generation in terms of putting together the evidence came when the hefter Research Institute decided to fund research studies to explore the clinical use of psychedelic mushrooms and its active ingredient psilocybin. But there was a major difference. The bad rap that the community and the field of research of psychedelic medicines had got made the founders of the hafter Research Institute think that it was crucial to perform and generate evidence and make sure that the studies were holier than the Pope. So the first study to ever formally explore the role of psychedelics in something close to depression or anxiety came from patients with end stage cancer. Charlie Grobe and George Greer published the study of a double blind randomised control study in 12 patients with psilocybin exploring at safety and looking for early signals on mood and anxiety in terminal cancer patients. It is crucial for people who listen to this episode to realise that to enable the study, the scientists had to demonstrate that there were two prior study that dose psilocybin by our carefully considered ethical clinical research that showed that psilocybin increased glucose uptake in certain brain regions. This was the first study that we alluded to in Episode Six that was funded by hefter Research Institute with Franz vollenweider as the principal investigator. So this study was an acute administration of the drug in patients undergoing brain imaging. So in essence, this was a mechanism of action study, the safety of psilocybin was carefully observed and explored in 36 volunteers were two doses of psilocybin was tested and confirmed to produce mystical experience. This study offered a surrogate of what would be called today as a phase one clinical study where the safety and tolerability effects were explored in healthy volunteers. This study was led by Roland Griffiths, who heads the Johns Hopkins Centre for psychedelic research. Then the study that Charles Grove performed in NCH cancer patients had both the information from the previous two studies to ensure an uninformed the ethical committee that patients who will take the required dose of psilocybin as part of the study will not be harmed. So the effects that was measured and published in the archives of general psychiatry was one that provided the confidence that the effect was real. This then prompted more widespread trials in depression.

JoJo 08:53

Clinical depression, as we know is not something that patients can just snap out of. It can be difficult for patients and those around them to understand and often takes many months or years to be self aware or be diagnosed. The symptoms of depression can be mild to severe, and at its mildest can be one where the person feels low in energy and spirit, and in severe cases, they might feel suicidal. The psychological symptoms of depression include continuous low mood or sadness, feeling hopeless and helpless, having low self esteem, feeling tearful, feeling guilt ridden, feeling irritable and intolerant of others, having no motivation or interest in things, finding it difficult to make decisions, not getting any enjoyment out of life, feeling anxious or worried, having suicidal thoughts or thoughts of harming yourself. The psychological symptoms can result in physical symptoms that one usually reports to the family physician or general practitioner. The physical symptoms of depression include moving or speaking more slowly than usual. Changes in appetite or weight usually decreased but sometimes increased constipation, unexplained aches and pains, lack of energy, low sex drive or loss of libido, changes to your menstrual cycle. disturbed sleep, for example, finding it difficult to fall asleep at night or waking up very early in the morning. The combination of psychological and physical can lead to the social symptoms of depression. those symptoms include avoiding contact with friends and taking part in fewer social activities, neglecting your hobbies and interest, or having difficulties in your home work or family life.

Arun Sridhar 10:49

Can we listen to a true event from the life of Brett as told by his ex girlfriend, Marianne? We can only say that it was mentally very taxing, just to hear the stories. But one can only imagine what it must have been like, for brand.

MaryAnn 11:08

MaryAnn Dimond, we met at a bar. On a Saturday morning, my friend Patti made me go watch the Irish game football which I don’t even watch. And we sat there and Brett rolled in. And he and Patti had a conversation for like two hours during the game. And I was like, stupid. And I don’t know, he turned out to be a really, really nice guy. And we ended up dating after that. And we live together. And that’s that’s how we met? Well, when I broke it off with Brent. I had been through a bunch of episodes where he was driving drunk. He smashed up my car smashed up his own body, who’s going out in the middle of the night to get vodka. And I tried to put them into a Rehab Centre. I tried to talk to family members and they had kind of at that point reached Enough is enough. So is a little bit on my own. And I knew I couldn’t do it. Be in that scenario anymore. So I did my best to get them into a rehab programme and ended our relationship. Yes, we remained friends, I still have left for him. I care about him very much. He’s a very, very kind soul. chatted, and to anticipate this coming, but he’s a very good person. And I don’t I don’t think he set out to destroy himself on purpose. And the second scenario here had gone through three rehabs, three of them. And the last one was here in San Diego. And he spent a year maybe a year and a half there. So over the course of the less, I don’t know, like two and a half years. He had been to three rehab programmes. And then when he graduated, I guess I don’t know what the proper term is for that. But when he graduated, this less last one. At that point, he had been in rehab for two years at three different facilities. The first one was a joke. The one I got him into. The second one was too gnarly, like up in Long Beach with a bunch of druggie gangsters. Um, and the second the third one and the last one Kleenex or something and Vista very faith based. He graduated he was doing well I could tell the difference when I spoke with him and it wasn’t very often but we kept in touch. And then in this last couple of months of the journey, we moved in together as roommates, nothing romantic. And apparently he started drinking shortly after moving into the house. And then it progressed to worse and worse and worse, to the point of where he wasn’t working anymore. And he was sleeping all day and not doing anything except for going out early in the morning and probably I guess By the end of it he was buying for a day. Yes, a lot happened. In fact, I would call it a number one, any one of those events.

15:16

You know what, I guess I’m not a psychiatrist in any way, shape or form, but like what they would call a major life event changing jobs moving, you know, so he moved, his ex wife, married his childhood friend, the best man at her wedding, who stood up for his childhood friend, what’s his other best friend from childhood? His, not his biological dad, but his real dad, the dad, the dad, who was a father to her dad died of cancer. Yeah, a lot of life changing events. His son also, um, have been transitioning, and they haven’t spoken in two years. And yeah, kind of all compressed into that a very short period of time. However, he was drinking in a more like social way, like a couple of bud lights or something, you know, before and then these moments occurred. And he had to experience them. And I don’t, I don’t think he could handle it. He was abandoned by his dad, and his mom went through multiple step dads. I just think he wasn’t given the tools to deal to cope. And to deal with these things. One of the most beautiful things about him and one of the most annoying ones for me was that he just made positive all the time. I tried to share with him that feeling these feelings that he’s having is part of learning how to deal with life you have to the more you ignore them, the bigger they pop up somewhere else, and a dark and twisty moody way. And and I thought we were getting close to doing some of that together just by talking and didn’t work out that way. But I think by suppressing all of that, it was like, I don’t know 50 plus years of suppression, abandonment issues, I think, why pretty much everyone he loved in his life, dad died. his ex wife not only left him, but he married his childhood friend. So that’s a twofer. One of his sons is transitioning and hasn’t spoken with him. And two years, basically, since the divorce. Mom has passed, but abandoned him way before that. Like I say, I’ve noticed psychologist but I think he died of a broken ribs.

Arun Sridhar 18:19

If you feel a bit sad, I must say you’re not alone. We share your pain. But let’s actually hear from Marianne, what did she think of the rehab programmes that Brett was in? And did it really help?

18:34

There’s the programming ones. Um, which brings a lot of higher power, religious kind of doctrine into it. I think, you know, the 12 step programme was definitely a part of some of them. You know, accepting, what you can’t change and blah, blah, blah, and all that stuff. Um, I guess, in just the short amount of time, I’ve had to try and look upon everything. Um, I think the regulation works. I think what has happened is somehow somebody fell into a person such as Brent fell into a situation that was excruciating ly painful, and maybe he was very young, and probably learned how to cope or numb with drugs, alcohol doesn’t matter what. And then his body chemistry changed. And, again, not a scientist or a psychiatrist, but um, so if your synapses are firing and Miss firing, and you’re doing it over and over and over again constantly now, you’re creating Amy’s habits that are not just emotional, but physical.

MaryAnn 20:08

I think because if you look at Brent as an example, he was a 55 year old man. He just turned 55. May. And this is habits. He started when he was 10 1112. I don’t know, somewhere in there parents are alcoholics, not Larry. But it’s ma definitely. And he suffered with it. It’s like 30 years, that’s 40 years 40 years of changing your brain chemistry, how is God or some 12 step programme, going to help him change something that is probably with a word. physiologically, something he can’t overcome. So now you put people under programmes, who are clearly dealing with something that probably started as an emotional trigger, Episode, experience, you plaster some Jesus bullshit on there. And you’re asking this person to, to change chemically, their brain. I don’t care how long you lock somebody up into a programme, my experience has been now with Brent. And it doesn’t mean it. It’s across the board for everyone. Obviously, we’re all different, but there’s no amount of steps or God or it’s got to be a two prong situation, something has to help your brain get back. And it might never, but you also have to go to the source of what the real problem is emotionally. Not a higher power, you can find that obviously, we all choose to or not. But I mean, I choose things that are not a higher power rate, but definitely a bigger than myself. You know, that was a word higher power. So I don’t know. I mean, I think it’s an excuse me, multi prong. I think it’s a you have to fix it with three different I mean, there’s medical, I mean, changing your physiology, right? brain chemistry, snap, I’m going to change that overnight bullshit. I’m going to change that with some behavioural, you know, psychology? No, it’s got to be like a couple of different things. And you have to address I think, the root of the cause, while also changing brain chemistry. Because you’re asking somebody who’s in a very, very tiny vulnerable, maybe it’s not tiny, but it’s a vulnerable place to be to go through something that is physical addiction. They’re not. Yeah, they are choosing but they’re also not choosing

Arun Sridhar 23:45

Maryann Brent, and a third roommate moved in together in April, two and a half months later, on 16th of June, Brent was found to be unresponsive in the shower. As sad as it may seem, we asked Maryann if Brent would have been willing to try other alternative therapies if it was available, like the psychedelic assisted psychotherapy.

24:08

I think he would have been open to it because I think that a certain points there was a level of what felt possibly like desperation that he’s challenged with the emotional and the physical. And I guess that I don’t know anything about this but when you start drinking again after not having been drinking that could be to folder manifested in a much higher way but are powerful way. I don’t know if I don’t know if he did kill himself. I mean, but I think that if he had the right kind of help that this bullshitty like, was your higher power. Oh, we’re not going to talk about the roof. Cause and we’re gonna force you to battle your addiction, your physical, chemical, physiological addiction, basically by cutting you off, giving you a breathalyser test, every day, checking your blood is not going to do anything he changed, the brain changed it.

Arun Sridhar 25:25

Once Brent was found to be unresponsive in the top, one can imagine the toll it took on him. And also on people around him, like Maryann. It was a start of the trauma and the frustration that is felt by many familial members who bear the weight of depression and addiction of the loud ones.

25:46

It’s interesting, because after they arrived, and oh my gosh, unbelievable. The just the firefighters and everybody involved. And somehow they were able after working on themselves for, I don’t know, 1520 minutes, they were able to get them to the hospital and they got him on life support. And I think you’re right, because we’re reason I don’t think Brett died here at the house was because he needed to talk to his son and say goodbye. So when they got him on life support. And we finally got a hold of bio spermine he finally came to the hospital and he called his son, Joe was able to talk to him. Yeah, even though he was on conference, and he died. Right. So no, I don’t think that he would have intentionally killed himself. Although I think he’s suffered on a lot of pain. From that he was not physically able to cope with his addiction. And, and the joke the joke of all of it was his rehabs are an absolute disgrace, or just moneymakers. In my opinion, the first one that I got him into was in Hawaii was a friggin vacation for her. They were like cliff diving. sitting out at the pool, waterfalls, blah, blah, blah. For a month is a joke. It cost $25,000 The second one was a bunch of convicts, ex convicts that were put into these programmes because they weren’t in jail. They needed to spend whatever time disgusting behaviour literally, absolutely the wrong thing. For somebody who is that vulnerable, psychically, you know, emotionally crazy. Okay. Oh, and how about all the authors that work at these programmes. They’re all ex addicts themselves. They don’t have any degrees in psychology as I do not either. But like, You’re telling me that that’s gonna cure though. It’s messed up, and it’s systemic now. I guarantee you, we’re gonna see way more of this.

Arun Sridhar 28:49

For a second, it is crucial to understand how depression comes about. While the detailed molecular mechanism is still not clearly understood. It is now widely accepted that patients with depression have a low levels of serotonin in their body. This is why the existing antidepressants inhibit the re uptake mechanism of, of serotonin from the nerve synapses in the brain. So by integrating the re uptake of neurotransmitters, serotonin, it technically start off to make serotonin more available for action. The issue is not so much with the intention of the antidepressant medications called selective serotonin reuptake inhibitors or SSRIs. But all the side effects that it causes, which we covered in Episode Seven. A few years ago, when the results of serotonin depletion and depression link came out. I spent a few weeks chuckling to myself. And let me tell you why. In the place that I come from Tamil Nadu in South India, good or yoghurt, as it is called by the Western world is a staple food. There is a saying that roughly translates to the following a blissful fool I only get rice with God or in my native language. It literally means Metallica moron shadow. While this derogatory while this is derogatory, and aims to convey, that one needs to work hard to enjoy the variety of foods, while a lazy stupid fool, just gets to eat white curd rice. I found this fascinating because while curd is eaten as a staple in South India, with every meal, meal products provide the tryptophan necessary to make serotonin in the gut. This was the relationship our relationship we explored in Episode Five, where we explored the pharmacology of psychedelics. So a few years ago, diet depleted and tryptophan was tested in human volunteers, and it showed that within a few hours of depletion of tryptophan in the diet, patients mood was affected. This causal link has forced many philosophers and scientists to expose the patients with depression feel like they are in a deep cavern. One way they can see the light, but are surrounded by darkness, and the light seems so far away. This puts added pressure on the patients and those around them in a familial and work settings and impacts productivity of the patients themselves. One might have heard of people taking up yoga meditation, deep breathing, running, increasing the time in the sun, eating more oatmeal, and bananas etc. As all of these act to increase serotonin levels and elevate mood. So that was the anecdote of the cultural view of a natural food provided to us by lacto bacteria. That helps us with our mood. Let’s swing back to how the effects of psychedelics on end stage cancer anxiety and depression was tested.

JoJo 31:54

Following on from the first study published in 2011, the second most detailed and carefully controlled study was published in 2016. Approximately 30 patients were randomised into placebo and silicides in assisted psychotherapy, and follow up at 6.5 months was studied. A second study was published in an additional 51 patients the same year. While these are small studies with less than 100 patients in each group, the effect size was substantial. This has prompted more philanthropic and grant funding mechanisms to further the research into depression. One of the significant studies the act to provide additional evidence for moving silicided from end of life anxiety and depression to more mainstream chronic depression patients was done at Imperial College in London. This study was published in early 2021 and should be seen as an example of a well controlled experimental medicine study. While the investigators David Nutt and Robin Carhartt Harris have been vocal about these drugs being illegal and therefore had to jump through the hoops and bureaucracy to perform these studies. It should not be forgotten that these investigators, despite the political messaging, have taken a stringent testing approach. buoyed on by the Johns Hopkins depression study in end stage cancer patients an early evidence of the effect in patients with major depressive disorders. The research group at Imperial College London took on a tough scientific challenge. This is the stage where I think it helps to pause and take stock. Much like how the phase three MDMA trials took on patients with PTSD who had long standing PTSD despite all therapy. These investigators took on the current medication regimen, from their patient cohort who were on antidepressants. They randomised the patients into two groups, one that continued with their current antidepressants, or ones that had silicided as the experimental treatment.

Arun Sridhar 34:01

Both treatment groups underwent psychotherapy for the entire duration of the study with the same protocol. Credit has to be given to the study investigators for ensuring that there was no bias in the study conduct that made sure that the two groups were identical. The psilocybin group was one that received six weeks of placebo, while the citalopram the current standard of care, anti depressant was given and administered to all patients in the citalopram group for the entire six weeks duration. Since they were testing the effects of psilocybin assisted psychotherapy, the psilocybin group had 25 milligrammes of psilocybin administered during the toots psychotherapy sessions, while the citalopram group had just one milligramme of psilocybin administered during the psychotherapy sessions. This was a bold decision. In the past when studies use niacin as a placebo. These study investigators wanted to ensure that subthreshold or barely adequate dose of psilocybin was used the study as a result compared the direct impact of psilocybin and the current antidepressant standard of care, head to head, and the results were published in the New England Journal of Medicine. The results were astonishing. two doses of psilocybin administered during the psychotherapy sessions was no different to the citalopram group, in terms of the antidepressant scores, but all the secondary outcome measures which includes lower depression scores, and a higher proportion of remission occurred in the psilocybin group. These promising results imply two things Firstly, that the two sessions of psilocybin therapy is as efficacious as antidepressant medications. Secondly, while the clinical trial was not powered for superiority, but only for early signal detection, the improvement in secondary outcome makes it amenable to design a suitable phase three trial with different endpoints such as remission rates, and other scores.

JoJo 36:09

Now let’s get back to the studies performed by Humphrey Osman Abra, ma Hoffer and Smithies in patients with alcohol addiction using LSD. More recently, another pharmaceutical entity that is already an existing anaesthetic is being used for psychotherapy with success. Well, most of the efforts in the United States focus on impact of this molecule on depression. emerging research efforts suggest promising results in substance abuse. One of the leading researchers in the field is Dr. Celia Morgan, Professor of pharmacology at University of Exeter as a researcher who started her career in the mid 2000s. Dr. Morgan’s goal is to help patients and ensure that this type of treatment is approved for use within the UK healthcare system, the NHS. She decided to focus on ketamine as it is scheduled to substance and more importantly, an abundance of data pioneered by a Russian scientist Eugenie Kubicki, who would use ketamine to treat alcohol use disorder a couple of decades earlier. Around the same time, early data with ketamine in depression was also coming to light. So Celia Morgan decided to focus her research efforts on ketamine and its impact on reducing drug addiction. Here is Celia Morgan.

Celia Morgan 37:29

Yeah, I my clinical trials been on alcohol addiction. I’ve done clinical trials of cannabis use disorder with other compounds and other addictions. So in a pod addiction and I’ve, I’ve conducted a kind of naturalistic study of treating substance use disorder with Iosco. But yeah, the clinical trial itself was ketamine and alcohol use disorder. So that’s the focus although there’s a group at Columbia University in the US and realise that quite as group have been using ketamine really quite successfully to treat cocaine use disorder. I guess the difference with a lot of the studies compared to depression where ketamine is given on its own predominantly the studies in in addiction, I think, almost entirely in fact, all of them have given the ketamine alongside some sort of therapy. So the early work in Russia was a kind of psychodynamic transpersonal type therapy, and is his work in the US has given ketamine alongside mindfulness training or motivational interviewing and our work has sort of been similar giving ketamine in a context of relapse prevention based Mindfulness Therapy, so quite a bit different to the depression work with ketamine. But yeah, I think maybe that is because there might be a slightly bigger risk when you’re giving ketamine to substance use disorder populations.

JoJo 38:49

So how does ketamine work?

38:52

Yeah, quite wildly different in a way that drugs legendary for people who have the experience of them will probably be aware of that. So in terms of the psychological effects of MDMA, because you’d get outwards, but not very sociable you get these kind of euphoria, empathy energy, the three E’s of ease being Sancho dips and then in terms of the brain you know, works on serotonin five ht transporter, and psilocybin equally you know, works as an agonist on five ht receptor, I would say the serotonin receptor, so not to use too much neuro scientific verbal, but get it and so I decided because it’s you know, lots of visual, colourful visual hallucinations, but you get a preservation of your kind of what we call your top down thinking so your cognitive processing, various Kasmin produces a lot more work. So complete different receptor on the N methyl d aspartate receptor, which acts on glutamate which is the major excitatory neurotransmitter in the brain. And ketamine seems What is it an analgesic drugs so it’s a class of drugs called a dissociative anaesthetic and dissociation is meant to be one Have the real hallmarks of the experience in that. Nobody says people feel just kind of mildly, oftentimes mildly drunk. But as this has increased, they feel kind of separate from their environment to really detach from their body, often gait going up to getting out of body experiences. So I’m quite profound. So the scene from the outside, completely catatonic, but inside there, we’re having these really intense journeys and who these nations often out of body experiences. So we think ketamine is probably the best of all the psychedelics and it’s not a classic psychedelic, because these are drugs like LSD and psilocybin that works like this at the five htt a receptor. But of all the psychedelics, I think it’s best at creating this kind of disembodiment. So separation from your body, we think that’s quite powerful, therapeutically, and some of our psychological therapy. So I’d like to get to a place where you could use all of these compounds in therapy and tweak it. So, you know, for we know that MDMA builds trust and increases cooperation. So in psychological therapy, we know that the alliance that you have with a therapist accounts for something like 60%, of the effectiveness of the therapy. So you can see a space where maybe giving MDMA early on to build that therapeutic alliance would be great, and then using ketamine to get these kind of out of body dissociative experiences, which to our I mean, it’s kind of a simplistic way of explaining it, but we think it’s like realogy, that gives you a different perspective on your life and enables you to process these completely differently. So if you’ve got stuck in a rut of thinking, which often is the case with all of these kind of, like mental health problems, so similar to depression and alcohol use disorder, it just get any was d scopist, out of that rut and get a different perspective on your life. And the encoding we think is what brings about these kind of transformational experiences that we see in our therapy. So there is a neuroscientific racist to that, in that preclinical animal studies have shown that in the hours and day following ketamine, you get an increase in synaptogenesis. So the growth of new connections, particularly the prefrontal cortex, your brain becomes more plastic, your brains more able to learn. And we think that might help psychological therapies work better because what we’re asking people to do in psychological therapy is to take different to learn new things and take a different perspective. So that kind of brain plasticity might be a neurobiological facilitator of that process.

Arun Sridhar 42:29

ketamine works on the mmda receptor, very unlike MDMA, that we saw in the last episode. ketamine is a dissociative anaesthetic. So we asked the same question on PTSD to SR Morgan, on how she chooses patients for the trial,

42:49

that he had to meet criteria for severe alcohol use disorder. And so that’s what is causing significant impairment to their, you know, their relationships, their ability to function in the workplace, you know, they’re spending considerable amounts of their time doing chemo seeking drinking. So that was one of the criteria and that is met in various different ways. There’s quite variable, the presentation of people actually wouldn’t be all, you know, you imagine your standard aquatics, you know, on a park bench is not all like that there’s very functional alcoholics, you know, maybe not even drinking every day, because that loss of complete loss of control and the significant impacts on your ability to do the things that you want to do in life and causing huge disruptions to your relationships. So that was one of the criteria. The other one is not to have had a substance use disorder of another kind. So he thought that was having comb over substance use disorder. Remember this is because it’s a clinical trial, we want to test it in the safest possible way to start with, and then we start rolling it out and seeing, you know, potentially more risky combinations. But that was one of the criterias may not have been a treatment for another substance use disorder. We allowed some small amount of recreational Kasmin use historically, so up to 10 times lifetime, but never more than I think it was once a year from memory. And other criteria for the clinical trial, people couldn’t be on antidepressants. Because we were looking at the mechanism as well. One of the ways we thought it might work is that when people detox from alcohol, they become depressed Germany because you’ve taken something away from them that they were using to deal with negative emotions. And we thought that being on antidepressants might potentially mask that actually, I don’t think that was a good inclusion criteria, because we ended up it turns out about 60% of the people that came forward, were on antidepressants. But yeah, we didn’t have criteria around treatment resistance. But actually, this is not a treatment that people of the people that came to us really considered as a first line treatment. I would say most people, their average age of people presenting was about 41, which is kind of maps on to the treatment seeking and alcohol use disorder. So they’re people who’ve had long history with alcohol and it’s getting more and more out of control where some people, you know, reduce their drinking, but they get older their alcohol use is escalating. But many of them had had a number of had tried. I mean, it was a feature of the patients, you know, they tried everything else. And they were at the end of the line, really. So they tried inpatient detoxes. They tried all local drug and alcohol therapy, they often tried. You knew other private private treatments. Yes. And, and always relapse? Well, that was what’s really gratifying seeing people maintain their sobriety on this, because there were people who tried a lot of other things. I mean, one criteria that we had for this trial, but I think we got really good data, that’s just we don’t need to have it again, is that people have really good liver function, we’re not significantly impaired, say not three times millimolar liver, like liver function levels, which were high levels of worse. And obviously, that’s a problem for alcohol, because alcohol affects your liver function. So in that respect, we might not have got, you know, a very broad group, because we had to exclude people with significant cirrhosis. That’s because Guzman’s broken down by your liver, so there was some worries around that. But actually, you know, there’s a trade off there, as with any medication, I guess, and what we shows is that we have a function improved in the ketamine group across the trial, partly because they reduce their drinking. So yeah, we feel confident that that would be potentially grounds to try that in the phase three trial. Hopefully See, try people with poor liver function. Just making up the face to child at the moment, yes. is part funded by awakened yet to take that in NHS settings say? Yeah, and that’s really exciting.

46:47

Yeah, going forward for that say, is what you always aim for with clinical trials, as you know. Yeah. So we only did a six month follow up. But we are doing a kind of just an opportunistic follow up after that. But that’s underway at the moment. So some of them have been now three years the but we did the formal for up to six months and 96 patients and we have four groups. Because I’m a psychologist, I was interested in the interaction with psychological therapy. So we had two ketamine groups, rather than just ketamine and placebo, we had cattlemen, and psychotherapy and ketamine and alcohol education, which was, so it was the match for the amount of time spent with a therapist. And because we know just if you’re a lonely person, he’s a drinker. And you know, you’re going through this stuff actually just coming and sitting in a room with someone for I mean, they did it was an intensive therapy course. So they did seven sessions and an hour and a half long therapy. So we wanted to match for the time spent with a therapist but have no therapeutic content. So those were our two ketamine groups. And then we had to placebo groups again, physiotherapy perceive education. And what we found was everyone did well during the treatment phase, which was short. So it’s four weeks, seven sessions, as I said, of an hour and a half long of therapy or education and three infusions of ketamine. But all groups, because they’re in a clinical trial phase, no treatment phase, they’re all doing really well and ever and so they enter the trial abstinent and they maintain that abstinent for that short period. But then we started to see the groups diverged at three months. And in the way that we predicted, which is a key, which was the best or the best, the greatest accidents within the ketamine and psychotherapy group, and then the ketamine alone. So that’s something that hadn’t really been tested whether ketamine alone was effective in alcohol use disorder, it seems like it is not alone. It was alongside education, but yeah, and then placebo and therapy and then proceeded education. So in that order, with the greatest accidents seen in the ketamine therapy group, and that the difference was still significant at six months, there’s still a greater difference. I think overall, in terms of there was a 60% reduction in the chance of relapse in the overall in the ketamine groups compared to the placebo groups, but actually, there was a 25% greater chance of maintaining abstinence if you gave therapy alongside the ketamine rather than ketamine alone. So that should emphasise to us the importance of giving therapy on the side of the Katzman. And yet we were blown away that it worked the way that we had hoped say, so it’s really exciting to be taking it forward to the phase three stage now.

JoJo 49:27

So you can see how the research group headed by Dr. Celia Morgan is slowly taking this already approved drug through systematic testing in stages. sylius study was a phase two study similar to the silicides and depression trial conducted at Imperial College London. It looks promising enough for them to consider a phase three pivotal study upon which the UK regulator will make a decision to make this available widely through the healthcare system. And what does the journey of a patient through the ketamine therapy look like? Here is Celia Morgan. giving us some examples.

50:02

I mean, I think, I think to some extent, it does happen with some current treatments, but it helps you work with maybe a bit more of the root cause of the problem rather than the symptoms. So it was very interesting in our patients, the things that were spontaneously come up, and they’re ketamine infusions, we didn’t really Shepherd them, we gave them an instruction to think about their life without alcohol. And they did sit we did some mindfulness training before they went into the infusions. But often they end up thinking about things in their childhood, a lot of unusual things would come up, I think of one patient who was really quite severely dependent. I think he was drinking seven bottles of wine a day, when he had just seen his life crumble basically, as a result of drinking, and he lost his way for this job, I guess, the standard picture, but he not really reflected on any of the reasons for that. And he’d been through impatient detoxes engaged and disengaged with our code services many, many times. And he said, actually, during the ketamine infusion, he had this sense of calm that he was was wrapped up in cotton wool and his sense of being safe, like for the first time in his life, and he could sort of look, he’s his abused by his father, and he could look upon his father, he saw his father, and he saw himself as a child, and he felt, you know, compassion and sympathy for both in a way. And he said, That was such a powerful thing. And then, you know, with a therapeutic context around that, you can then go in and pick it. But that’s why I think that’s really important to be able to have that space for people to have those experiences and then to be able to pick them afterwards. And this guy who didn’t, you know, never say, since he was, I think, for 20 years, they’d say, for longer than a month, and still say 18 months later. So it’s really incredible to me, those kinds of experiences, that people it just seems kind of transformational process. I think. Many people have these sudden epiphanies that you just don’t get on. Sometimes you get in like therapy, but it takes a long time. It just seems I think it’s like acts as a catalyst, that process to maybe dig down, to not be scared to kind of approach the trauma in the past, or the things that are maybe underpinning some of these problems was probably an overly simplistic explanation. But yeah, I’ve seen in action with a number of patients. So it’s really gratifying to be involved in this work. Actually. I’m really exciting.

Arun Sridhar 52:27

That was the story of ketamine, and already approved drug use currently as an anaesthetic, but currently being explored for an expanded indication in psychotherapy for alcohol addiction. Now, can we turn our attention to a psychedelic that we have discussed extensively in the last two episodes, MDMA. MDMA, as we know inhibits the serotonin reuptake in the synaptic terminals, and therefore makes more serotonin available for action, triggering the psychedelic experience. We know that the experience with MDMA is very different to what has been experienced with LSD, psilocybin and DMT. The constituent in Alaska, a UK clinic run by a psychiatrist and a psychologist is attempting to take the lessons learned from MDMA psychotherapy sessions, pioneered by maps and applying it to substance addiction. We invited Laura heatbed, psychologist at the psychology clinic Awakened Life Sciences. Since we spoke with Laurie, awaken life scientists has expanded to drug discovery, and aims to open clinics in almost every major city in the UK. They have also followed an interesting fundraising path that we will cover very soon. But for now, here is Laura heatbed.

Laurie Higbed 53:47

Thank you for having me along. As you said, my name is Laurie heatbed. I’m a clinical psychologist, and I’ve been working with people with addiction problems. So in drug and alcohol services for about the last 10 years or so. That’s been really rewarding, challenging work. And then more recently, in my psychology career, I’ve been working alongside Ben Sesa and David Nutt and colleagues at Imperial College London, investigating psychedelic assisted psychotherapy. And we’ve been focused on treatments for alcohol use disorder, and using MDMA. And I also work in a depression trial. So we’re using psilocybin to support people with long standing depression problems.

JoJo 54:40

And for us here at scraps, it’s not just the fact that these molecules provide therapeutic benefit. We’re going to dive a level deeper. A therapy or a science or a paper is only as good as the people who work on it. So we asked Laurie why she got into this field. Here’s her story,

54:58

just a little bit about why wanted to work with MDMA might might be of interest because, you know, it’s quite, it’s quite an interesting story how I came to be working in this field, which is, as I said before, I’ve been working in addiction services for a long time. And it was very rewarding work. And I met some wonderful colleagues and some fantastic clients, many of whom did recover, and some of whom, who didn’t, who, who, you know, tried their best and everything they could into their recovery, but kept needing to come back for support. So, you know, I was in this position of trying to support my clients as best I could. And then a new psychiatry is rocked up to our service corps, Dr. Ben Sesa, and we started chatting about, you know, how, essentially, our caseload were full of people who had trauma histories, and we’re doing their best to try and cope with their distress. And, you know, if they hadn’t picked up alcohol, or heroin, or use crack cocaine, to try and cope, they just be in mainstream mental health services, but because they chose an illicit, you know, illicit substance or try and mask their pain here, they were in our services, and doing their best, but often struggling to engage in the therapies that they that they needed to. And from my point of view, as a psychologist and a therapist working with those people, you know, if they were fortunate enough to be able to sit down with me to try and work on their trauma, it was a real challenge for those people usually, because they have to think and talk about their pain, and their, you know, trauma experiences. And that’s really tough. And there’s that sense of it can you can feel a little bit worse before you get better. And you know, that so even though those therapies, traditional therapies, I’m thinking things like cognitive behaviour therapy, and which are good therapies, we see quite high dropout rates, because of the reasons I just described. people struggle with them. So here was talking about thinking, Oh, what could we do that’s, that serves our, our, our clients better. And then he started telling me about his work with psychedelics. And this is about 2014. And I didn’t know much about the field at all, then. And then we started chatting, and he said, You know, I’m going to do a research trial with alcohol use disorder. And we’re going to use MDMA, because we have, in 2014, we’ve had those that seminal work from maps, and from Michael and Annie MIT Hoffer, who, who published this phenomenal paper, about, you know, the success of treating PTSD with MDMA assisted therapy. And we thought, these are this is real similar cohort here. So that’s why we went down this road of MDMA for alcoholism. And then so to answer now to your second part about training, again, for a real fortunate experience for me that I was able, this is in 2016, to fly to America, and be trained by Michael and Annie MIT Hoffer, who absolutely, you know, revered in this in this field, and have done most of the MDMA assisted therapy on on maps, research trials, and you know, what you have, so it’s kind of a couple of weeks of a, an intense programme, where you are kind of watching videos, and you can do kind of some of your own role plays as well. But, and that is extremely helpful to kind of reflect on the material that you’ve seen. And to and obviously, to, you’ve got Michael and Annie’s therapist modelling how, how to be an MDMA therapist, and then what you get to do and, and you’ve kind of referred to it being a challenge, but you can absolutely do it within them within our kind of maps. protocol, is you can go and have your own MDMA assisted therapy,