Psilocybin-Assisted Treatment for Alcohol Dependence – Michael Bogenschutz

Thanks, everybody, for coming for the first talk of them morning. We’re going to be talking about [the] application [of] psilocybin for treatment of alcohol dependence. In this talk we’ll start with a brief review of the research on use of classic hallucinogens for treatment of addiction, then talk a little bit about possible mechanisms of action, and then I’ll move into the description of our current pilot study and give you a little bit of preliminary results that we have available at this point. Psilocybin is a classic hallucinogen. As most people probably know, drugs in this class are defined by their action at the serotonin [5-HT]2A receptors, although they act at a number of other serotonin and other types of receptors as well. Other terms that are used for these drugs are “psychedelic” or “entheogen.” Those terms are used for drugs in other classes as well, so “classic hallucinogen” is a slightly more specific term. There are [a] large number of both naturally-occuring and synthetic compounds in this class. They all produce fairly similar somatic, perceptual, and psychic effects, but these effects depend strongly on not only the dose of the drug that’s taken, but the set and setting in which it’s administered. The naturally-occurring classic hallucinogens have a[n] extensive history of use in ritual contexts in many cultures, especially in the neo-tropics. Importantly, these drugs don’t produce a classic addiction syndrome, but it’s important to remember that they can be misused and can pose some significant risks with uncontrolled use. However, in clinical research contexts, there’s extensive data at this point showing that they are quite safe. These are just a few of the most well-known classic hallucinogens: psilocybin, here, and psilocin both are very similar structurally to DMT and serotonin. Psilocin differs from psilocybin only be having a hydrogen here at the R position, rather than the phosphate group. When psilocybin is ingested, it’s rapidly metabolized to psilocin, which is probably the main biologically active form. There’s a long history and fairly extensive literature on the use of LSD in the treatment of alcoholism, which I’ll review here briefly. Clinical use of LSD for alcohol dependence began in Saskatchewan [Canada] in 1953, and it actually became an accepted form of treatment there. It was used clinically, completely outside of [a] research context, and many thousands of individuals were treated. The initial rationale for this mode of treatment was that the LSD experience, which was then primarily conceptualized as a psychotic-type experience, was thought to mimic the experience that alcoholics have when they’re going through DTs [delirium tremens]. So they would have this horrible, nightmarish experience, and hopefully hit bottom and see the light and have a turning point, and stop drinking. But in the clinical applications, what people found was that the experiences that the alcoholics were actually having were not so much like the DT experience, and that many people were reporting very positive experiences, transcendent, mystical, transformative experiences, that were…much more positive than what they had expected. Under the influence of these experiences, and also some input from Al Hubbard, there was a shift to the psychedelic model of treatment, which emphasized the importance of the peak psychedelic experience, or a single overwhelming experience that would lead to persisting changes in personality, in values, in understanding of self and others, and ultimately in behavior, including but not limited to drinking. There were many reports in the literature on clinical use of LSD for alcoholism. The early reports showed improvement rates of up to 70% in samples of very severe inpatient alcoholics. Scientifically, these reports weren’t terribly convincing, because there were not adequate controls, so it wasn’t clear how much of this effect was due to the specific treatment and whether these were really representative patients. But there were randomized trials done in the late 1960s. The results were considered to be mixed, and if you read any of the reviews that were written prior to 1912 [2012?], the consensus was that these results were really inconclusive. Some of them suggested there was something going on. Others were less positive, and so you just really couldn’t say whether there was any effect going on. Then, clinical research with hallucinogens came to a screeching halt in the early 1970s, due to increased regulatory barriers, including the Controlled Substance Act and growing concern about adverse social and personal effects of these drugs. Just to put us back in the mindset of what things looked like at that point, this is [Timothy] Leary and [Richard] Alpert, back in about 1965 at Harvard. They’re looking pretty conservative and harmless, and probably focused mostly on getting tenure. A few years later [laughter] things had changed dramatically. I think it’s important to remember that this was a frightening time for many people. LSD was an important part of the mix. I put this up not to pick on Timothy Leary, or anybody in particular, but just to say that I think the backlash was inevitable, and to remind us that this legacy is something we’re still contending with. [For] many people, still, when they think of LSD, this is what they think. So we’ve still got some work cut out for us. But, getting back to those studies, [Teri] Krebs and [Pål-Ørjan] Johansen published a very nice meta-analysis last year of the 6 randomized controlled trials that were published. These were all double-blind studies, at least until the drug administration. Two of them broke the blind at that point. Almost all of the participants in these studies were male inpatients and these were all single-dose studies: one dose of LSD. Doses ranged from 210 to a whopping 800 micrograms. The control conditions: a couple of the studies used a low dose, which was 25-50 [micrograms] of LSD, still quite psychoactive doses, psychostimulants, or no-drug control. There was great variation in the psychosocial package in which these treatments were conducted, in terms of the preparation, the support that was given, the amount of therapeutic alliance that was established, the debriefing procedures, and the psychosocial alcohol treatment was really not controlled at all, because it was just part of the inpatient treatment that people were in. In spite of all that heterogeneity, this is from their paper. This is the figure showing [the] first available followup. The studies varied in their followup schedule, so these time points range from one month to 12 months, but you can see there’s a really quite consistent effect favoring LSD, and the overall odds ratio is very close to 2, which translates into a number needed to treat of 6 to 7 for the drinking outcomes at this first followup, which is slightly better than the effects that you see with naltrexone at end of treatment, naltrexone being the most effective FDA-approved pharmacotherapy for alcohol dependence that’s currently available. This effect appears to be maintained at 2-3 months and 6 months. In the studies that had 12-month followups, the effect is no longer apparent. Effects from a single session lasting up to 6 months is…I think it’s pretty impressive. There are obvious limitations to these studies and to any meta-analysis, but I think that’s fairly persuasive evidence that there may be something going on, [and] that we should be looking more closely at this. So that was about it in terms of controlled studies that were done with classic hallucinogens for addiction. There was one LSD study in heroin addicts that had a positive outcome, a study using dipropyltryptamine in alcohol dependence, which did not have a significant finding but had very poor followup rates, and really [there were] no controlled trials with psilocybin or mescaline. Ayahuasca was not very well-known in those days. So there haven’t been clinical trials of any of these other drugs, although there’s certainly been some clinical use. Stepping back for just a moment, how can taking a drug just once or twice cause lasting behavior change in any way? There’s not a lot of evidence that speaks directly to this question, but what we have done is try to pull together what’s known about the effects of classic hallucinogens in general and what’s known about the process of recovery from addiction and try to formulate some hypotheses that can be tested in further research. This model is not a model of what happens; this is a model of really a number of possible pathways that we need to investigate and see what’s actually going on. Starting with the drug and the participant and the setting…I say participant rather than set, because there are a number of individual characteristics that could be important predictors of the treatment response beyond their mental set, including their individual biology, their drinking history, [and] other personal history that’s not just their mental set. The drug is ingested and there are acute brain effects, which include the direct effects on serotonin receptors, secondary effects on glutamate receptors, second messenger systems, and so forth. Concomitantly, there are acute psychological effects. Of course, there’s been a lot of emphasis on the transformative or mystical experiences that many subjects have, but there are a number of other psychological experiences which are of potential value in terms of insight or changes down the line. These acute effects by themselves can’t really directly cause changes in drinking; there have to be some intervening variables. Persisting effects on the brain level could include a number of neuroplastic or functional changes, which could be measured, potentially, with neuroimaging. Improved mood or decreased anxiety is something that at least in the short term has been reported. Changes in personality, changes in beliefs and values…So these are some of the psychological domains that could be affected. Finally, to lead to changes in drinking behavior, we would need to be affecting some of the change mechanisms that are known to lead to changes in drinking. This could include changes in craving, improved self-efficacy, which is a strong predictor of successful outcome in alcohol treatment, increased motivation, maybe improvement in executive function, although [I’m] not sure there’s evidence for that at this point with these medications. So ultimately, the endpoint would be reduced substance use, although of course we would be interested in improvement in other areas as well. A little bit about the mystical experience business, because this has been such an important theme and hypothesized change mechanism in addiction application: The link between mystical experience and addiction recovery has been emphasized going back at least to William James, who said…over 100 years ago, the only cure for dipsomania is religiomania. Carl Jung also felt that for some severe alcoholics, religious conversion was really the only hope. Interestingly, he also conceptualized addiction as a misguided quest for spiritual connection, which I think is interesting. The Oxford Group was a Christian movement, prominent in the 1930s, which developed a whole program of ministering to and saving alcoholics through religious conversion. They were more or less the direct forerunner of AA, which emphasizes spiritual awakening as the key to 12-step recovery. A lot of people don’t know that Bill W[ilson] heard about the work that was going on in Canada and was interested in these LSD effects, and in 1956 he had his own first LSD experience with Sidney Cohen at the LAVA and claimed to recapture his 1934 famous white light experience by taking LSD. He became an enthusiastic support of the use of LSD to help alcoholics understand the spiritual aspects of recovery. We know from the work of Bill Miller and Janet C. de Baca that spontaneous transformative experiences happen, in and outside of the context of addiction, fairly commonly to people, and [these] seemed to cause lasting changes when they occur in that way. The work of the [Johns] Hopkins group with psilocybin has demonstrated that more than half of normal volunteers receiving high-dose psilocybin in their lab will have a complete mystical experience, and that the mystical experience is associated with persisting meaningfulness of the experience, and also increase in the personality dimension of openness. So that’s pretty impressive information. Then, finally, there’s the use of 5-HT(2A) agonist…plant materials containing these substances in religious contexts. There are clearly very low rates of alcohol and drug misuse in the people participating in the ayahuasca churches that have been studied. Also, probably in the Native American Church, alcoholism rates go way down, although…there aren’t a lot of really good data from that group. Of course, in the religious context, you’re talking about a whole constellation of beliefs and practices in addition to the pharmacological effects of the plant. Also, regular use in a religious context over periods of years is very different [from] the models that have been used clincally, where we’re talking about one to a few high-dose sessions, which are supposed to produce lasting changes. It’s different, but it’s still interesting that there also in this context seems to be an inverse relationship between use of these substances and [other] substance use. Moving on to our pilot study, we thought there was strong justification for reopening this question and starting to look at whether we could develop and test a model of using psilocybin in treatment of alcohol dependence. So this pilot study includes 10 individuals. We’re recruiting 10 people in a single-group design, and they received 2 psilocybin sessions in the context of 12 weeks of psychosocial treatment, and then we follow them out for an additional 6 months, so 9 months total. The doses we’re using are .3 and .4 milligrams per kilogram. Everyone gets .3 in the first session, and then the dose may be increased up to .4 in the second session. This is a pilot study, so we’re looking at assessing the acute effects, demonstrating tolerability and feasibility, evaluating pre/post changes in drinking, and then looking at number of the psychological outcomes that may meditate the changes in drinking that we hope to see. A month. So here’s the overall design. There’s a month of psychosocial treatment, then the first psilocybin session, another month of psychosocial treatment, second psilocybin session, and then 4 more months. So it’s sort of a psilocybin club sandwich. Psychosocial components: for the alcohol treatment, we’re using motivational enhancement therapy, which is a standard evidence-based brief treatment for alcoholism that’s aimed at enhancing motivation to change. We’re using two co-therapists. One of them is doing the motivational enhancement therapy. The other is managing the preparation and debriefing. So there’s one person [who is] the alcohol expert, and the other is the psychedelic therapy expert. We’re conducting the sessions using the standard model that goes all the way back to the ’60s and the University of Maryland group, and has been used in most of the recent clinical work with psilocybin. We’re measuring a number of other, in addition to drinking, outcomes, using the timeline follow-back. We’re measuring craving, self-efficacy, motivation, mood and anxiety symptoms, mystical experience, personality and values. So, all the things I had up on that mechanisms diagram earlier. In the last couple of minutes…[These are] some results from the first five participants. Two additional people have received the first session since I made these slides, but we don’t have the post-session outcomes for them. Overall drug effects [show] a curve similar to what’s been seen in the normal volunteers. It’s starting to look like there may be…less sensitivity in the alcohol population. We haven’t done a direct comparison, but we’ve had some experiences that seem to be milder than would be expected at this dose. But the overall response is similar. This is percent [of] heavy-drinking days, which is our primary drinking outcome. So this is pre-treatment, going back [for 3] months prior to treatment. That first month where they’re receiving the psychosocial treatment only is here, and their drinking, for these folks, it’s pretty much stayed the same. During the month following that first [psilocybin] session, we’ve seen some dramatic drops in heavy drinking days. If you look at percent days abstinent, that’s similar too. [There were] big increases in abstinence. We’re seeing craving drop, especially during the 1 week after the psilocybin session, and then possibly rebounding a little bit. Confidence in ability to stay abstinent is rising dramatically in that week after. Qualitatively, I[‘ll] just say that we’ve seen a very broad range of experiences from the mystical to the interpersonal and biographical, some very intense, some not so intense. People have uniformly reported strong decreases in their craving for alcohol and increased salience in some of their positive values like family, religion, health, productivity, being [a] useful member of society, and they felt rejuvenated and optimistic. There really haven’t been any significant adverse events to date. In conclusion, I think we’ve demonstrated that this is feasible, that these experiences are well-tolerated, that they seem to be leading to decreases in drinking and craving and increases in self-efficacy. So I think we’ll finish up this trial, this pilot, and then I think we’ll have a strong rationale for proceeding to randomized trials to see if we can really demonstrate that there’s a specific effect going on. So, just a quick thanks to members of our team and others who have contributed, and thanks to the Heffter Research Institute for providing funding for this study. We’ve got a couple [of] minutes for questions, I hope. [applause] Q: I may have missed something at the very beginning. In the Canadian studies, did you mention anything about Nicholas Chwelos and Duncan Blewett? Was that mentioned? A: No. Q: They did a study using LSD in a 30-day inpatient stay with sclerotic liver patients who were doomed, in the late ’50s, early ’60s, using one individual session after a couple of weeks of prep time…of individual psychedelic psychotherapy…followed a week later by group psychedelic psychotherapy with two therapists, one of whom took the psychoactive stimulants with the patients. [They] found that, amazingly… about 25% of the people immediately stopped drinking, and 30% of the people, approximately, were able to return to appropriate social drinking: a glass of wine, a beer, no longer having craving. … what patients reported…they described later having had a forced viewing of [what were] formerly perceived to be unacceptable self-perceptions, but once integrated through the psychedelic experience, they understood it and integrated it differently and were therefore no longer motivation to drink. A: Yeah. That was one of many of those uncontrolled and very positive and encouraging reports that came out. I think this self-examination mechanism, it’s not an either/or thing, but that, in addition to the mystical and self-transcendent aspect, for some people that seems to be very powerful. Q: Right. They also wrote a lengthy manual about how to prepare patients and work with patients and take them through the experience, that predated Leary’s manual by a couple of years. A: Yeah. We just have time for one more question, so I’m happy to talk with people after. Q: I was just wondering if you had any plans for more longitudinal studies, or if you think the model will go more with a biannual/annual treatment with psychedelics and alcoholism and addiction. A: I think we need to start with a small number of sessions, especially given the data that we have from the studies from the 1960s, that there do seem to be some persisting effects, even from one session. I think we need to find out what the effects of that are. Then, assuming that that actually has a measurable effect, if it’s not optimal for all people, we can start to look at the effects of periodic boosters, sure. Okay, thank you very much. [applause]

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