Psilocybin-Facilitated Treatment for Addiction: Smoking Cessation – Matthew Johnson

At the risk of sounding redundant, I’d also like to thank Amanda and the Beckley Foundation for really taking a leap of faith with us. Smoking hadn’t been a clinical target, even in the older era of research. So thank you, and also, thank you to the Heffter Research Institute for providing supplemental critical support for the study. We feel very, very fortunate to be doing this work. As Roland [Griffiths] said, we actually started cooking up this idea back in 2007, so it’s been six years since we’ve been involved with this research project. Fortunately, it’s really accelerated recently. We’ve got some numbers and some really exciting data, so let’s get going. The first question is “why in the world would you use a classic hallucinogen to treat addiction?” You probably have a clue about that if you attended Michael Bogenschutz’s talk and Steve Ross’s talk early today, but I’m [going to] give my rendition of the rationale for that. I think there’s some substantial overlap, but that’s a good thing. I think the evidence is pointing us all in the right direction. I put the rationale into three categories: one, looking at the ceremonial use of hallucinogens within indigenous cultures and syncretic religions. The second area of evidence comes from early research using hallucinogens to treat addiction from the [19]50s through the ’70s. Then, finally, the research on nonaddicted individuals in our studies at Johns Hopkins and the mechanisms that are suggested there, that seem consistent with an anti-addiction effect. The suggestive anthropological evidence is that a number of reports have shown that the ritualistic consumption of hallucinogenic compounds, and these are classic hallucinogens, within ceremonial contexts, has been associated with decreased rates of addiction and substance use in a number of studies. A number of studies have shown this observationally for peyote use within the Native American Church, peyote, of course, containing mescaline. Also, a number of studies have observed that within ayahuasca-using groups, both indigenously and in syncretic religions, that there’s reduced rates of addiction. However, a big caveat to these studies, of course, is that they’re observational, and that participation in any religious group is associated with decreased rates of addiction. Certainly they don’t take the place of controlled experimentation, but they are highly suggestive, and suggesting it’s worth looking at. Then we have the early research era from the ’50s through the ’70s, using classic hallucinogen-facilitated treatment of alcoholism and other forms of substance dependence. This was primarily LSD in the treatment of alcholism, although there was a controlled study for opioid addicts. So while some studies prepared participants and utilized supportive conditions, other studies administered high doses of LSD to unprepared and physically restrained patients, not the conditions that you would predict would be associated with therapeutic outcomes by a modern understanding. So here’s a picture of the session room from some of the folks that were doing things the right way, much like the rooms of the modern studies that you’ve seen pictures of throughout the conference, hopefully: very pleasing and comforting, with a supportive study staff. Here, on the flipside, some of the studies restrained patients with these types of restraints in a hospital bed, with virtually no preparation…other than “here’s a different experimental drug” and “let’s see what happens.” You can see there’s a stark contrast between these older studies. Results across the studies have been considered inconclusive due to such variation in methods, lack of experimental rigor in the other non-controlled studies. Several of these [used] a relatively small sample size. However, recently some clarity has been brought by the meta-analysis published by Terry Krebs and [Pal-Orjan] Johansen, taking the studies that had controlled conditions and performing formal meta-analytic techniques. That’s just a way…you can take different studies and pool their results together by using a common language of effect size. So even if [there are] single studies that didn’t have enough participants to be able to show a significant effect, you’re able to pool the studies together and potentially see if there’s a significant effect with those larger numbers. This is just one set of results from that study, showing results from the first followup, which ranged from 1 month to 12 months across studies. What you’re seeing here in this figure is the odds ratio of the treatment. So, any result falling on this side of the line in the middle shows a positive effect for LSD, and anything over here shows that the control group did better. These are the individual studies, and this big guy is the average of all studies. What you can see here, interestingly, [is] that all the studies fall on the LSD side, and even the studies that strapped people down and didn’t give them any preparation, even though they weren’t statistically significant in that study, they all fell on the LSD side. You pool them together and you get a highly significant result. In terms of what that really means, it roughly doubled the odds of someone being successfully abstinent at that followup time point. I think it’s very intriguing, if you’ve seen Roland [Griffiths]’s talk earlier, and you’re familiar with some of our research, we’ve really shown this very special… …there are several findings that show that it’s not just receiving the drug psilocybin that’s associated with the various positive outcomes; it’s the nature of the experience that occurs, particularly the mystical-type experience. There were some suggestions of this in the earlier clinical work, that the mystical-type experience may have mediated successful clinical outcomes in these addiction studies, and the same thing was also shown for the cancer work, although it wasn’t very rigorously looked at. However, then the dark ages came. Really…it was a real tease. There were these positive signs of efficacy, there…was enough variation across the studies for potential skeptics to be able to dismiss the entire agenda. Then there was the much larger social phenomenon of LSD primarily becoming associated with the counterculture, and everything [that] went along with it. The behavior of a few less than responsible research groups contributed to that. Followup studies that provided both careful participant preparation and support during experiences, combined with rigorous experimental design, were never really conducted. Human research with hallucinogens in the US became dormant soon after. A lot of folks say hallucinogen research became dormant, but in fact, during that period, some of the most important work was conducted, not in humans but other work exploring the mechanisms of hallucinogens during that time. But human work was dormant. The dormancy, importantly, was really not due to a credible scientific critique or medical critique of the studies. It was really due to those larger sociological concerns, that I mentioned earlier, about the use of LSD on the streets. So the third category of suggestive evidence that there might be a signal here [is] findings from our laboratory. We have evidence of behavior change from volunteers and community observers, so not just the folks having the experience, but people around them, saying, “there’s something different about this person.” They were allowed to…tell us that there was something different on the good side and bad side, and it fell on the good side. There wasn’t a lot of specificity to those ratings, because everyone brings their own issues, and there was no specific target, behaviorally, for people to change, but that was very suggestive to us. Also, self-reported long-term positive behavior change, that was in our 14-month followup study. So folks [were] saying things were still different, not just their attitudes but their behavior over a year after [the] psilocybin experience. In looking at those studies, we really have what I see as evidence of long-term mood-elevating effects. You could call them anti-depressive effects. That certainly can play a role in addiction. With the earlier mentions of behavior, of course, the exciting thing there is that with addiction, we’re talking about behavior. That’s really been the focus of my career…to look at addictive behaviors, even before I started with psilocybin research. While it’s great that people say this is one of the most important things that’s ever happened in their lives, and it’s been very meaningful to them, the real proof is in the pudding. Are lives being changed? Are people doing things differently, both with themselves and others? You can’t ask for a better test than highly entrenched addictive behavior. Then there’s the highly salient mystical-type effects with sustained meaning and spiritual significance. If you…attended the talks this morning, you got a little bit of the history of the association between spiritual experiences and addiction recovery, with the probably most well-known case being that of Bill Wilson, founder of AA. Then finally, we have the pooled analysis of the first two studies, that Catherine McLean authored, showing that increases in personality openness occurred as a result of psilocybin exposure. Interestingly, again, it wasn’t just psilocybin per se; it was those people who were exposed to psilocybin and had a mystical-type experience who showed the increase in personality openness. So certainly, that’s addiction recovery. One has to be open to change. One has to be open to viewing themselves in a different way, and moving [on] a different path. Why would we look at smoking? As I mentioned earlier, it was alcoholism that was the primary focus of earlier work, and nothing had formerly been done looking at cigarette smoking. But Roland [Griffiths] alluded to…the reason why. We really wanted to develop the approach, and we wanted to be cautious and demonstrate feasibility for addiction if there’s any possibility that that efficacy is there. We didn’t want to start with the most difficult challenge. We wanted to see if the signal was there. So with that in mind, cigarette smoking was selected as a model system of drug dependence because it… has a relative lack of social and economic impairment that often accompanies other drug dependencies. Typically, no one’s spouse has left them, no one’s lost their home, no one’s homeless because of it. As Roland said, it’s almost a pure addiction in the sense that it’s a pure self-control issue that something is dealing with, something that [they have] wanted to change for years, often, and [they] just haven’t been able to do it. The motivation is there but it’s not. There’s this intrapersonal conflict. That’s what I believe is addiction. Then there are some anecdotal reports of quitting after psilocybin and LSD. I was familiar with just a few of those at the very beginning, but the more and more we’ve been presenting this work, people come up to us and tell us. Then there’s trip reports out there that will speak to it, and some accounts, [not in] the formal scientific literature, but in books that have been written. I know what some of you out there may be thinking. “Okay, psilocybin for helping people” “quit smoking?” I know some of you might be thinking, “Come on. I know some cats that love” “smoking cigarettes when they’re on mushrooms.” Right? How many people have known cats that love smoking cigarettes when they’re on either mushrooms or LSD? This cat here, [laughter] I talked to him. [With a] quarter-ounce of mushrooms, this guy said he had a full-blown mystical experience when he put that cigarette in his mouth. [He was] really enjoying it. I’m not denying at all that…plenty of people have smoked during their psilocybin experiences and that they’ve enjoyed it, and that plenty of people have… had psilocybin experiences and they haven’t been inspired to quit. But in my mind, it’s amazing that it ever occurs that someone would quit smoking when it wasn’t their intention to, if it spontaneously occurred during a psilocybin experience. So if we could leverage that within a prepared clinical model, [we] could really just tweak up the gain of that, and increase the percentage of success. It’s not just a good potential model system, if you will, for other drug dependencies. It’s a beast in itself. When considering the potential impact on human suffering, if this is effective for smoking…This figure is showing US drug-related deaths per year, in the thousands. When we’re up here at 500, we’re talking about a half-million people. Over-the-counter pain relievers, all illict drug use combined, all the heroin, all the cocaine, all the methamphetamine etc. [is] right there. Prescription drug use: a little more. Alcohol, as devastating as it is in terms of mortality, there it is. Tobacco, it kills more people than all of them combined. Even though psilocybin, yes, would never be for everybody as a means to quit smoking… if it was effective for even a small portion of the people that want to quit smoking, we’re talking about unbelievable potential to change people’s lives and alleviate suffering. I was speaking [about] the US just there. About 5 million deaths per year worldwide occur with smoking, so again, huge suffering. I personally wouldn’t be interested if [we were] talking about folks that aren’t looking for help, if they enjoy smoking and understand the risks that they’re undertaking. But in fact, the large majority of people smoking, at least in the US, want to quit, and they’ve just been unable to do so. For those people [who] want to quit, even the most effective medications out there fail to help the large majority of patients [to] remain smoke-free for a year. So here’s what we did in our pilot feasibility study. We integrated cognitive-behavioral therapy, which is really the backdrop to a lot of smoking cessation programs, with traditional… psychedelic therapy. I think it doesn’t get enough credit, but it’s really this paper by Chwelos et al., 1959, in the Saskatchewan group that really first defined psychedelic therapy in the literature. [There is a] high dose of a psychedelic combined with [an] introspective framework: eye shades, music, supportive study staff. Multiple sessions were given, up to 3 doses of psilocybin, ranging from the first session, being at the target quit date for quitting smoking, up to 8 weeks after that quit date, first session being 20mg, body weight-adjusted, and the second and third session moving up to 30 mg, body weight-adjusted, although we had the option built in, if 20 [mg] gave a sufficient response, we could [stay] put right there and have 20 [mg] be in the other sessions. Participants were guided through advertisements, seeking smokers wanting to quit, and it did mention psilocybin. We got daily dependent smokers; they had to be daily dependent smokers with multiple previous quit attempts. The Fagerström Test [for] Nicotine Dependence score had to be at least five. That’s just a widely used clinical measure of smoking dependence, and they had to smoke at least 10 cigarettes per day. “Healthy” [w]as determined by interview, medical questionnaire, physical exam, ECG [electrocardiogram], routine medical blood and urinalysis laboratory tests. Just giving you some quick demographics, these people were about 50 years old, smoked almost a pack a day on average [and had] been smoking about 30 years, and had 6.2 previous quit attempts. So these were real smokers that had been smoking a long time that wanted to quit. We followed safety guidelines at our lab, as published, for safely administering psychedelic compounds. I’ll briefly go over the study timeline description. There were 2 screening visits involved, 4 preparatory sessions for the people that qualified for the study upon those visits. Those prep[aratory] visits lasted 4 hours each with the treatment team, which included two staff members, who also served as psilocybin session monitors. In the first 5 sessions, this was me in the sessions, along with Mary Casamano for the first 4 sessions, [who] handed it off to a talented post-doctoral fellow working with us, Al Garcia, who gave a talk on our qualitative results on Friday. But that’s really helped us accelerate study progress most recently. We assigned a target quit date with them. We picked a date where they would quit smoking and have their first psilocybin session. The participant[s] developed, with our encouragement, a mantra, really. “What does it mean, deep down, to you?” “Why do you really want to quit smoking? What’s the one phrase you want to say to yourself” “in the future if you may be tempted to have a cigarette?” We went over cognitive-behavioral therapy techniques for smoking cessation: a lot of standard things: keeping a smoking diary, identifying queues, consequences of smoking, techniques to break the automaticity of smoking, how to deal with potential lapses once they quit, acceptance of some not inevitable but likely weight gain. Guided imagery was used; that was a part of a previous surprisingly successful smoking cessation program. We thought it would fit quite well with the introspective framework of the study, so we used some of those guided imageries. Like our other studies, it included a discussion of life, history, family, relationships, philosophical/spiritual/worldview orientation, like “what’s your big picture of things?” and their smoking history as related to all of those other dimensions. Specific preparation for the psilocybin session day: what to expect, what’s going to happen logistically. We had the target quit date, no explicit focus on smoking during the session itself. …Within 2 weeks after the target quit date we had 2 additional sessions, 1-2 hour meetings with the treatment team to discuss both the psilocybin session and to reinforce the cognitive-behavioral therapy techniques. Two weeks after the first session, we had a second psilocybin session, going up to the higher dose as a default. We always have a check-in visit with the people the day after every session. Weeks 3-7: we had again weekly 1-hour meetings with them going over the same things. The third psilocybin session [was] on week 8 after they quit, a day [afterward] followup, and then 2 weekly meetings, again reinforcing the CBT techniques and discussing the psilocybin session. We got outcome measure at 6 months and 12 months, including biological verification of smoking at all of the time points, all of the interactions. We do have a little quit-smoking ceremony at the end of our target quit date, the first psilocybin session, when they stamp out their last cigarette and tear up the rest of their pack. Okay, here’s the money shot right here, the success rates. We’ve had 15 people in the study. I’m showing you data on 12. Two additional people have had sessions…too recently for me to get the data in here. One person has their session coming up. I’m showing you two biological measures of smoking: urinary cotinine captures smoking over the last couple of weeks, and breath carbon monoxide, capturing smoking within [an] immediate time frame. Across the x-axes in both these figures, we have all of the study visits where we measure these things. Right here is the target quit date. You can see the trend. Boom. It just dropped with the target quit date. Out of these folks, we only had one person here that was doing some chipping, if you will, although at a substantially reduced rate compared to his baseline performance. Then we had one person that showed a little evidence of smoking, and I’ll say more about him later. By the carbon monoxide measure we didn’t see any evidence of smoking. So even that confirms that this person was [doing] pretty low-rate smoking. About that one participant [who] dropped out of the study, that’s the person that had that little blip at the very end, the 12-month followup. He dropped out of the study in between, even though we still followed him up, missed seven sessions including the third psilocybin session. He thought that would have helped him more. He had 40 cigarettes between the 6- and 12-month followup[s], so that’s a pretty low rate of smoking. This guy was [smoking] a pack a day coming in. So even our so-called failure is still doing a lot better than he was. As I said, he reported that he thought the third session would have been helpful to him. He wished he hadn’t missed it. One participant reported 143 cigarettes between the 6- and 12-month [followups], although she was completely clean at the 12-month time point. …Essentially, her boyfriend broke up with her, she went back to smoking full-on, [a] pack a day for two weeks. She snapped out of that; she remembered her mantra, what she learned in the study, and actually stopped completely by herself without any interaction with us. She’s absolutely a success in my book. One person reported smoking four cigarettes, [it] might be a little bit more, between the first and the third session. He hasn’t gotten to his 6-month followup yet. Interesting, like I said, about the effective mystical experience. Too early to make definitive conclusions, but it’s very intriguing. Excluding the guy that dropped out of the study, which is a special case, we have 9 participants who did not lapse. Their mysticism scale score was 215. This was the Hood Mysticism Scale that we’ve used in our other studies. The two participants who had lapses had a mean mysticism scale score of 160. [It] looks like the people who have mystical-type effects in their sessions are the ones who are able to remain smoke-free. I’m going to go very quickly over this. We asked people within 2 weeks…if it helped, how it helped them quit smoking. [The] most common one was… we said check all that apply; that was the framework. They said changing one’s orientation towards the future so that long-term benefit outweighed immediate desires…[The] second-most commonly endorsed one was it strengthened your belief in your own ability to quit. [The] third-highest was endorsing changing life priorities or values such that smoking was no longer more important than quitting. Next was reducing stress involved with quitting. Next was reframing quitting as a spiritual task. …No participant responded that psilocybin wasn’t helpful. Everyone thought it played a role. Additional reasons listed were awareness of the addictive process, increased determination to quit, greater perspective, and increased distance between the desire to smoke and taking action. I wish we had included that last one. A lot of people were saying things like that, like there [was] this space that they could have in the days and weeks following their session, where they could make a conscious decision. I think there’s going to be more interesting stuff on that. Just very quickly, case descriptions: First participant [was] from the DC area, said he was involved with politics. [laughter] Actually, no. Obama did quit a few years back, not in our study, although if he was [in our study] I wouldn’t be able to tell you. Confidentiality. But our first participant had been smoking many years [with] multiple quit attempts. He said some very…his descriptions of his sessions…really, certainly highlighted the mystical nature, really a sense…of freedom, a sense that…everything was okay as it is, and that he didn’t need to smoke. I’m about out of time, so I’m going to go through… [I] just have some quotes from his various sessions. …We only go up to a year [with] formal followup, but he’s kept in contact. He’s been smoke-free for actually three and a half years, about, now. In conclusion, the low sample size and lack of control group and placebo condition preclude any definitive conclusions regarding the efficacy of psilocybin per se. However, results could be, and undoubtedly partially are, driven by expectation, the cognitive-behavioral therapy techniques, and/or the relatively high level of psychosocial support. We know now that the approach is feasible, and subjective reports do attribute a substantial role to psilocybin. Continued promising results…I would say the results we already have definitely support future controlled-trial testing [of] the specific role of psilocybin. I’d like to thank all of the important members of our research team, the folks that have contributed to the smoking study, [applause] and again, the Beckley Foundation and Heffter Research Institute. Thank you very much. [applause] [moderator:] Thank you Matt. So we have some time for just a couple of questions, if anybody would like to come up to the mic. We’re a little bit over, but let’s take a couple. Q: Thank you, Matt. That’s great, and obviously the potential significance of something like this is enormous for medicine. Twelve months is a great long-term followup, but as we know, smoking isn’t about stopping for twelve months; it’s like 5 years, 10 years. Do you envisage booster sessions, so rather than having to go through the whole thing again for people who relapse, [the] possibility of just having a much briefer course of therapy with psilocybin in the years afterwards? A: Yeah, that’s a really interesting question…First, I think we probably should, as we move forward, we should build in some auxiliary followups to the people who [have] participated in our previous studies. Maybe we can get them back in, they’d have to sign in to a new protocol, and just…see what the landscape is. Are people relapsing or not? And if people are relapsing after a year or so, absolutely. I think [that] if you have a therapeutic technique that works for an entire year and you have to readminister it, any other medication would be called a miracle drug by that standard. So that’s an interesting possibility. Q: [I have a] followup to Ben’s question: People that relapse after they’ve gone through the psilocybin study, I would be interested to have that compared with people that relapse [after] quitting without using psilocybin, and if psilocybin actually helps quitting again, the second time, easier than not taking [psilocybin.] A: Well, we’ll have to keep our eye out on that one. Hopefully with a much larger controlled trial, we’ll see what the landscape is like and if there are those folks. That’s a possibility to look into. Q: One quick question is: were any of the subjects who quit using nicotine replacement therapy? A: No. There was no NRT in this… Q: The second question is: do you feel that…obviously the psychological mechanism via the mystical states was clearly extremely important, but do you think there was perhaps a physiological mechanism by which neuroplasticity effects via increased BDNF [brain-derived neurotrophic factor] may have consolidated the CBT training? A: Perhaps. I think any number of biological mechanisms [are] at play. I think the findings…on default mode network functioning, that are occurring acutely, if those are occurring after the effect, I think that’s really intriguing in terms of people being a little more conscious about their decisions going forward. Absolutely, I think there are psychological ways to look at this and biological, and we’re looking to get into some more biological meat behind this pretty soon. Q: Thanks for your work and presentation today. My question’s kind of similar, along the same lines. Do you feel like maybe impulse control after using the psilocybin has something to do with them not going back to smoking? You said something about that… when the feel the need to… A: Absolutely, and I think it’s what I said about that space that’s opening up; [it’s] almost like the background chatter in the mind has settled down. What’s left is this ability to just [say], “oh, this is when I would normally grab for my cigarettes,” “aha, I see what I’m doing. I’m conscious. I don’t smoke anymore.” You just have that little window of opportunity to make a decision. That’s decreased impulsivity. Q: Do you think we’ll be able to maybe see that with brain scans and stuff? A: Yep. Q: Great. Q: I had one question about the internal consistency of the study. You mentioned [that] there [were] a couple people who have reported relapse of use. I think it was like 20 cigarettes and 140 cigarettes. Are those the subjects you saw the plasma levels of, I forgot, the metabolite of the nicotine…but are those the two subjects [in whom] you saw spikes? A: Yes, absolutely. That was consistent. Q: One more question was: during this 12-month study, when was the last period of time where participants received a dose of psilocybin? I missed that portion. A: That was 8 weeks after the target quit date. Q: So it…sounds like about 100 percent basically quitting, of these 12 participants. A: Well, there was one person, who still hasn’t reached his six months, that has had some cigarette smoking before his 10-week, his end of his active phase of treatment. Nonetheless, very high, over 90% success rate by that time point. No matter how you slice it, at least by absolute rate it still blows out of the water the existing treatments. Again, we need to do more work to confirm this. Q: The description you gave of how the mastery over impulse control seemed to develop in these folks sounded very similar to reports that I read of folks who were trying to treat severe obsessive-compulsive disorder with psilocybin. I know that there has been some MRI work done in that area. Do you know, are any folks making comparisons in terms of that impulse control ability between addicts and obsessive-compulsives, or are they too dissimilar for that to be useful yet? A: I think much more work needs to be done. It’s an interesting idea. Certainly, more work needs to be done, even in demonstrating the efficacy for obsessive-compulsive disorder. The published trial actually shows that a low dose had the same effect as a high dose. You could interpret that as “even the low dose works,” or you could interpret that as “it’s a placebo effect driving everything.” So I think more work needs to be done in that area…and more work needs to be done in this area too. But they’re both too early to make any strong statements about that connection, but it’s a great idea. Q: Thank you.