The Science Of Serotonin: How Do Psychedelics Influence Behavior?

Podcast Highlights

Although Zach started out as a student of psychology and philosophy as an undergrad, he decided (on the advice of his tutors) to move into neuroscience. He started working towards an understanding of the detailed mechanisms of the brain – at the level of individual cells and synapses.

After some years, Zach became frustrated with the perceived lack of progress in this area. He decided to move away from the cellular and molecular level, and start studying behavior. It was around this time that he first encountered psychedelics, and one LSD experience in particular helped to reinforce his interest in behavior and cognition.

Now, Zach runs a neuroscience program at the Champalimaud Centre for the Unknown in Lisbon, Portugal. His goal is to understand how the brain gives rise to intelligent adaptive behavior – including decision making. Much of his research is focussed on the neurotransmitter serotonin, which most classic psychedelics mimic in the brain.

SEROTONIN AND LEARNING

The latest research from Zach’s group shows how serotonin is involved in re-learning associations. In their study, mice learned a certain association (i.e. lever push = treat). Then, the conditions were changed: the lever now produced an uncomfortable effect (a puff of air to the face). The mice now had to re-learn their association of the lever with a positive effect.

Previous research had shown that serotonin is involved in this re-learning process, making it easier to forget the old association. What Zach’s group wanted to know was how serotonin was doing this – and they found, by looking at single neurons in the mouse brain, that serotonin was enhancing neurons’ response to surprising events. Overall it means that serotonin allows the brain to be more adaptable to a changing environment.

WHAT DOES THIS MEAN FOR MICRODOSING?

How is this relevant to psychedelics and microdosing? Zach is hesitant to make speculative leaps in judgement, but mentions studies that show serotonin reducing impulsivity and promoting patience. He says it would be interesting to see the effects of microdosing in a task that requires impulse control. Maybe microdosing could be useful in helping people break out of habitual behaviors.

Could microdosing have a role in human evolution? Zach points out that evolution needs a component of variation to work. In our case this is genetic diversity. Microdosing could be a new source of variability in cognitive evolution, by promoting more divergent ideas and new ways of thinking.

Overall, Zach wants more research to fully understand the effects of microdosing, and emphasises the importance of set and setting, even with small quantities of psychedelics. He believes that microdosing has the potential for harm as well as the potential for healing.

Show Links

1. Zach’s research group at the Champalimaud Centre for the Unknown
2. Zach’s latest research into serotonin and behavior
3. Zach’s twitter

Podcast Transcript

0:00:28 Paul Austin: Okay hey listeners and welcome back to the Third Wave podcast. We're actually doing a slight re-branding which we'll roll out in more details in an email newsletter. If you're not on our email list yet, subscribe to that, get our newsletter but we made a team decision to re-brand from the Psychedelia podcast to Third Wave and this is just gonna be the podcast of Third Wave, it's a bit simpler and allows us a bit more flexibility with what we're doing.

0:00:55 PA: So welcome back to the Third Wave podcast. It's great to have you guys all back again. I'm actually recording this from Amsterdam, in the Netherlands. I am here for The Next Web conference which is one of the leading tech conferences or probably the leading tech Conference in Europe and I'm here to speak about microdosing.

0:01:11 PA: I will speak on Friday, May 19. So you guys, if you're already listening to this, it already happened and so I'm kind of in urgent mode preparing for the talk. It's probably the best professional opportunity yet because I will be speaking about microdosing to a tech and entrepreneurial audience. Most of the talks that I've done so far, the seminars that I've done so far have been to a largely psychedelic audience. I think many of these people at the conference will either be psychedelic naive or curious about psychedelics or may know a thing or two but haven't done it before so it's a phenomenal opportunity to bring more of the messaging to a new audience and I'm super, super, super excited for that.

0:01:46 PA: So a few things for this week in psychedelics. One, an entrepreneur is building a DMT machine to allow communion with aliens. He is looking for tens of thousands of dollars in funding. His name is Egon Arenberg. He's a web marketer from South Florida and he's one of a handful of people who think he's found a new way to contact aliens through DMT. This article is on The Rooster which is a website that Third Wave has been featured on a number of times and like I said, he's looking to raise thousands of dollars.

0:02:24 PA: I think it's interesting. I think it's fascinating. I would love to use it myself. So we'll see if he can get the money necessary to make it happen and this was written by Riley. Hey Riley, if you're listening to this. Riley's a good friend of mine. He's written a few pieces for The Rooster about microdosing that we've been featured in.

0:02:43 PA: So DMT machine, tens of thousands of dollars, that's really interesting. Fundamental, just released their campaign video. Fundamental.NYC, they are supporting psychedelic research for mental health through crowdfunding. They're trying to raise millions of dollars for research into alcoholism, into cognitive ability for microdosing, into end-of-life anxiety and into PTSD, that's the last one. End-of-life anxiety, cognitive ability, PTSD and alcoholism. That's what they're trying to raise money for. It's through a crowd funding campaign. They've done a really good job of designing the website and I highly recommend you guys go and check that out.

0:03:28 PA: A couple more announcement, there's a video review of the Psychedelic Science conference by Reason TV. Reason is independent media outlet and they usually have pretty good stuff. I haven't watched the video myself but if you want to get a fairly objective view of the Psychedelic Science Conference that would be really cool to check out and news from Germany, 1P-LSD will possibly be illegal in Germany soon following advice from independent experts to the government. This announcement was translated on Third Wave's forum. Go check out Third Wave's forum, if you haven't yet, by a German member.

0:04:00 PA: Obviously, that's not going to make a difference. You can still order things from the Netherlands and you can still order things from elsewhere. Yeah, it's just silly. Governments are silly, governments are out of touch. They really don't know what they're doing when it comes to psychedelic substances. So let's get into the show this week.

0:04:12 PA: So for this week, we're joined by Zach Mainen who is a neuroscientist at the Champalimaud Center for the unknown in Lisbon, Portugal. Zack is one of three research directors. He's been in Lisbon, Portugal since 2007-2008 and he leads a team of 20 researchers where they basically try to test the role of serotonin in decision making for rats and Zach studies the role of serotonin in behavior and learning. He explains what his results could tell us about the way psychedelics work in the brain and we're also discussing future research into microdosing that could help us understand its true potential.

0:04:48 PA: So what I really, really tried to push Zach on and press Zach on is okay, when we're microdosing, what is going on in the brain? What's happening in the brain? We know that for example, psychedelics disrupt the default mode network. We also know the activation of 5HT2 receptor leads to plasticity, it also leads to more patients to impulse control so when we microdose, what's going on? We try to come to some conclusive conclusions. I hope that you guys get a lot of value out of this podcast. It's one of the best podcasts. Zach is incredibly informative.

0:05:18 PA: We do get a bit abstract at times, using terminology from a neuroscience perspective. However, I think overall, the messaging is very good so please take a look and take a listen and I would love to hear what you guys think about this podcast. A couple of things before we go, if you could, please leave a review on iTunes, thank you. If you enjoy the show, it helps other people find us and we're on Patreon, patreon.com/thethirdwave.

0:05:45 PA: This podcast is 100% listener-supported. There will never be advertisements and I wanna keep it that way but the only way I can keep it like that is if I have enough money to pay for rent and food and stuff like that so your donations are incredibly appreciated. It would go a long way to helping us continue to carry out this message. So without further ado, here is the podcast with Dr Zack Mainen.

[music]

0:06:25 PA: Can you just give some background about who you are and your professional background and your psychedelic background in whatever context, in whatever context you wish to share?

0:06:35 Zack Mainen: My professional background, I studied psychology and philosophy as an undergrad and it was pointed out to me when I was deciding what to do that I would be better off doing psychology than philosophy by both my philosophy and my psychology advisers but I took that as a statement about philosophy and not about myself so I ended up going into... I was interested in artificial intelligence, that's how I got into psychology and I started working in a lab, that was a neuroscience lab and decided to do a PhD in neuroscience and I actually got sucked into a very low-level mechanistic understanding of the brain or trying to get to a very detailed understanding of the brain.

0:07:20 ZM: So I was studying things like how does one neuron talk to another neuron through a synapse? How does the synapse change? What are the molecules that are involved? What are the dynamics of the molecules involved? So really small nitty-gritty stuff. I did my PhD in San Diego and then I came out to New York to a place called Cold Spring Harbor Lab and continued to work at that level and then around '99, I was promoted to have my own group at Cold Spring Harbor and at that time, I was burned out and bored basically with that.

0:07:58 ZM: We kept basically saying, "We found this mechanism at the level of the synapse which works like this and we're pretty sure that this is gonna have really big implications for how we understand complicated behavioral and cognitive processes. We can't really quite tell what they are but it's gonna turn out to be important." So it was always sort of too far off and I decided to switch quite radically and start studying behavior. All this work is being done in animals so this was synapses in animals because you can't study really synapses in the living state in people.

0:08:34 PA: Sure, it's just not allowed. Right. [chuckle]

[overlapping conversation]

0:08:38 ZM: So at that time I said, it would be... I really wanna study consciousness or cognition. I want to study why the big questions. Why, why, why are we here? How does it all come together? It was actually at that same time that I encountered psychedelics and actually, I would recount a particular moment in which I had taken LSD and I was contemplating the experience itself. I was saying to myself, "Oh my gosh, this is the most profound kind of insight that I've ever had into my own mind. It's amazing how could it possibly not be true?"

0:09:21 ZM: And then it occurred to me, the only way it could not be true is if the substance itself, this chemical itself, had somehow tricked my brain by pushing the button that says 'This must be true and important.' So if that was happening, then the thought that I was having was not true and important, it was just that I had taken some substance that had deluded me into thinking whatever it was that I was thinking was true and important.

0:09:48 ZM: But that, in itself is interesting, it is really interesting. Actually, that idea that there could be a chemical which would interact with something in the brain which would send a signal of importance, of meaning, of certainty, almost seemed to me more interesting than whatever else I was thinking about at the time.

0:10:08 ZM: Actually, what I was thinking about the time, I subsequently mostly forgot about but this idea that there might be a mechanism in the brain that is central to the evaluation of truth, of central to certainty, is basically what's been motivating my research ever since then so for the last 18 years and I've taken a number and followed different threads in trying to address that in different ways.

0:10:34 ZM: So we've studied for example, how humans report or even animals report their sense of confidence. When you ask someone to make a decision, where there's some degree of uncertainty, you can then ask them "How confident are you that you took the right decision?" and they can tell you very confident or not very confident. Animals, even mice, can be asked the same question. Of course, you don't ask them verbally but you put them in a situation in which they make a decision and then you ask them to gamble on the result of their decision.

0:11:07 ZM: They gamble by waiting and if they wait and the reward that they're expecting is not delivered, then the more confident they are, the more they're willing to keep waiting for this expected but not delivered reward. Same thing that would happen say if you were waiting for a bus and you weren't exactly entirely sure when the bus was going to come, if you were really confident that it was gonna come, you'd be willing to wait longer before packing it in and going home.

0:11:37 ZM: So it's this idea, you can report confidence, you have a sense of confidence, well that seems to be something that's not unique to humans. It seems to be something that animals have as well and we can therefore start to try to understand in a mechanistic sense where it comes from and perhaps link it to the receptors that are activated by a drug like LSD.

0:12:00 PA: Why is that important?

0:12:01 ZM: As an example of a thread that takes off from that idea. Why is that important?

0:12:06 PA: Yeah, why is that important to tie the mechanistic to the understanding to LSD or so someone could facilitate that?

0:12:12 ZM: So the basic goal of modern or contemporary neuroscience is to take the understanding of the brain that we've had so far and to take it to the next level. The next level is to understand the brain as a kind of circuit or a network. So the human brain, as you know it's of over 100 billion cells, 100 billion neurons. For a mouse brain, it's more like 100 million and they're organized in a very complicated network and so we build models. We would like to have a model of those networks in detail that links the single cells, which we understand fairly well, to the global behavior of the thing.

0:12:57 ZM: So there's a big gap in scale between cells that we kind of know what's going on. We know how a single cell takes inputs, synaptic inputs, basically connections through other neurons integrates them in space and time and then decides whether to send a signal to the next neuron or not. There are detailed models, I worked on those sort of models when I was a PhD student and there are still details that are left out but kind of think we know roughly what's a decent model for a single cell.

0:13:32 ZM: So we would like to link that to the level of behavior, to the level of thinking or cognition but between that scale and the scale of the whole brain, between the scale of single cells and the whole brain, it's very very complicated. So to understand the effect of a psychedelic on the whole brain or on one's thoughts, one would need a good model of what are thoughts or what is taking place in this vast network and how is that being modulated? That's what we're striving for.

0:14:06 ZM: In other words, we can make up whatever theories we want and I could tell you how I think about it at a top-down level from a cognitive perspective or from a psychological perspective but in order to really understand it the way we're trying to understand the brain, we need to map it onto our picture, our growing picture of what these networks do, how they process information.

0:14:35 PA: So let's go with that angle, let's go with that thought. Specifically when you're talking about thoughts because I think this is an important part of what we're now discovering from a medical application side of psychedelics is, I sent you those pieces on the default mode network, for example which Carhart Harris has talked about in the research he's done in Imperial and there seems to be this aspect and I don't know how this is related to the default mode network but people who struggle with depression have a tendency to fixate their thoughts on the past.

0:15:00 PA: They have a tendency to become stuck in the past so to say, to dwell on the past and that can affect their present moment. So what have you done at your lab, the research you've carried out, for example, the piece that you recently published or the paper that you recently published showing this relationship between serotonin receptor activation, cognitive flexibility in rats, what are those implications for the thought process and how it relates to the applicabilities of psychedelics in the medical context?

0:15:25 ZM: You've got a lot in there. I don't believe in next...

0:15:26 PA: Well, you could take it apart, you could take it apart.

0:15:29 ZM: Let's leave the thoughts per se out for a second and just talk about... Let me address... Let me just try to address what studies we're doing and what we mean by plasticity and how might that relate to psychedelics.

0:15:42 PA: Good.

0:15:42 ZM: How about that?

0:15:43 PA: We'll start there. I feel like sometimes I just go for the home run. I'm like I just ask too big of a question.

0:15:49 ZM: You got it all, you got it all there. Okay, so let's see, the first thing we have to say is, what is a psychedelic? It's more or less defined as something which binds to a type of serotonin receptor one of about a dozen.

0:16:05 PA: Which one? The 5-HT2A, right? I just wanna... I'm like... 5-HT2A okay.

0:16:11 ZM: Yeah. 5-HT2A. There's some debate about that at a certain level but let's say by and large that accounts for a lot of the observations so what we've done in my lab is to back off and say well, let's ask what does serotonin itself do? So serotonin is also something that binds to the serotonin 5-HT2A receptor and we actually don't know very well what it is that makes serotonin be released in a natural circumstance.

0:16:40 PA: Endogenously, we can say, right?

0:16:40 ZM: Endogenously right but it is absolutely the case that serotonin is a very important endogenous transmitter in the brain, extremely important and that at least in part what it does is probably mimicked by a psychedelic. So would it be interesting to understand what the neurons themselves, the ones that when they get active, do the same thing as psychedelics, why do they get active? What circumstances, what can make them more active? So that was the question we had in mind when we started the studies that you're referring to that were published... It was in January, in E-life, January or February.

0:17:21 PA: Yeah, recently, it was quite recent.

0:17:22 ZM: Fairly recently. So again, working in mice, we were actually picking up on experiments that had been done previously by other groups, notably Trevor Robbins group had done some important work on this where they had trained animals, it can be done with monkeys, it can be with humans, it can also be done with mice, the animals are trained to expect a reward in a particular situation. The situation is signified in our case, by an odor. It could be anything, it could be sign on the wall so a particular trial...

0:17:57 PA: Like olfactory in nature.

0:18:00 ZM: Well, it can be any sign, it's anything that's predictive. So it sets the condition. It sets the context or the condition in which the next few minutes, moments are going to unfold. So say if it's a mouse, mice are quite eager to... Quite attuned to odors so that's a very convenient thing to do, if you're working with humans, you're gonna to probably look at visual stimuli. It's kind of irrelevant but what's important is that that stimulus, that cue is arranged to always be followed by a particular outcome and you could use a reward or a punishment, a significant, a salient, a meaningful outcome.

0:18:35 ZM: So for a mouse, the mouse is thirsty, getting water is really meaningful so if you repeatedly pair the presentation of a particular odor with a little bit of water later, they'll quickly come to anticipating the water whenever they receive that odor as has been observed for well over a century. You've heard of Pavlov and the dogs, I'm sure you may have even seen it in your own experience with your own pet so you can easily condition animals to anticipate something.

0:19:07 ZM: In these experiments you then play a trick or you shake things up by reversing the association. So an odor that was previously rewarding is now either simply not rewarded or is now followed by a mild punishment so for a mouse for example, it's a bit of a puff of air to the face. So it's quite mild.

0:19:31 PA: Gentle.

0:19:32 ZM: Gentle.

0:19:32 PA: We're being gentle with the mice, right? Even though we're gonna feed them to snakes later, we're being gentle to the mice.

0:19:39 ZM: We're being gentle and in fact it's much more difficult to work with animals in a situation in which you have punishments involved. So by and large, we only improve the experiments by not tormenting the animals any more than is absolutely necessary. So this this is a paradigm called a reversal task. So the animal has learned say odor A is followed by water and then at some point, odor A is no longer followed by water and it has to now re-learn the association. It now has to not lick basically. They normally lick to get the water. If it's reversed, they have now to not lick.

0:20:15 ZM: You can also play it the other way around. You can take an odor that's reliably followed by nothing or by a mild punishment and then flip it so that now it means reward and they again have to re-learn so this is considered cognitively more demanding than just learning the original association because you now have to sort of overwrite the previous habit or the previous association needs to be gotten rid of and it also requires, in a sense, the animal or human to withhold a normal response.

0:20:52 ZM: So you could say there's potentially two components, a re-learning component would require some kind of plasticity and a impulse control or a withholding of a response. So you're used to always pushing the button and now the button is broken and you have to avoid fruitlessly pushing that button or the sign...

0:21:16 PA: To learn quickly, right? You have to learn quickly. You have to adapt quickly.

0:21:19 ZM: So adaptation eventually should occur. You should eventually re-learn but there's a period that animals and people go through in doing this kind of re-learning where they often unconsciously start to show a kind of hesitation to perform the action that they normally would do. So in this kind of reversal task, it had been shown that locking serotonin receptors can affect the performance of this kind of task. In particular it makes it more difficult for people or animals to learn to stop responding to the response that was previously effective and what we did was to follow those up by asking "Okay, so what are the serotonin neurons doing normally in such a situation?" and that was an unknown.

0:22:09 ZM: There are very few recordings from serotonin neurons. We wanted to know what type of signal do they have that might indicate that they really are involved in detecting "Hey, something is wrong. What used to be good is no longer good or what used to be bad is no longer bad." and the key question was actually, do the neurons respond to surprises? That was our...

0:22:37 ZM: We generally expected that they would respond to surprises but is it specific to whether the surprise is a disappointment or a fortuitous... There's no great antonym of disappointment actually but an opposite of disappointment so the question is, are serotonin neurons happiness related or are they just surprise related? Because... Or perhaps the opposite? Maybe they're even preferring disappointments.

0:23:05 PA: Are they happiness related or are they surprise related?

0:23:07 ZM: The reasoning would be if they're involved in anti-depressant actions, which is another drug effect that serotonin is associated with, then they should like positive surprises perhaps. The serotonin if it's promoting happiness should be associated with the transition from something that wasn't good to something that's now better than expected but this reversal task, the way we construct it has that type of positive surprise and it also a negative surprise. What we found was that the neurons don't prefer the positive surprises. They are activated by both positive and negative surprises. They're activated by just being surprised.

0:23:48 ZM: So they seem to report at least in part, this is where I make sure I put on my proper scientist hat, where we... There are some complications and details and I don't think this is the end of the story but we overall saw that there's no... Actually and other experiments have led us to the view that serotonin doesn't report or have much to do with the emotional valence of an event but has more to do with it's certainty or it's predictability or it's surprising-ness.

0:24:18 ZM: And that makes sense in the context of this reversal task because what we had known from previous work was that if you block the action of serotonin, the animals are not as good at responding to these reversals. These reversals are basically surprises so if the neurons get excited by these surprises, they contribute serotonin and that serotonin acts in some way, we don't know yet exactly how, to help the brain change or to help it stop what it's doing at the moment because "Hey, I don't know what's going on. I should not do what I normally do." That makes a lot of sense.

0:24:56 ZM: So at least within the context of this kind of learning experiment, it makes sense and reinforces other experiments that had been previously done. Where one place it clearly leaves things a little bit more complicated is, what about the anti-depressants? Why are serotonin re-uptake inhibitors used as anti-depressants? So that's a big question from our point of view right now and another question that you could ask is "Well so what does that say about what do psychedelics do?" Which are probably the more... The main question for the current conversation.

0:25:13 PA: Well and I wanna get into that, right? Because we've been abstracting out of it and we've been using really specific terminology.

0:25:13 ZM: I'm using a lot of words and some of them I'm using them very carefully and some of them not so much and so...

0:25:13 PA: Right but this is natural. I think someone with a neuroscientist background is gonna understand everything we just talked about. Some people who don't might have trouble with that.

0:25:13 ZM: So feel free to back off and make me put some of this down too.

0:25:13 PA: I wanna make it more concrete for people because a lot of people who are listening to this podcast are interested in microdosing.

0:25:55 ZM: Microdosing. Yes.

0:25:56 PA: Right and we talked about this when we had met what six weeks ago or something when I was in Lisbon last time. By the way, we're having this conversation from Lisbon, just so people know and yeah, what's your professional... You run a lab here in Lisbon, right?

0:26:09 ZM: Currently. So yeah, I didn't quite say that.

0:26:11 PA: Quick say that and then I'm gonna get the concrete side of things.

0:26:14 ZM: No one asked for a linear podcast I hope. So to go back to my professional background, I came to Portugal in 2008 to help to start a research institute where I still work called the Champalimaud. Actually, the building is called the Champalimaud Centre for the Unknown, wonderful name and the research program is called Champalimaud Research, used to be called Champalimaud Neuroscience Program. There are about 250 scientists working in the program and our goal is to try to understand how the brain gives rise to intelligent adaptive behavior, things like decision-making, even a broad range of things going on in different individual labs.

0:27:04 ZM: Some labs study different parts of the brain, others different transmitter systems, different species so there's quite a diverse bunch of research going on and I'm the overall... One of three overall research directors and I have my own group, that's 20 scientists in my group, that's more focused on serotonin and decision-making and I also oversee the work going on more broadly.

0:27:29 PA: Cool, okay so let's get into the concrete. The microdosing thing.

0:27:32 ZM: Microdosing things.

0:27:33 PA: And I'll just try to summarize what were some things we've spoken about so far. So for example, which serotonin receptor did you study with this research, was it the 5-HT2A or was it all 13?

0:27:44 ZM: In the work that I was talking about, what we did was I didn't explain this. We used a technique that involved genetic engineering to optically monitor the neurons themselves, not the receiving end where the receptors are but the sending end.

0:28:02 PA: Gotcha.

0:28:02 ZM: So most of the serotonin neurons that are relevant for let's say, the effects on cognition are located in a part of the brain called the dorsal raphe nucleus.

0:28:13 PA: Okay.

0:28:13 ZM: When you get into areas of the brain, you get all sorts of lovely names. That's by no means the worst. So by introducing genetically-engineered... Actually a virus introduce a sensor into the set of neurons, specifically the serotonin-producing neurons, this allows us to visualize when they get activated by looking at basically the amount of fluorescence that they're emitting. They're basically changing their... The way that they respond to light and that gives us a signal of when they're on and when they're off. Basically, when they're firing or when they're not firing.

0:28:50 PA: Gotcha.

0:28:51 ZM: So it doesn't tell us which receptor they were activating. That is they get activated, they therefore are firing, they therefore can be releasing seratonin and then that can be picked up by both serotonin 2A receptors, serotonin 1A receptors and all the other receptors. So we don't actually know those receptors could be more or less activated by the events that we're recording. That's another step.

0:29:18 PA: Gotcha. Okay, so let's tie this into microdosing and we'll try to speak in more concrete terms. In terms of there's an individual or like I've done microdosing... A lot of people are interested in microdosing and they're taking this. It's activating the 5-HT2A receptor or something of that nature. We don't have the research on it yet though in terms of why it's working. It's clearly, it's doing something and it's been working for a lot of people.

0:29:39 PA: There could be a small degree of it that is relatable to placebo but there's obviously some mechanism that's going on and if there's no mechanism going on that people can see, then you just need to take a little bit more I think because what's the difference between 10 micrograms and 100 micrograms of LSD? Something's going on at 100, something must be going on at 10, especially...

0:29:55 ZM: Are you referring to something must be going on and it's not just placebo or?

0:30:00 PA: Correct. Correct, yes.

0:30:00 ZM: So is there some thought that it might be a placebo effect?

0:30:04 PA: I think some people... You have some of the more like David Nichols, for example. Who, you know David? Has led a lot of the research on rats as well in the United States from out of Purdue. He has said to Jim that maybe some of it could be placebo. I was talking to someone else who's doing research with microdosing with older people and there was so much in there. There is a somewhat of a placebo effect with this going on, which is natural for depression for example.

0:30:30 ZM: Yeah, I was going to say that it seems that a lot of... Well there's a very strong effect, placebo effect in depression.

0:30:38 PA: Sure.

0:30:38 ZM: It doesn't necessarily mean that the serotonin effect is not...

[overlapping conversation]

0:30:42 PA: Yeah. You can have both, right? It's not one or the other.

0:30:44 ZM: There may very well be a placebo effect.

0:30:46 PA: It's not one or the other, right. But this is what we get into Dr. Bruce Lipton who wrote this book, The Biology of Belief. If we accept the mind and the body are connected, then our mindset, our view on the world also then dictates things like what happen on a cellular level, with like quantum mechanics. So we're not completely separate. Even if there is some placebo effect, the intention or the purpose behind why someone is microdosing maybe... It might be just as important as to actually taking the substance itself because you don't take things within a vacuum.

0:31:15 PA: There's always environmental context in which you're taking a substance. Even with psychedelics, the difference between you take in a room at Johns Hopkins with a professional therapist, you're going to have more healing through that process than most likely, than doing it when you're 19 after a couple of beers with friends in the basement of a fraternity house. That's what I did and it was an okay experience but it wasn't that impactful. We have these scale of things. So this is what I think about with microdosing.

0:31:42 PA: Anyway, let's kinda get back to the main question. Based on your research with what's going on with the serotonin system and based on your understanding of microdosing, what do you think is happening with people from a neuro-scientific perspective?

0:31:54 ZM: There's so little that at least that I know about studies on microdosing that it's a bit of a challenge to start speculating in the absence of data.

0:32:06 PA: I wanna say speculation leads to questions, better questions lead to better answers. Or they can.

0:32:10 ZM: Yeah. Okay sure, yes. So what would be our hypotheses?

0:32:13 PA: Hypotheses, let's not speculations, hypotheses.

0:32:18 ZM: So let me...

[laughter]

0:32:19 ZM: To answer that question, let me tell you another story about another paper that we published in the last of couple of months that's also related. So this one is actually a bit simpler. So we did a really, really simple experiment with mice again. We put them in a open field, basically, an arena in which they can run around and we kept putting them back in the same arena every day for several weeks and we just measured their pattern of movement and they run around, they tend to stick a little bit to the walls because they're a little bit afraid of an open environment and they don't really have anything to do, there's no food or stimuli in particular, there's just this box.

0:32:58 ZM: And then we started stimulating serotonin neurons and we would stimulate them in a brief pulse. So a few seconds at a time, intermittently. So a few seconds and then wait and then a few seconds and then we looked at what was the effect of that on their movement and the only effect that that has on the movement pattern of the animals, at least as far as we've been able to see, is it slows them down. So they maybe going at an average of say, five centimeters a second, normally and when the serotonin is turned on, it's 2.5 centimeters a second so it's a pretty big effect.

0:33:36 ZM: If you put animals in a more constrained task, in which they actually have to slow down, they have to wait, you could do this by making them wait in a particular location before you give them their water. Serotonin stimulation also facilitates their waiting. It makes them less jumpy. They're less eager to get on to the next action and they make less impulsive choices. So that result that serotonin stimulation seems to reduce impulsivity has been made by a number of groups and there's a couple other experiments that we've also done that I don't think I need to tell you about that reinforce that.

0:34:19 ZM: So one of our... Wasn't our hypothesis but what the data is telling us from our experiments, from a bunch of other experiments is that somehow serotonin has a role to play in let's say patience or some people could say impulse control, preventing impulsive responding.

0:34:39 PA: This is the term that people are using with microdosing.

0:34:41 ZM: Okay so I was not even aware of that.

0:34:43 PA: Exactly and I know you're not. Yeah. Okay, this is interesting.

0:34:46 ZM: So we have now two things that I brought up from our research. One was this role in plasticity and related to reporting surprise and the other was something about impulse control and if you wanna call it patience. It wouldn't be immediately obvious if you're thinking about psychedelic effects to think about patience or at least for me it wouldn't be obvious but as a hypothesis about microdosing, that would be what I would like to look at in say, if I was doing a human study, I would like to see if I could detect an effect of micro-doses of a psychedelic on the performance of a task that required impulse control.

0:35:31 ZM: So maybe if there's more known... As anecdotally, is it the case that microdosing is associated with an increase in patients. Yes, so this could be very useful for people to avoid falling into habitual responding, falling into patterns of behavior that are natural responses or say learned responses to a particular situation that happens over and over again. Those are the type of responses that we think are being inhibited by stimulation of serotonin and could be part of the action of these low doses of serotonin agonists.

0:36:13 ZM: There's still clearly a gap in our understanding between what's going on in the natural situation or when we stimulate with this fancy technique in mice versus what's happening with a particular drug that you're taking. So there's certainly a lot of speculation there but that seems like an interesting possible connection. Maybe tapping into that aspect of serotonin function. The other function, plasticity is also a possibility so going back to the study with mice...

0:36:42 PA: Well, let's take it in that before you... What is the relationship we know so far about psychedelics and neuro-plasticity?

0:36:48 ZM: Well, I can answer more easily about serotonin and plasticity.

0:36:52 PA: Okay, let's do that. Serotonin and plasticity.

0:36:55 ZM: So as you know, serotonin has been better known as an anti-depressant or the happiness molecule but for the last, even now, a couple of decades, there is a line of research that has shown that serotonin seems to promote certain kinds of plasticity in the brain and when we say plasticity in the brain, usually what we mean, what neuroscientists are talking about is some kind of synaptic rearrangements of the type that happen when you learn something and you can study that in different ways, behaviorally like in this reversal task, that evidence that I was discussing before that increasing serotonin helps reversals or decreasing serotonin hurts the ability to do reversals.

0:37:42 ZM: There's also evidence at a physiological level, if you look at how synapses between pairs of neurons change or pathways between sets of neurons change, there seems to be an effect of facilitating a kind of unlearning process so there is thought to be a process for making new synapses or strengthening existing synapses which we call potentiation and then a process for erasing or depotentiating synapses and there are several studies that have linked serotonin to the depotentiation or the sort of losing...

[overlapping conversation]

0:38:03 PA: Like SSRIs. People consuming SSRIs...

0:38:27 ZM: These studies at this level are animal studies with agonists of serotonin or antagonists of serotonin receptors in very reduced like, I would say reduced preparations.

0:38:37 PA: It depotentiates.

0:38:39 ZM: It seems to be promoting a, what we call, long-term depression, which sounds bad but is not necessarily bad. [chuckle] But you could think of it as what needs to happen to get rid of... Well, to allow new pathways to be formed, it's sometimes necessary to get rid of old ones or to just basically keep everything in balance. You may not be able to constantly keep increasing everything just building, sometimes you need to clean house and un-build before you can rebuild. So that, at the cellular level, there's evidence that ties serotonin to that function.

0:39:14 ZM: And there is another particularly, I think, interesting and important study that showed serotonin is important or can open a window of plasticity during... For what is a developmental process. So there's certain processes that as your brain is wiring up or you could say as you're going through childhood and adolescence, which is when a lot of your brain is wiring up, parts of the frontal cortex are still not completely wired until you're through adolescence.

0:39:43 PA: Sure. So like 25? Is that generally...

0:39:46 ZM: Something like that.

0:39:47 PA: Sure.

0:39:48 ZM: I could put too fine a point...

0:39:49 PA: Sure, sure.

0:39:49 ZM: Or a number on it...

0:39:49 PA: But generally, you know, people might say...

0:39:51 ZM: But certainly through teens...

0:39:53 PA: Absolutely.

0:39:54 ZM: And very likely into the 20s of course these things vary from person to person but there's a lot of plasticity going on that will later be tuned down. So part of the reason that you can't learn a perfect accent in a foreign language or not without great difficulty, when you're in your 30s but you can when you're in your lower teens has to do with some type of plasticity that is not there later on.

0:40:20 ZM: If you have one eye shut and so if you grew up with an eye problem, there's a critical period for your visual cortex developing proper wiring and if you go through that entire critical period with your eye not seeing properly, it's very hard to reverse that process later. It's much easier if you do it while you're still in the critical period.

0:40:40 ZM: So it turns out there are critical periods for all sorts of things and they vary and we understand something about how they work at the cellular level, at the molecular level even and it was shown by a group in Italy, lab of MFA, that serotonin can reopen the critical period for plasticity, particularly, visual plasticity in their case. So basically, you have an adult animal that would normally never be able to recover normal function, when you activate serotonin, believe it's not the 5-HT2A receptor but I'm not sure what... If I would go down that road too far.

0:41:19 ZM: So that's why I like to talk in terms of serotonin more generally 'cause a lot of times we're not completely sure on the molecular level what's going on. At any rate, the window for plasticity is re-opened. So it's several different examples I've given at different levels of analysis that serotonin seems to have something to say about causing and enabling that type of plasticity. So one could easily imagine that microdosing affecting those functions.

0:41:45 PA: Absolutely. So making people more open, making people maybe... It's easier to learn as a result of that, it's easier to learn language, it's easier to...

0:41:52 ZM: It could be.

0:41:53 PA: To access flow states. These are the self-reports that we're getting from people. There's a guy, Steven Kotler, wrote this book, Stealing Fire, all about accessing flow states and the different tools that we can use and one of them he mentions is microdosing in terms of possibly reopening these aspects, if we get to a neuro-level like these aspects of plasticity and so you have someone like myself who's now 26 where it's tremendously helped with the synthesis of different learning parts.

0:42:22 PA: This is the bedrock of creativity. It's divergent thinking. It's taking different ideas and finding ways to put them together in which other people hadn't thought of before. This is an aspect of plasticity and we could say it's something that results from plasticity and since we're seeing these results when people are microdosing...

0:42:39 ZM: I see. So it's interesting to talk about creativity or these processes. I think that's another angle so when I think of plasticity, I think when you're in a situation, how ready are you to adapt to that new situation. I think of... You could think of learning a language or something like that, you could think of moving cities, you could think of having a change in your personal...

0:43:06 ZM: Basically, I think about adapting to a change in context. When I think about creativity, I think more about say having a particular model of how things are or a particular way of thinking and I think creativity involves juggling or reconfiguring your model, accessing alternative ways of seeing things.

0:43:31 ZM: Now, if you had more of that, more flexibility of your way of seeing things, that could certainly help you to adapt but they're not necessarily... One isn't necessarily required. One could imagine plasticity without creativity or creativity without plasticity so I don't know whether... I would imagine this is exactly the sort of thing that we would like to get out of our studies on serotonin. We start with a whole bunch of effects say caused by this one molecule. Probably psychedelics activate a certain subset of those effects, a particularly interesting subset but even within the subset of things that are activated by psychedelics or maybe several different components that have different interests for different people or different situations, right?

0:44:20 ZM: We're kind of going back and forth between, let's make... We always wanna make finer distinctions and not lump everything together and be careful about associating things but we also, of course, want at some level a holistic understanding in... As you can see from... The experiments get very detailed and we haven't barely even started talking about the different parts of the brain and how they might be involved differentially in different aspects of things.

0:44:46 ZM: And a lot of this we just simply don't know. I can't really tell you which part of the brain and which receptor for this thing and that. The research just hasn't really been done. So there's a level at which there's a lot of work to be done to connect the things that we know clinically or anecdotally from experience about psychedelics to what are they actually doing in the brain and the part of that is just 'cause we don't understand how to think about the brain, all that in great detail, I mean...

0:45:11 PA: We're still in the infancy somewhat of understanding the brain, right?

0:45:14 ZM: We really are.

0:45:15 PA: With microdosing you mentioned and I just wanna say something about that. You mentioned this difference between creativity and adaptability more or less, when you can adapt quicker to a situation. We're seeing this research with serotonin and microdosing seems to be helping with that. It's like Jim Fadiman contextualized it in that jerk at the office that you usually have to deal with, they seemed to be just like a little bit less of a jerk basically. Where you're just more patient with them, you don't have as much of reaction, there's more impulse control in that as well and that's different than creativity.

0:45:50 PA: At the same time, if we're using terminology correct, it seems like adaptability could also be related then to, for better lack of a word, natural selection or the ability for the organism to survive whether that's as an individual or collectively. So then my question and you don't have to answer this necessarily but when I think about, what role does microdosing play in transhumanism?

0:46:10 ZM: [laughter] I thought you were getting... You wanted to go into something like transhumanism. Before we get there, I think that the evolution perspective maybe is an interesting one to give people an idea how I was thinking about this. So for animals to adapt evolutionarily, the first thing you think of is some sort of selection process, that the ones that are fit survive and the ones that are not fit don't survive but in order for the process of evolution to work, there has to be a variation component. That's I think the classical term. Variation in the phenotype. Variation upon which selection can act.

0:46:53 ZM: So if you think about evolving better behaviors or better ways of thinking or better cognitive strategies, you could also think in the same terms so you need ideas to be generated, perhaps which I'd say, variability to be in your thinking, creativity if you will on which then selection could act. Selection could be an internal process of critiquing your own ideas or it could be an external process of actually trying them out and finding out which ones work and which don't and of course, to some degree, both of those things happen. So if microdosing affected creativity that in this way of thinking that could feed into the process of evolution of ideas by generating more material on which selection could act. So, it need not necessarily generate immediately better ideas, it could simply generate more divergent ideas and that would open up perspectives, open up hypotheses that would not have been accessed otherwise.

0:48:00 PA: And I think some...

0:48:00 ZM: And it need not be... It could be neutral. It could generate as many bad ideas as good ideas by loosening the grab of the current. So imagine a species that's reasonably well-adapted to its environment but lacks the ability to mutate. Now the environment changes and the animal, the organism, the species is stuck. Only by generating mutations will it ever get out of being stuck.

0:48:26 ZM: So mutation is always a dangerous sounding thing and it may actually be bad for the individual but many of those mutations will lead to failures but one of them may lead to a much better solution. So that's a fairly obvious metaphor to think about why that type of randomization might actually be beneficial for the species or even for someone's individual's thinking.

0:48:49 PA: I wanna tie that into a practical level in terms of, if through this process we're able to generate more ideas and that means we'll have, I don't know if standard deviation curve is appropriate but you'll have something where you'll have a lot of okay ideas, you'll have a lot of maybe bad ideas, you'll have a lot of good ideas in terms of... And we can define bad, neutral, good by what works in the real world to maybe accomplish a certain objective or do something.

0:49:13 PA: And so in the past, it's been very hard to get feedback in terms of whether an idea is valid or not. Meaning that if you wanted to start a business, you would have to invest a lot of capital initially and then you would eventually be able to "validate" your idea from a business perspective and the way you validate it is of course are people buying it or a non-profit are you getting donors, or whatever it might be.

0:49:33 PA: It's businesses changing dramatically now and the ability to test ideas is changing dramatically where it's much, much easier and it's much, much quicker and it's much, much cheaper to be able to validate ideas in terms of whether they're good, they're neutral or they're bad. So it seems like well yes, you're getting more ideas generally because of whatever you wanna call it, technology or the internet, because you have the ability to validate them faster and decide which ones work and which ones don't, essentially you generate more good ideas over a period of time which will, if you have them in line with certain ethicals or principles or values, then that leads to a better world potentially.

0:50:11 PA: And so my question and I don't know if I'm asking the question necessarily or just thinking out loud but I think from my perspective, it could be why microdosing is really interesting because if we have the foundation of the context from which people are taking this and they are noticing these benefits, they're able to generate more ideas as a result and if more of those ideas are good and they can actually carry them out, does that help to accelerate change in a faster pace to address issues like ecological crisis and food crisis and water crisis, all these things that we're dealing with as a species?

0:50:41 PA: Maybe. I don't know, maybe I just took a lot of... I probably took a lot of leaps so you're probably thinking "Paul, those are way too many leaps." But from a big picture, I'm trying to contextualize the practicalities of microdosing. Those are things that I think about.

0:50:53 PA: Every substance has perhaps it's role to play. Opiates are terrible scourge in middle America but they're incredibly useful medical tool for people that are in severe pain. So I have no doubt that micro-doses can be very useful in certain circumstances and probably will work better for some people than for others. It's rare that there's a drug that is gonna be good for all people in all circumstances and the way I think we should approach it is to encourage research and to try to identify better... To understand better what the specific effects are.

0:51:33 ZM: So does it really affect creativity? How do we measure that? The work on creativity is a little bit less-grounded than say on plasticity because it's very easy to measure plasticity and it's not so easy to evaluate creativity, there aren't tests designed to measure creativity but even on their face, they're not. It's not so obvious how you even do that but I'm open to the possibility that that's one of the effects. I think that could, if it is the case that microdosing accesses those sort of effects then your argument would be that because it's easy to test ideas then we would be okay with the sort of more liberal generation of ideas even if some of them are crazy. That seems reasonable.

0:52:15 ZM: The thing that you said that I guess maybe concerns me a little bit is the fact that we can test ideas quickly is potentially a good thing but what criteria do we want to use to evaluate ideas? It's not completely obvious that the ones that gain more investment dollars immediately or the ones that gain more clicks or what have you, are the ones where our long-term interests are actually going to benefit.

0:52:41 PA: So how do we...

0:52:42 ZM: I think the problem with climate change, with environmental destruction, it almost seems to be exacerbated by the fact that things are fast and feedback is fast and companies are more encouraged to take quick decisions and do what's good enough for now and there's some benefits to that but without some critical faculty of say long-term thinking or without people who decide that what's valuable is not just what happens to my company today but to my grandchildren or to other species, it's long-term thinking that we need.

0:53:20 ZM: So if serotonin promotes patience, if not taking the short immediate payoff and being able to withhold from responding for that carrot or that drop of water or that buck, if that were something that serotonin or microdosing improved, made people less overwhelmed by the reward structure of their immediate environment, even if it had nothing to do with creativity per se, that could be a big benefit.

0:53:49 ZM: So I think you may know more about than me. I'm sure you know a lot more than me about the topic but the creativity aspect is one thing but I don't know, maybe that turns out it's a figment of your imagination because people report all kinds of things. I don't know, maybe it works for some people.

0:54:05 ZM: I think we need to know, we need more experience compared to the amount of experience that, the amount of research that was done on full-blown psychedelic effects and the number of trips that have been taken, I think that what we know about micro-doses is much less still, right? Probably maybe will eventually reverse.

0:54:22 PA: Eventually.

0:54:23 ZM: It seemed to be...

0:54:24 PA: Right now...

0:54:24 ZM: Safer, easier, more approvable etcetera but I wonder for example, maybe I turn the question back to you. If I said dose is one thing and micro-dose is the other thing, what differences do you... Is a micro-dose simply one tablespoon of a full liter of full psychedelic experience? Or is there some important way in which a micro-dose lacks some positive or negative or whatever aspect of a full experience? Is it just spreading the same thing out over more days? How do you think?

0:54:53 PA: I think you have to look at them as two mostly separate things and ideas. Microdosing and we could say macro-dosing where of course, you're taking a psychedelic but the experience that you're going through, whether from a snapshot perspective in terms of when you're under the influence of the substance or whether from a long-term perspective when you're integrating, it's different. So microdosing is non-threatening, microdosing is usually a tenth of a regular dose, is kind of the "standard" or typical amount that you would say if a standard dose, for example, of LSD is 100 mcg, a micro-dose might be 10 mcg.

0:55:26 PA: And a micro-dose is just very subtle. I like to have a more general perspective in that it's an amount that you take where you don't really notice anything that's too different but things are a little bit better and over those period of time, maybe two weeks, three weeks, a month, two months, you're a little more patient, you're a little more mindful, you have a little more energy, you're a little bit more engaged in relationships and it's not a one-time snapshot thing, like I think the high doses of psychedelic.

0:55:54 PA: A lot of that has been, what is the actual one time, three-hour, six-hour experience like? And although there is obviously follow-up on how they've integrated it, a lot of the crux of it is the experience that the individual went through and what effect it's had on their life. Microdosing, it's not three or six hours, it's a month, it's two months, and six months and I think for me that's the biggest difference that I see.

0:56:17 ZM: But within that difference do you see... There's a big difference in the strength of the experience and the time window. But do you think that it's essentially the same thing spread out? Or...

0:56:28 PA: No. No.

0:56:28 ZM: How? What hypotheses? What would you invoke as the... What's recruited by a full dose that's not...

0:56:35 PA: The mystical experience. Having the sense of oneness, having the sense of unity, the sense of transcendence, the sense of... Well, we could say non-duality. What we spoke about earlier, what got all these Buddhist thought leaders into Buddhism was psychedelic because they had a mystical experience, they had a spiritual experience. This is what happened to Sam Harrison.

0:56:53 ZM: So, do you think that the microdosing experience is...

0:56:56 PA: The microdosing experience is more "physical in nature", we could say. You could tie it to a certain, what you're saying, mechanism that's going on. With macro-doses, I don't know if it's completely mechanistic. I think there's an aspect of maybe an unexplainable thing to it. You know George Greer? Do you know George?

0:56:56 ZM: No.

0:56:56 PA: He's the Medical Director at Heffter Research Institute. I quote him in some talks that I do about basically, he did this ask me anything after they released the results of the NYU and Johns Hopkins suicide and assisted for end-of-life anxiety and depression. They released the studies he didn't ask me anything on Reddit and basically said "We don't think that high doses, it's completely biochemical. We think there's an aspect of having some sort of spiritual shift or change that's part of the lasting effects of this treatment."

0:57:47 PA: So I think microdosing... I don't know how lasting effects that they will be... People will get from microdosing particularly people who struggle with depression. I think the more lasting effects are going to come from higher doses where people go through this really intense rigorous experience that results in some sort of mysticism and unity. I perceive it as becoming more popular, like kind of in the same vein that Crossfit has become popular, where people are willing to put themselves through hell so to say, willing to take that risk because they recognized the utility and the benefit afterwards.

0:58:19 PA: Crossfit isn't fun, it's not really enjoyable.

0:58:20 ZM: So you're talking about being more popular now full-blown psychedelic experience?

0:58:24 PA: I think so. In the public's mind, once we can significantly tie the benefits to the actual experience people will be willing to go through the chance of having a bad trip or a challenging experience to access these greater benefits over a long period of time. 'Cause there are significant benefits to them and if you can create that from a cultural perspective then you solve one of the major problems in psychedelics, which is that for an order many times for people to heal from psychedelics they have to want to do them in the first place.

0:58:55 PA: Meaning, if you give someone who doesn't want a substance, they're gonna have a bad trip, they're gonna have a bad experience that's gonna make them even more unlikely to wanna do it in the future. So how do you provide a culture? How do you create a culture in which more people are willing to accept the fact that psychedelics can help them? I think that's the biggest question that we need to answer because you can have all the research in the world but that really doesn't...

0:59:17 PA: It convinces like I said, it convinces well-educated people with PhDs and masters but it doesn't convince people who live in rural areas, people who are naturally irrational and illogical. You need something else to do that. You need to tap into like a more emotional thing rather than I think a purely intellectual thing. You need the science. So you need that as a foundation but I think at some point you have to... It requires conversations and it requires speaking to them on where they're at, instead of where we are.

0:59:44 ZM: Yeah, I think you've said a lot of things and I think what sticks in my...

0:59:50 PA: [laughter] It's hard for you 'cause you're like...

0:59:51 ZM: What sticks in my mind... Yeah, where to shoot? So what sticks in my mind is, if I just think in terms of plasticity and let's say we like to talk about priors but you could think of prior expectations or the way you think about things before you get any evidence about how they really are, that's a prior. If those priors go down and plasticity goes up, that seems to explain the elements of a full-blown psychedelic trip and it seems to explain elements and maybe not all of what you've described with microdosing and it also may explain most of what's going on with SSRIs as well.

1:00:30 ZM: So the ability to basically adapt to new circumstances and the ability to break out of old patterns, the ability to get over depression, you don't have to break some bad habits of thinking or some really stuck way of approaching the world. So maybe these things are all actually tapping into something fairly similar but acting in different ways.

1:00:56 ZM: SSRIs have their weird three-week time scale to act whereas microdosing takes effect immediately and full-blown trips or at least some aspect of it takes effect immediately. Are they all doing more or less the same thing in different ways? Is the end of it that you need to rewire your brain basically? It seems like the reasonable hypothesis.

1:01:15 PA: It does.

1:01:16 ZM: And then if that's what you're primarily doing, no more happy pills, no more... Not necessarily even like seeing the truth or the light but rather just being open to seeing what is already there, which can sound a bit spiritual, it could be a bit spiritual in some sense but it's opening you up to the context. It's opening you up to your actual situation or your current situation which means that's gonna be incredibly important, the context of the therapeutic situation or the context in which you take them, it's kind of the oldest platitude about...

1:01:55 PA: Set and setting.

1:01:55 ZM: Yeah, platitude about psychedelic set and setting. It should also be true for microdosing and it probably is also true for SSRIs. If you take these things in the wrong circumstance, they may very well lead you even into a worse pit than where you were before. So that all makes a lot of sense I think. Then in thinking about this kind of context, how do you provide the right context, I know from previous a conversation we've had, you think in terms of a change in culture. I think that that's very interesting.

1:02:26 ZM: I guess you could step back and even just say well, like sort of from a medical perspective or from a like less, let's say from a more modest perspective, what's the best way to... If it turns out that governments are willing to legalize these drugs which they ought to rationally. There's really no good case for keeping these substances in the kind of schedule where they have absolutely no purpose, it's completely non-scientific, non-evidence-based policy.

1:02:53 ZM: So if that changes, it still leaves the question of how you set the right context for using them correctly because if it's not a happiness pill, it's not like you just wanna give a prescription to somebody and say "Go home and take this." You really probably don't want to legalize psychedelics and let people just start partying with them. Some people that will work fine but for many people that will lead to real problems, right?

1:03:20 PA: Sure.

1:03:20 ZM: And the medical context is not generally set up very well to deal with this. When I remember reading about Trump's proposal for healthcare was to cut mental health services entirely from one of the programs, I don't remember the details but mental health service is important, something that's been messed up for a long time. We used to lock people in institutions when they were messed up. Now we lock them in prisons when they're messed up. So the right way to deal with it doesn't end with getting the substances available, it only sort of begins. Then what are the ways to do that? In the absence of a full-blown cultural shift, are there reasonable ways to build context in which people can get better?

1:04:11 ZM: Whether, maybe it's a type of doctor, a type of psychiatrist or a type of psychotherapist that becomes adept at working with these things. We probably need that. For other people, it may be a more religious context or more spiritual context, it's hard to see it being one thing for all people. I'm not really sure if you're ever gonna see the average Midwesterner going for the same type of spirituality that the... Let's say the tech billionaire goes for or the whatever, upper west side lady goes for.

1:04:44 ZM: There are a different cultures. So I don't know if it's necessary to have everybody going through the same thing but this kind of context is important and rather missing from many people's lives. That's the sort of hole that religion used to play and the downfall of religion has positive aspects and negative aspects and the negative aspect is it's something that you have to acknowledge.

1:05:06 PA: It's like a lack of meaning.

1:05:07 ZM: Yeah.

1:05:07 PA: In a way and then that meaning has been replaced with materialism.

1:05:11 ZM: Yeah. Religion provides meaning in a cultural context with a group of like-minded individuals who believe in the same myths that you believe and have believed in what's meaningful and not and by and large, those myths are harmless and harmless for society and very good for the people who believe in them but religion has a tendency to take over aspects of society that it ought not to take over and when that impinges on other people who have different beliefs, then that becomes a problem.

1:05:40 ZM: But then we get rid of religion and we're left with materialism, which provides no meaning and leaves people for injecting or taking whatever they want, whenever they want. It's not a recipe for smooth sailing, right? I think I could see psychedelics and microdosing as playing an important role in society going forward and that being a good thing but it won't happen unless the rest of society supports that.

1:06:10 ZM: For some, people will continue. People who have found their niches and can incorporate psychedelics into them will continue to benefit but it's probably a relatively small fraction of people that can all put it all together and can reconcile what they read in the newspaper and what their neighbors think and it's a very kind of small crack into which you must fit unless you're really deeply embedded in a psychedelic community that's a relatively rare thing.

1:06:40 ZM: If psychedelics become extremely popular, what are we going to do? Are we going to reinvent the '60s? Are we going to go through some sort of a huge cultural revolution and subsequent backlash? Probably that's not...

1:06:52 PA: That's what we don't want.

1:06:53 ZM: That's probably what we don't want. It's a bit like the Arab Spring, we're gonna throw over the... [chuckle] Throw over temporarily the dictators and then find that they've just come back even worse the next time.

1:07:05 PA: Where can people find you? Do you have a Twitter or...

1:07:09 ZM: My name is unusual enough that if you Google me, you'll find me pretty easily.

1:07:12 PA: Zach Mainen.

1:07:13 ZM: There's a website for my lab. I occasionally tweet, not much. Zach Mainen. Z-A-C-H M-A-I-N-E-N.

1:07:23 PA: Easy. Well, thanks so much for doing this, I really appreciate your time.

1:07:27 ZM: Thanks for having me.

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1:07:44 PA: Okay, we're now back with questions. So, we're back with questions, we had the intro, we talked about this week in psychedelics, then we had the podcast, I really hope you enjoyed it. If you did enjoy it, please leave a review on iTunes or go ahead and donate on our Patreon page.

1:08:01 PA: Three questions this week from Beau Jocque, from Heather and from Colin Foster. So the first one from Beau Jocque is, "Can psychedelics do anything for migraines, not cluster headaches but migraines that happen once or twice per week?" So we have an article about using psychedelics to treat cluster headaches, which we first recommend reading if you guys are interested in these questions. We really don't know with conclusive proof if it would work for migraines also.

1:08:27 PA: However, there might be reason to believe that there's a similar mechanism going on with migraines as there is for cluster headache but we still don't know what psychedelics are doing for cluster headaches. So we're in the dark here. My assumption is microdosing maybe with higher doses could help with migraines. If you are struggling with once or twice per week migraines, maybe try out microdosing to see what that goes. But obviously, this isn't medical advice so if you are having frequent migraines, the first step should always be to talk to your physician about the best treatment options and I've emphasized this in the seminars that I've done before, I'll also emphasize it now.

1:09:02 PA: If you don't feel comfortable talking to your physician about the fact that you might microdose to help with migraines, find a new physician. There's enough research, there's enough anecdotal reports now that show that psychedelics are effective at treating cluster headaches but there could be reason to believe that they're also useful for migraines. Psychedelics are much less toxic than a lot of even mainstream pills that people will take for migraine issues.

1:09:23 PA: From Heather: Would you say the positive effects from microdosing are only temporary or can they cause positive permanent changes that last after your microdosing regimen? My assumption is that there are positive permanent changes going on sometimes but like all things it depends on the individual. So I'll give you some context on that. I think what happens when you're microdosing, the neurotransmitter okay, serotonin, it's activated by the 5-HT or it activates the 5-HT2A receptor and we know that leads to plasticity, neuroplasticity, we also know it leads to impulse control.

1:09:58 PA: So if we continue to send that message through microdosing two times a week for 10 weeks, 20 weeks, 30 weeks, there's reason to believe that we might be training the brain to operate in a different way, to start communicating in a different way and just like with mindfulness meditation, we have research that shows that consistent mindfulness meditation actually creates new gray matter in the brain.

1:10:18 PA: Now, if you meditate consistently for a year and then you stop meditating for six months, some of those benefits are going to subside. Not all of them but some of them. So it's probably similar with microdosing. You'll start to notice the best benefits as you're microdosing, if you stop for a month, some of them might dissipate, not all of them but if you stop for like a year, those could continue to dissipate.

1:10:38 PA: So I think what's important to emphasize is that it's really helpful to combine microdosing with a meditation habit for example, so that you get the synthesis of both modalities in terms of building neuroplasticity in the brain.

1:10:50 PA: Last question from Colin Foster: What are the first steps to legalizing sacred use of Ayahuasca? I'm going to assume you mean within the context of the federal government. Now, some of you might know in New Mexico and Oregon, the religious use of Ayahuasca is now legal for certain church members, it's also legal in much of South America. For example, in Brazil, Peru, Colombia. In terms of the first steps to legalizing sacred use of Ayahuasca, I think the easiest way to start making headway is to work with local officials who are in a position of authority that can help you start to get things passed on a city-by-city level or even on a state-by-state basis.

1:11:30 PA: The two cases that we have so far in Oregon and New Mexico, I believe that was a combined case that was taken to the Supreme Court and they won. They ended up winning and that was largely pushed by Dr. Jeffrey Bronfman who is an heir to the whiskey Seagram's. He's an heir, yeah his family started that so he's very rich. So he put money forward to get Ayahuasca legalized within a religious context for I believe, the UDV and that they have churches in Oregon and New Mexico. I may be slightly incorrect about that but that's the general push.

1:12:05 PA: So, if you wanna legalize it nationwide, that's a good question, that's a really good question. I think there are various ways that you can go about it. I think the best way though is to start working with local and state-based officials and possibly setting up some sort of UDV in the states themselves and then trying to bring courses to the Supreme Court to see what happens but again, that's just a thought. I'm no expert on the political policy sides of making these substances available.

1:12:32 PA: So guys, thanks so much for tuning in. A sneak peek for next week, we're having Rachel Harris on the show, author of Listening to Ayahuasca and we talk about Ayahuasca in that show. So just stay tuned next week, that's coming up.