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How to Choose the Right Psychedelic Substance Ft. Dr. Giordano

“How to Choose the Right Psychedelic Substance ft. Dr. Giordano” delves into the fascinating intersection between neuroscience and psychedelic drugs. Hosts Jimmy Nguyen and Nicholas Levich interview Dr. James Giordano, a professor in the Department of Neurology and Biochemistry and the chief of the Neuroethics Studies program. 

Dr. Giordano provides a historical context for the development of psychedelic drugs, noting the reasons behind their initial development. He details the changes in public perception that influenced their stigmatization and their now reintegration into therapeutic scientific research.  

Later, the conversation moves on to a more granular discussion about the different types of psychedelics and their effects. Dr. Giordano explains the characteristics of various psychedelic substances such as psilocybin, LSD, DMT, mescaline, and molly.

Our hosts offer advice on how to select the appropriate psychedelic drug for an individual’s specific needs. They explain the importance of a more personalized approach to the use of these drugs, considering factors such as genetics and physiology. 

Episode 37 – How to Choose the Right Psychedelic Substance ft. Dr. Giordano 

Jimmy: Welcome to the Psychedelic Passage podcast. My name is Jimmy Nguyen. I am joined here by my co-host Nick Levich. We have a very exciting topic for you all today as well as a wonderful guest on our episode. I’d like to take a moment to introduce Dr. James Giordano. 

He’s a PhD and a master’s of philosophy. He’s a professor in the Department of Neurology and Biochemistry, chief of the Neuroethics Studies program, leads a sub-program on military medical ethics at the Pellegrino Center for Clinical Bioethics. 

Special advisors to the Brain bank, co-director of the O’Neill-Pellegrino Program in Brain Science and Global Health, Law and Policy at Georgetown University Medical Center in Washington, DC. 

And Dr. Giordano is also a veteran serving in the past as a US Naval Flight surgeon serving with the United States Marine Corps. And so thank you for joining us here Dr. Giordano.

Giordano: It’s a pleasure. Thank you for having me, I really appreciate it.

Jimmy: Yeah, you have quite a list of things [Nick laughs] on your accolades and so we’re really grateful to have the opportunity to pick your brain and have a dialogue that we feel may be helpful to our listeners. 

And today’s topic will revolve around “How to go about choosing the right psychedelic substance for you.” And so, Nick and I get this question so often– [crosstalk]

Nick: Pretty much every consultation call.

Jimmy: Yeah, pretty much every interaction that we have with folks given that we mostly talk to more psychedelic curious folks, folks who are newer to psychedelics. Oftentimes Nick and I find ourselves being able to talk anecdotally about some of these factors. 

I’m really excited to have a scientific background and some “why” around these things. But before we get into that, I’d love to just learn a little bit more about you, Dr. Giordano, and how given your history and your resume, what got you into this intersection with psychedelics? So curious.

Giordano: When I was 10 years old, a cousin brought me to Woodstock.


Giordano: I usually use that as sort of a personal introduction. But truth be known, I was trained as a neuroscientist and a molecular and biochemical neuroscientist, and as a neuropathologist. 

A lot of work that I had done, both my doctoral work and some of the clinical work and then subsequent work I’ve done, examines various types of neurochemical networks, processes, specifically the serotonin system of the brain and dopamine system together with the opioid system.

These systems are rather labile in some of their effects to a variety of different substances, most notably the psychedelic drugs that have been known to act directly through the serotonin system. But then also affect a number of things, if you will, downstream. 

And of course, you recognize that there are other drugs that have been used both recreationally as well as therapeutically and in some cases illicitly that engage the same systems of the amphetamine drugs and the stimulant drugs working through the brain’s dopamine and norepinephrine system. 

And certainly, I mean, unless someone’s been living under a rock, we understand that we’re in the midst of an opioid crisis, most notably the tragedy of fentanyl. Those drugs work through the brain’s opioid system, which then also engages other mechanisms in the body. 

But we were very interested early on in the brain’s serotonin system. It’s a rather old evolutionary system, so it’s not only present in humans, it’s present in a lot of other animals. 

What’s important about the serotonin system in humans, as we came to learn, literally, as I was going through the academic ranks and engaging my research and sort of going up the, if you will, scholastic ladder, and associate professor, etc. there are a lot of diversity in the system. 

The way the system works is really parsimonious. I mean it really keeps its system, and very simple. You’ve got one brain chemical called serotonin, and it’s capable of interacting with a whole bunch of post and presynaptic receptors.

Let me make that easier for the listener. That’s sort of like saying you have a single key, that can turn a whole bunch of different locks. 

And those locks are on very different doors, and those doors are nodes and networks within the brain that open us up into various rooms of thought, emotion, experience, capability of imagination, memory, and a whole host of behaviors very often that go along with them both in health and disease.

So, harnessing, if you will, that key in understanding those locks is really a very important aspect of medical neuroscience. But also it interfaces, as we know, with social neuroscience, legal neuroscience, and there are ethical issues that arise in and therefrom.

Jimmy: Which came first? It sounds like the excitement and curiosity around neuroscience maybe was the foundation and then at some point, you had come across these psychedelic compounds and substances and maybe saw that interconnectedness there. Am I understanding that right?

The Exploratory Spirit of the 60s and the Modern-Day Psychedelic Renaissance

Giordano: A bit of both. I grew up during the 60s. I was a kid of the early 60s, and I remember growing up and vividly watching those first rocket shots, the Mercury program, the Gemini program. 

I remember watching on television when Neil Armstrong took that first step on the moon. So, this was an age of exploration. I think that it was always a question of exploring the next frontier. 

I mean, if you recall during the 1960s, there were some very innovative exploratory approaches to the highest reaches of the Himalayas and other mountain ranges.

We were going to the depths of the ocean. And if you recall during the 1960s, the Jacques Cousteau series was huge. And the Bathysphere and the Bathyscaphe, and the Trieste going down to the depth, depth, depths of the Mariana Trenches.

But then also there are a tremendous amount of scientific and biomedical discoveries that turn that lens inward. So that now, if you will, the exploratory frontier was the body. And probably at the cutting edge of that frontier was the brain.

And so that iterative knowledge of the brain was very, very influential while I was growing up. And I’ll tell you a true story. I’ve said it before in other lectures, but I don’t mean to sound redundant. 

But when I was about six or seven years old, my dad took me to see this movie Fantastic Voyage with the now recently deceased late Raquel Welch, Stephen Boyd. The premise was that they use military technology, a miniaturization technology to miniaturize equipment. 

What they did is they miniaturized a submarine with the crew that they inject into the human body, to then travel into this diplomat’s brain to be able to then use a new weapon at that time.

Which was a laser beam, I’m not kidding, to be able to dissolve a blood clot and therefore get this individual well, to be able to then transmit these secrets to the United States from what would essentially be a cold war country.

Well, I saw that movie with my dad and I was about six or seven at the time, came out in 1966, I guess I was about seven. And I thought it was the best thing I’ve ever seen. 

I mean the whole idea of this going into the brain, and they were waxing very philosophical in the movie “That this is the basis of our thoughts and our memories and our essence.” Well, I just thought it was the coolest thing I’d ever seen. 

Plus, all the glow-winking gizmo toys that they were using, I thought, “This is what I want to do.” It didn’t hurt that I’m six years old, seven years old seeing Raquel Welch in a wetsuit, I was like, “Yeah, this is cool.”

So, here I am, and now in my middle 60s, and in fact, this is really what I’ve been doing for the past 40 years. 

Not necessarily being injected into the body per se, but being able to take those exploratory journeys into different areas of the brain through the different tools that we have, and we have at our disposal. And it’s been, for me, a fantastic voyage ever since.

Jimmy: Except you didn’t need a miniaturized submarine. It turns out there’s some naturally occurring medicine substances, fungi out there that are essentially doing the same thing. 

I really appreciate what you said about the era of the 60s being this sentiment on how far can the human go, how far can human potential go, and it seems like a lot of that was directed internal as well and so I’m curious, and getting into our dialogue and our conversation about how this affects the modern-day psychedelic curious person.

We have a resurgence of information, of social acceptance, of anecdotal experiences. In our society, in the United States, there’s likely a handful of psychedelics that folks will come across. 

More of the classic “serotonergic psychedelics”, we’re talking about psilocybin-containing mushrooms, LSD, DMT, and ayahuasca. Maybe a handful of others. There are a couple of other classes MDMA, ketamine. 

What would you start by sharing with folks? Because when Nick and I have these conversations, we’re talking about effect, we’re talking about duration, we’re talking about intention, we can’t get too, too far into mechanism of action. 

Can you give the audience a little bit of a primer on what you would share with folks when they’re trying to determine what the right psychedelic substance is for them?

From MK Ultra to Brain Research: The Evolution of Psychedelic Science 

Giordano: Absolutely. It’s also important to discuss a bit of the history and historicity because they speak to the current attitudes, both medically as well as socially. 

As you recall, many of these drugs began, if you will, their trip. No pun intended, well maybe a little one, as potentially therapeutic agents.

I mean many of them had been developed because they had the potential to be able to alter cognition of emotion and behavior with at least an eye towards some tangible therapeutic application or benefit. Number one.

Number two, they were very, very effective at doing what it was they were doing. If you actually follow some of the work in psychiatry during the 60s, which, again, was in many ways limited by the toolkit it had, particularly the investigative toolkit. 

What we knew about the brain in the 60s is discriminably different than what we know about the brain now in 2023, primarily based upon the tools that we had at our disposal. But clearly, these things worked to do something. 

So coming out of the 1950s into the 1960s, absent some of the more garish experiments, the one that probably comes to mind for most folks is the military one called MK Ultra. But here too, the goal was, look, these are very effective drugs. 

Could they expand the cognitive performance capabilities of either our own personnel or could they be used at a variety of doses where dose may be impendent here to sort of say,

“All right, could they affect, negatively affect, the cognitive, emotional and behavioral activities of opposing forces?” In other words, could they be weaponized? That idea still comes up from time to time. 

What happened is that the relative success of the outcomes gained with these drugs, in that they did produce literally psychedelics, in other words, the ability to be somewhat mind-expanding, changing patterns of cognition, changing existing patterns of emotionality, and various aspects of an emotional fixture, etc.

And then in some cases, the resultant behaviors that went along with that both acutely and then more durably. Well, like anything else, the cat gets out of the bag. 

If you follow some of the literature of LSD particularly, and look at some of those early experimental trials, for example, with Dr. Leary, the success of those investigations and experiments was such that things get out there, and then at that point they became socially used and then perhaps misused. 

What tended to happen during the late 30s and early 70s is there was a conflation, a social, legal, and therefore at least publicly ethical conflation, that all of these things represented heinous drugs of abuse.

Well, let’s face it, one of the more destructive drugs on the market is acetaminophen, Tylenol. You can overdose on that like that and if you’re susceptible to any kind of liver dysfunction, you’re sort of walking a thin line. 

It’s not necessarily that the drug is dangerous or not, but it has to do with dose, understood mechanisms, patterns of use and is it being gate kept effectively.

And is it really being usurped for its therapeutic benefit or has it just gotten “out there” and therefore, these patterns of social use and potential misuse have become de rigueur. 

So here we are in 2023. Let’s look back on the 60s and 70s and some of the strictures, the legal strictures, and social strictures of the 70s. Come through the 80s, the 90s, we had here in the United States a congressionally declared decade of the brain.

Fast forward, for example, to most more recently, the BRAIN Initiative, Brain Research Through Advancing Innovative Neurotechnology, launched by former President Barack Obama in 2013.

That spent a lot of government money developing tools and technologies to be able to assess the brain so as to more accurately access and effectively affect the brain in those ways that were therapeutic on one hand, but that were also enabling on another. 

Occupationally, lifestyle purposes, and to just get a better understanding of what constitutes brain health, inclusive of preventive brain health. 

So, now we revisit the psychedelics in that light of new science, with new tools, better understanding both of the brain and a far more granular approach to the way these drugs can be used, which then affords us insights to how perhaps they should be used.

Nick: How do these new tools and this new understanding of the brain, how do they intersect with psychedelics? What has been the backbone of your work as it relates to the brain and psychedelics?

Genetics Research & Brain Imaging For Our Psychedelic Understanding

Giordano: I think there’s really been three, certainly coming out of the early 90s and in through the 90s, we have the Human Genome Project and part of the mission of the Human Genome Project was to help to define, and in that way establish what might be our neuropsychogenome.

In other words, what genes were at least contributory, if not directly responsible for those structures that ultimately had functions in our neurological and cognitive capabilities and our psychological capabilities. 

Also, what genes were responsible for the development, execution activity, and patterns of activity as well as the susceptibility of these various neurochemical systems in the brain, inclusive of the brain’s serotonin system. 

Functioning not only in health, but also in disease and injury patterns, as well getting some understanding how various substances, both potentially therapeutic substances and others, interact with individuals based upon their genetics and based upon the physiological expression of their genetics called their bodily phenotype.

What that really led to is the idea of personalized precision medicine. But personalized precision medicine, I think, is a very important facet of a larger lens, that seeks to understand that the more we know about the structure and function of the body.

The more we’re able to assess when things are going right, when things not only are going wrong, but they may have some bias or predisposition for going wrong under a variety of different environmental conditions, and what things work on what people, at what time, for what reasons. 

So the idea is dialing in that level of precision. We’re not taking the buckshot approach, but now we’re taking a much more stringent, sharp-shot approach. That’s a very, very different orientation to understanding how brains work literally from the genes up, that’s number one.

Number two is the idea of being able to create far more selective compounds. Now, here we’re looking at various areas of bioengineering and we may be able to use much more selective compounds, number one.

And certainly lower doses if we can develop pharmaceutical preparations that get these compounds into the brain more effectively, and don’t necessarily distribute their effects more widely in the brain and the body. But once again, seek that sharp shot. So, here we’re looking at the technologies. Another technology–

Jimmy: Yeah. I hear this around a lot of the pharmacological experiments to try to, let’s say, like, shorten the duration of an LSD experience or maybe create psilocybin analogs that are more visually laden. Or maybe have a two-to-three-hour arc of duration. 

Or even try to affect some of the common after-effects or during effects such as nausea or headache or some of those things. Is that related to what you’re talking about around this bioengineering?

Giordano: If you think of the fact that any drug will produce a sort of menu of effects, well, there are certain things on the menu you want, and there’d be certain things on the menu you don’t want.

If the structures and processes that are involved in those things you want and you don’t, you can augment certain things you want, and you can mitigate certain things you don’t. 

Well, to some extent we have that capability. The other issue then becomes, well, okay, we now also have synthetic biology, and we have gene editing.

For those things that are plant derivatives, could we literally make these things brand new or modify existing substances that come from fungi, most notably, for example, psilocybin? 

But also, certain plant derivatives that we know are important to the activity of a hybrid mixture, like ayahuasca, so as to literally create a cocktail that maximizes the effect, optimizes its beneficial, and or what individuals would feel enjoyable. 

Or literally, mind-expanding capabilities, and minimize the potential and reality of those side effects that individuals find burdensome, or in some cases, risky or harmful.

The last point, the last technology, and this is huge, is that there was a revolution in around the middle 80s that allowed us to essentially peer into the living brain, utilizing ever more iteratively increasingly sophisticated and capable types of brain imaging. 

Now what we can do with brain imaging, again, casting all limitations aside, and there are some, but we understand, those working in the field, is it allows us to peer into the living brain to see where certain substances are working and gaining an effect. 

And also to seeing how the connectivities, the interactions, the real-time areas of nodes and networks that are communicating and talking to each other or not talking to each other in the brain, are engaged, are modified, and may actually be sustainably changed even after a particular pharmacological experience. 

So, that’s given us some real mechanistic and anatomical insight of what these things do and where they do it. We can apply that, in some cases, very generally.

But I think part of the mission is using these tools far more specifically on a personalized level to be able to determine who should get what, how it works, and what they shouldn’t get.

Nick: I think we should dive into that question because to the average listener of our show, either psychedelic curious or psychedelic interested, how do they navigate all of these various substances like how do they choose what’s best for them? 

I mean, Jimmy and I give our spiel when we chat with folks from our perspective as facilitators but I’m curious from your perspective as a researcher and a scientist, how do you determine?

Start Low, Go Slow: The Key to Safe & Effective Psychedelic Use

Giordano: One of the reasons I’m actually on this program is because what you do provide to your listeners and to those who you mentor and counsel is a prudent, pragmatic approach to that type of guidance. 

I think that’s important because what you’re doing is you’re translating the science that I and colleagues who do what I do, but like what I do, then provide to give your people the best information they can. 

If we distill that essentially as we started the conversation, I mean, we really have about three major true psychedelics and some derivatives, and they all have slightly different effects.

Certainly, we have one of the older substances which is psilocybin, derivatives from mushrooms, both the dry mushrooms as well as other preparations as well as the extract. 

We have lysergic acid diethylamide, LSD, and we have dimethyltryptamine most characteristically as part of an ayahuasca preparation that’s multicomponential. Let’s just take a look at those three first and then let’s take a look at some of the others. 

There are really only two that we really want to deal with here, which is the methylphenidate amphetamine, methylenedioxymethamphetamine, ecstasy or other preparations, molly, and ketamine which is a completely different animal but we’ll leave that for a little later.

Nick: And what about mescaline? Do you guys [crosstalk] that at all?

Giordano: Yeah, we have, but I mean, I think one of the problems here with mescaline is that the dosing of mescaline is highly variable. And then of course the other issue is the mescaline preparations have been highly variable to date. 

I think one of the things we’re seeing from the mescaline research is that there’s a need for standardization of mescaline preparations, so that the individual who obtains mescaline, inclusive of the clinician who may look to use mescaline therapeutically, can get a preparation, number one-

Has high purity and good quality, and number two are therefore able to dose that appropriately without worry about contamination at either dose level in terms of the actual level or other substances.

Some of the other stuff with psilocybin and or LSD and or DMT, most people in the scientific side would advise a relative engagement just along that pathway. 

Psilocybin might be for those individuals who are totally psychedelically naive, who may have some experience with other drugs but are looking for a psychedelic experience that, number one, is very strongly dose-dependent, not only on the extent of the experience, but on its manifestations. 

That doesn’t really engage, at least at the lower doses of such a high level of situational and circumstantial derealization and do a sort of a discontinuity with one’s sense of self, but certainly could. 

But that also allows iterative psychédélices where you do feel the mind-expanding capabilities very, very visually, at least at first. That also involves certain changes in cognitive patterns. 

What one can find when dealing with psilocybin is that low doses of psilocybin can be very effective for the psychedelically naïve. 

And then mid-level doses after someone achieves what is the right dose for them to do, what they want the drug to do can be persistent over a fairly long period of time without any tolerance. 

Again, sort of determining what is the best for you. We like to always say start with something that you’re most going to be comfortable with and for most people that’s psilocybin.

Start low with a dose, go slowly with using that dose and sort of feeling out the parameters on the different circumstances and situations in which you’re tripping, and always have someone who’s there reliable for you

And then at that point when you’re comfortable, you ask the question, is that enough? Is that providing for me that level of psychédélices, whatever that means to me? 

Cognitive expansion, emotional release, re-identification, and I’m good with that. If it ain’t broke, don’t fix it. However, for those individuals who’ve had some experience with psychedelics, what they may find is that there are certain psychedelics that are literally more viable for them.

For example, there are some folks who will swear by LSD. Yeah, Psilocybin works for them, but LSD does what it wants, they want it to do. It gets them to that point of mind expansion, openness, creativity. 

Perhaps also allows some level of sort of disaffiliation with the self that allows them to ground their emotionality and gain representatives on things. Psilocybin for them just didn’t do it. 

But, again, here too, if one is psilocybin experience and now one is going to go over to using some other compound, whether it’s LSD or let’s talk about DMT in a moment. Start low, go slow. 

Interestingly, when we look at something like dimethyltryptamine, the potency of the dimethyltryptamine, as well as some of its ancillary neurochemical effects, creates a bit of a more potent experience.

It’s far more of a transcendental experience for most people. I mean, colloquially, it’s referred to as the God molecule. 

The issue there is that what you’re seeing with dimethyltryptamine are three things. Number one, it binds very quickly and very hard. Number two, it stays bound for a while. 

The fact that it stays bound changes the node network activities of a number of those involved networks in the brain that utilize serotonin. 

What people are getting are sort of compound experiences in the first person, the phenomenological first person that for them can very, very quickly take on spiritual, transcendent and existential characteristics. So, that’s a little more potent. 

The other issue is that it’s pretty rare to find individuals just doing DMT as a standalone and most DMT is delivered as part of the ayahuasca preparation. And as you know, there’s a whole ceremony that goes along with the ayahuasca preparation. 

And indeed, part of that is purgative. People feel they want to purge, they want to throw up. There’s a change in individuals, both physiology as a consequence of multiple ayahuasca inductions as well as their cognitive appreciation of what’s happened to them. 

But again, the ritual, the circumstance, and the engagement of the other activities and preparations in ayahuasca, other than DMT are important to that experience. So, you can categorize those three.

Jimmy: If I can jump in here really quickly, just to give a little bit of context for our listeners. For DMT, there’s typically two formats that most folks will encounter. One is a Smokable version of DMT or vaporized version of DMT, which is usually synthesized. 

There’s also another smokable version which is called Changa, which is a combination of different DMT-containing herbs, plants, and then also combined with MAOIs, which are monoamine oxidase inhibitors.

What many folks find is that if you’re vaporizing or inhaling DMT, that duration is very short and very intense because of the way that your body metabolizes that. 

But then in combination with an MAOI, and then ingested, that typically then follows the format of more traditional ayahuasca experiences where you have a longer experience. And so, those are very different.

Even with LSD, we’re typically sharing with folks that that’s a longer experience. You’re strapping in for 8, 10, 12, sometimes 16 hours. 

Something that you said in an article that I read in the past possibly mentioned that it’s the way that that specific chemical compound binds to our serotonin receptors and the way that it fits exactly allows for a longer mechanism of action. 

I think it’s really interesting what you said between psilocybin and those other two, because very practically, not scientifically related, is it’s about how you receive the medicine and you receive the compounds.

Psilocybin just happens to be one of those psychedelic medicines that proliferates quite easily in your local area. It’s one of the few places where you can get the direct medicine as opposed to LSD, where maybe it’s in a vial, maybe it’s sprayed onto blotter paper with DMT. 

Also, hard to gauge dosage. I’m just sensing that there’s both the neurological functioning that you’re talking about here, then also in practicality on how you receive it and your dosage and how you’re intaking these medicines as well.

The Difference Between Inhaling & Ingesting Psychedelic Substances

Giordano: They’re one and the same. So, if we take a look at any drug, any substance, there are really two things we have to consider when we’re looking how the way it’s going to work at the body. Number one is called pharmacokinetics. 

How does it get around to where it’s got to go. If you’re smoking something, you’re rapidly taking in through the mucous membranes and characteristically getting very rapid penetration into this circulation, circulatory system that delivers it directly to the brain, very quickly. 

Very often what you’re going to then get is very strong, we call, a pharmacodynamic effect. It gets where it’s got to go. It hits its target keys, so to speak. Key goes and lock, turns that lock. 

But what you’re seeing is very often the dosing of the way you would take that in is relatively short. And it comes, you’re not really huffing on this and huffing on this. So, what you’re getting is a rapid dose, very, very quickly into where it’s got to go. 

You get a spike effect and characteristically going to come down, as that then wears off pharmacologically. In other words, it dissociates with its, if you will, that key comes out of the lock, things fall back to normal.

Once you start to ingest something, what happens then is now it takes longer to get where it has to go, but characteristically you’re going to be absorbing it over a longer period of time as it goes to that area of your GI tract that absorbs it. 

Once it gets into that compartment, you’re getting it not only initially, but you’re getting it throughout this full-time period of its absorption, distribution, and its use. That’s going to last longer. This is what happens with things like LSD, or if you take things by mouth, like DMT by mouth.

The other issue is in the preparations of DMT that do include a monoamine oxidase inhibitor. What you’re getting is a double whammy. 

Now what you’re doing is you’re breaking down one of the principal enzymes that is necessary to break down the principal chemical through which the drug works. 

So, you’re elongating the effect of the chemical because you’re making more serotonin available in the synapse, you’re also making more dopamine and norepinephrine available, which then downstream augment this effect.

Now there are some caveats that go along with that. I mean obviously one of the things you see with the monoamine oxidase inhibitor is those drugs have also been used psychotherapeutically.

One of the risks of using monoamine oxidase inhibitors is that it works not only on the brain’s monoamine oxidase but also on monoamine oxidase wherever it’s found in the body. 

And this can lead to a whole bunch of problems with blood pressure, the possibility of cardiac and cardiovascular effects that might be pretty robust and burdensome. And they’re also looking for interactive effects. 

So, we know some individuals, for example, are very sensitive to monoamine oxidase inhibitors when they’re taken with cheese products, pickled foods, dried meats, pickled meats, smoked meats– [crosstalk]

Jimmy: Yeah. The presence of tyramine, I believe.

Giordano: Correct. That’s what’s it’s called, it’s tyramine characteristically, a hypertensive crisis because what then happens is your body metabolizes tyramine the way it would perhaps other forms of viable precursors, and those precursors then feed into that system and blow your neurochemistry. 

So, we have to be somewhat cautious with that. One of the interesting parts of LSD is, as you mentioned, LSD fits into that lock very tightly. And once it’s in there, it hangs out.

So, what we see is that it’s not only rapid binding to serotonin receptors, but it’s rapid tight binding to those receptors that turn that lock, opens that lock, and then stays in there for a while.

That’s going to be a fairly elongated trip, as you say, which can last anywhere from 8 to 20, 25, 30 hours depending both on dose and susceptibility of the individual.

Jimmy: I’ve approached those hours before. [laughs]

Nick: Same. That’s the reason we candidly give a warning label associated with folks who are seeking LSD experiences. It’s like, this can be a really powerful experience. Don’t get me wrong, I’ve had my fair share personally. 

But there’s a lot of times where you get to hour 8, hour 10, hour 12, and you’re ready for it to be done and there is no off button. And it’s so person and dose and situation dependent. 

That’s one of the challenges I think, with LSD that not many people talk about is when you have a tab or a piece of blotter paper or gel tab, whatever it is, you don’t know the density with which that was laid. You can test to make sure that it’s LSD. But determining dosage is actually really, really challenging.

Giordano: There’s a number of factors. I mean how you’re taking it in? Are you taking it as sublingually? Are you actually swallowing it? How much is actually there? Do you know what you’re getting? It’s also very what we call ecologically dependent.

What’s going on in your body that’s going to predispose the way that drug is distributed and bound? And then what’s going on in the actual environment, the trip environment? 

What a number of people find is, yeah, they get to like hour eight or nine, they think, “This is good, I’m coming down.” Only to then get a re-trip occurrence around hour 12, hour 13. 

Not necessarily as a flashback because what’s happening is the kinetics of the dynamics of the drug are altered in that person. You essentially get a rebound effect, which can then be problematic for some folks.

Jimmy: That key is still in that lock.

Giordano: Yeah. In other words, they think they’re down.

Nick: Well, and often that’s worse. Often that’s worse is thinking you’re done and then finding out you’re not because you’ve crossed the finish line in your mind, only you’re not actually there.

Jimmy: Yeah. I love this, by the way, because one of the nicknames that I have for our podcast is the “It Depends Podcast.” [Nick laughs]

What I’m hearing is that not only is there, what you call the pharmacokinetics and the pharma dynamics around these medicines and substances, their mechanism of action but then it’s also your own physiology, your own body chemistry, your own neurochemistry. 

And so, it depends. One of the takeaways that I hear from you is you got to know how the locks and doors in your own system somewhat operate. 

It seems like one of the really only viable ways to do that is this low and slow experimenting, testing at low dosages, just to get some parameters on how these medicines work with your body.

Know Thyself and Your Limits: Dr. Giordano’s Psychedelic Safety Tips

Giordano: There’s a couple of adages that I think go a long way, and I’ll give you actually three. First is the saying we throw around frequently in the brain sciences, which is C1 brain. C1 brain. 

Brains have a lot of things structurally in common, but as I said earlier, the devil is in the data, it lies in the details. 

If we think about the fact that brain cells that fire together, tend to wire together, and I’m being metaphorical. What happens is that individuals develop node and network patterns that are just that they’re individuals. 

And, of course, although the generalized function is going to be pretty much ubiquitous, universal, it’s the specifics and those are specifics that are very susceptible to these types of drugs. Point number one. 

Point number two, means the oldest adage of wisdom from antiquity, know thyself and know thy limits. I mean it was the inscription on the pillars of Delphi.

Know thyself, what are you looking to do with these drugs? Know your limits, have you taken them before? What effects have you had before? 

Have you not taken them before, given that, what are your limits in terms of experience? What things might you need to have on board to stay safe environmentally? 

A friend, a tripping buddy, so to speak. As well as a safe spot. A safe spot that for you is environmentally secure, but that also has the necessary resources. If, in fact, you feel, “I need medical help here.”

The third, and I think this is most important, we’re talking about start low and go slow, correct. This brings us into what sometimes we call a research dilemma, called the Collingridge dilemma. 

In other words, you sometimes won’t know unless you go, but you have to be prepared to take the trip. The best way to be prepared is to gain as much information as you possibly can. 

Again, the beauty of podcast like yours is that it not only provides that information in general, but it also provides a resource to the listener to be guided or at least to be mentored to some extent.

But also understanding the literature, and again, your podcast is a good resource for that but know yourself. What have been your experiences, not only with psychedelic drugs but with other drugs? 

What have your experiences been with alcohol? Are you using other substances at this time? Prescription drugs, illicit drugs, alcohol? Do you have medical conditions that might in some way be affected by the mechanism or process of these drugs? 

So, again, knowing thyself and knowing thy limits, is the best stance of preparation to then engage, start low and go slow, because you won’t know unless you go.

Jimmy: This has been a really, really engaging and interesting topic of conversation, I think, for this episode. I can already tell that we have a lot more that we want to discuss and dive into with Dr. Giordano. 

This might be a good time for us to pause this part of the dialogue, and then we’ll continue on with episode two, a part two, let’s say, of this dialogue so that we can dive deeper into not only the mind of Dr. Giordano but the mind of all psychedelic curious folks. 

So, that’ll wrap it up for Part 1 of our episode with Dr. Giordano. 

Thank you for listening to this portion of the episode. You can download episodes of the Psychedelic Passage podcast anywhere you find your podcast, whether that’s Apple Podcast, Amazon, Spotify, IHeartRadio

If you like the show, please give us a rating or review. We’re always open to feedback and comments from our community so that we can continue to provide this thought-provoking dialogue. So, thanks for joining us this week.

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