We've all heard of the opioid crisis by now, or at least most of you have. The opioid crisis refers specifically to people taking exogenous opioids, taking opioids, right? So taking pills that activate particular receptors in the brain that lead to analgesia in some cases, so pain relief that lead to changes in mood.

There's a lot to be said about the opioid crisis. It's called a crisis for a reason. Many, many people are addicted to those compounds. That's a discussion for another time. Keep in mind that the receptors those drugs bind to are opioid receptors. And those receptors that you and I all have, by the way, do not exist in order to bind drugs that are made by pharmaceutical companies.

They exist in our brain and body to bind to the so-called endogenous, naturally made opioids that we all make. And those receptors have different names. The mu-opioid receptor, the kappa-opioid receptor, et cetera. They tend to have the names of Greek letters to differentiate them. Now, ketamine can bind to various opioid receptors.

And when opioid receptors are bound, we know that creates certain effects, things like pain relief, things like changes in psychic states, dissociation, for example. If enough of them are bound, you can get euphoric states. Under certain conditions of high dose binding of ketamine to those opioid receptors, you can start getting into planes of anesthesia where people lose consciousness and actually have no response to pain whatsoever.

If you recall the clinical studies we talked about earlier where ketamine was used to relieve depression, well, the dosage used in that study, as you recall, was half a milligram per kilogram of body weight. That is the dosage that will induce these dissociative, mild euphoria, those sorts of states of mind, but where people are still conscious.

When you start getting to dosages of ketamine that are in the range of one to two milligrams per kilogram of body weight, now you're talking about anesthetic doses. And when that happens, you're going to get full parking, full saturation of all the potential receptors that ketamine can bind to.

Those NMDA receptors, it's going to block those. It's also going to bind to the so-called mu-opioid receptors, and maybe this other type as well, for those of you that want to know, uficionados, also the kappa-type opioid receptors. And so what we've got here is a drug, ketamine, that is hitting two different systems, the glutamate-related system and the endogenous opioid system.

And researchers and clinicians have logically started to ask whether or not some or all of the effects of ketamine are due to the opioid system, and they want to know which effects those are. Now, this is where things start to get really interesting, both in the context of clinical treatment of depression and recreational use.

First of all, when people take ketamine, again, it enters the bloodstream and it goes into the brain, but it is metabolized to something called HNK, which is hydroxynorketamine. Now, I don't expect you to know what hydroxynorketamine is, and I don't expect you to care about it until I tell you what I'm about to tell you, which is that hydroxynorketamine has an incredible specificity for the mu-opioid receptor, and maybe that kappa-opioid receptor as well.

In other words, when we talk about ketamine, that's the drug people take, but when it goes into the body, it's converted into yet another drug, and that other drug, hydroxynorketamine, is selectively activating the opioid system. So this led researchers to ask it a very important question, which is when a human being takes ketamine in order to treat their depression and they get some relief from depression, is that the consequence of neuroplastic changes and all those NMDA, glutamate, BDNF-related circuits that we talked about before?

Or is it the consequence of something happening in the opioid system? You can't ignore the fact that ketamine has this property of binding to these opioid receptors because they have such a powerful effect on our thinking, on our mood, on our state of consciousness. It's entirely reasonable that the opioid system could be a major player, if not the major player, in this whole depression relief thing, and maybe even in the creation of dissociative symptomology when people take ketamine recreationally.

So what researchers/clinicians did is they undertook a series of experiments where they gave people ketamine for the relief of depression, but they also blocked the opioid receptor system. And they did that using a drug called naltrexone. So what I'm about to describe to you is a study done by my colleagues at Stanford School of Medicine, namely Dr.

Nolan Williams and Alan Schatzberg and colleagues, entitled "Attenuation of Antidepressant and Antisuicidal Effects of Ketamine by Opioid Receptor Antagonism." And as a consequence of me reading you that title a moment ago, you now already have the conclusion of the study. What they observed is that when people were given ketamine, they got relief from depression.

That wasn't surprising. Again, many studies had shown that before, since the early 2000s. If, however, individuals were given naltrexone to block the opioid receptor pathway, and they were given ketamine, well, then the antidepressant effects of ketamine were no longer observed. Now, that suggests that it is the opioid receptor system that's responsible for the antidepressant effects of ketamine.

And perhaps this HNK, this hydroxynorketamine, which is the metabolite of ketamine, is the way in which ketamine normally relieves depression. Now, a lot of people took note of these studies because after all, there are probably dozens, if not hundreds of studies looking at the effects of ketamine on all that NMDA receptor stuff.

And indeed, neuroplasticity and mood-related circuits can't be discounted as one way in which ketamine provides relief from depression. But what was very interesting is that in people given ketamine and naltrexone, those people still experienced the immediate effects of ketamine, the mild euphoria, the dissociation, the feelings that one would normally expect when people were under the effects of ketamine.

But what they didn't get were the longer term changes in mood that we would call relief from depression. Now, of course, the goal of modern psychiatry is to treat depression, not to block the effects of these drugs that are capable of treating depression. Now, what this study does, and by the way, there are several studies like it that support these general set of findings that part of the critical role of ketamine in providing relief from depression is to activate the opioid system.

But what this study does is it really points to the fact that when we say ketamine treatment, or we talk about somebody taking ketamine recreationally, for that matter, we have to pay attention to what's happening while they are under the influence of the drug. We also have to pay attention to what's happening in the days and weeks after they're under the influence of the drug.

And perhaps most importantly, this calls to mind a really important idea, which is that whether or not you're talking about ketamine induced relief from depression, or psilocybin induced relief for depression, or MDMA induced relief for PTSD, a topic that I covered on a previous episode of this podcast, we have to step back and look at the idea that the effects of the drug that people experience, whatever those may be, because obviously it's going to depend on what particular drug they took, those immediate effects may not actually be related to the long-term clinical benefit of those particular drugs.

Now, I realize that many people might not like that idea. And frankly, I don't actually think that's the way that it works. I don't think it's going to be an either or situation. However, because drugs like ketamine, psilocybin, MDMA have such profound effects on people's psychic states when they are under the influence of them.

And because at least in the proper clinical setting and use, they do seem to provide impressive relief from a lot of these psychiatric challenges like depression and PTSD. People naturally correlate those two things. They couple those two things. In fact, they collapse those two things and presume that their experience of what they saw, what they heard, how they felt while they were under the influence of the drug was actually the stimulus that created the relief from their clinical condition like depression.

But what these data on combined treatment with ketamine and naltrexone to block the mu opioid receptor really show us is that that may not actually be the way that it works. It may be that the effects of a drug like ketamine that one experiences, while interesting, perhaps even profound, perhaps great insight comes to one when they do that therapy in the proper context, it is not clear at all that it is that experience and the effects of those drugs in those immediate minutes and hours that's actually what's causing the relief from depression.

Now, again, I don't think it's an either or. I like to view the whole situation more or less as a sort of wave front that the experience that one has subjectively while they are under the influence of a drug like ketamine or psilocybin or MDMA sets off a series.

And in fact, multiple series, is that a word? Multiple types of processes in the brain, some of which rely on things like NMDA receptor, BDNF, et cetera, type neuroplasticity, others which rely on the opioid receptor pathway. And that each of these have different time courses such that some provide immediate relief in the days and hours after treatment, some in the weeks after treatment, and some more durable, long-lasting changes that can occur over months or maybe even years.

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