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Saturday, April 13, 2024

This Is My Brain on Salvia

The last thing I remember from base reality was the piped-in voice of a researcher counting down to zero. Confined within an fMRI machine in the basement of a research hospital in Baltimore, with a mask over my eyes and the countdown crackling through my earbuds, I felt as if I were an astronaut about to blast into orbit. But where I was headed was far stranger than space.

I had lent my gray matter to researchers at Johns Hopkins University for the first imaging study of what your brain does on salvinorin A, a potent, naturally occurring psychedelic produced by a plant called salvia divinorum. I was lying inside a machine that would use massive magnets to peer into my brain, and, as I reported on my experience with the study in 2019, I had just inhaled an unspecified dose of the pure crystalline substance from a hose attached to what one of the researchers characterized as an “FDA-approved crack pipe.” Over the course of an hour, I was given two doses—one placebo, one salvinorin—but I hadn’t been told in advance which was which. I hadn’t felt anything from the first dose, which meant that this time, once the researcher reached zero, I would start feeling the drug's powerful effects.

I knew what I was getting into. I had done a trial run the day before, lying on a couch in a laboratory that was furnished to look like a tastefully trippy living room. During that experience, I had felt my physical self disintegrate as a stunning diamond pattern began rolling from both sides of my face toward a boundless horizon. Any sense of self washed away and time became a meaningless abstraction. I was pure existence having an encounter with the infinite.

My psychedelic experience in the fMRI machine was markedly less otherworldly. On the second round, I saw some colorful pinwheels and felt as though my body had merged with the machine. But I didn’t enter another dimension or dissolve into pure being. This may have been because I received a lower dose. Or it may have been because it’s harder to give in to the experience when you’re inside a giant machine making a racket while it soaks your head in a powerful magnetic field.

But I wasn’t here to touch the face of God. The point was to allow the researchers to watch my brain and those of the 11 other volunteers in the study on salvia. The team was led by Manoj Doss, a postdoctoral researcher in neuropharmacology at Johns Hopkins University working under the guidance of the veteran psychedelic scientist Roland Griffiths. A decade earlier, Griffiths had orchestrated the first controlled study of the subjective effects of salvinorin A. To get a better understanding of how the drug produces its incredibly strong psychedelic effects and whether it might have any clinical relevance for treating conditions like depression or drug addiction, they needed to see what was happening at the neural level. So I got high … for science.

Last week, the team published the results of the study in Scientific Reports, detailing what they saw in our brains as we tripped. The most prominent effect seen in all 12 subjects was a significant decrease in the synchrony of the default mode network. This network is a mesh of brain regions that is primarily associated with internal thoughts but also plays a role in memory and emotion. It’s activated when we’re thinking about ourselves and others or orienting ourselves in space and time. Different regions of the brain will show increased activity when we focus on a specific task outside of ourselves, like reading or playing an instrument, but the default mode network is what pops back on when we turn our attention back on ourselves.

When your attention turns inward, the communication between the brain regions in the default mode network syncs up like musicians in an orchestra. Other fMRI studies of volunteers high on better known psychedelics like LSD and psilocybin, the psychoactive molecule in mushrooms, have also shown decreases in coupling among the areas involved in this network. It’s as if the musicians in the orchestra stop following a central conductor and each start keeping time with separate metronomes. Some researchers think that the decreased activity between these network connections is part of the essence of what makes psychedelic drugs so psychedelic.

But the Johns Hopkins researchers think this is not the whole story. “Research on classic psychedelic drugs like LSD, psilocybin, and DMT has been focusing on the default mode network because it has been hijacked by a Freudian narrative that requires a concrete ‘ego,’” says Doss, referring to the psychoanalytic concept of self. This, he says, has caused researchers to focus less attention on changes in activity elsewhere in the brain, even though those changes are often larger than in the default mode network. Moreover, non-psychedelic drugs including cannabis and alcohol also cause decreases in default brain network activity, which complicates the idea that it might be the root of a psychedelic experience.

The fact that salvinorin A selectively targets the network only adds to the confusion, because it’s so different from classic psychedelics in most other respects. Perhaps the biggest difference is that while most psychedelics primarily act on serotonin receptors, salvinorin A acts on the kappa opioid receptor, which seems to play a role in regulating pain and modulating the effects of common opioids like morphine and fentanyl. “Salvinorin A is unique as a kappa-opioid agonist that has psychedelic-like effects, and this calls into question whether reduced default mode network connectivity is really a specific mechanism of ‘classic’ psychedelic drugs,” says Fred Barrett, a neuroscientist at Johns Hopkins and a coauthor of the study.

In other words, what’s interesting about the team’s results is that they seem to show that salvinorin A isn’t special among psychedelics when it comes to decreasing activity in the default mode network. It’s an atypical psychedelic in pretty much every way, yet its neurological effects are stronger in the brain network that many researchers think are key to experiencing the effects of classic psychedelic drugs than those drugs themselves. “Considering salvinorin A has subjective effects quite different from classic psychedelics, it certainly doesn't bode well for the idea that the default mode network is key to their effects,” says Doss.

The molecule is produced naturally in salvia divinorum, a type of sage in the mint family. The plant is endemic to southern Mexico, where it has been ingested ritualistically by indigenous peoples for centuries. But it wasn’t introduced to researchers in the United States until 1962, when Harvard botanist Gordon Wasson described its psychoactive effects and botanical classification. It took another 20 years before scientists isolated its primary psychoactive ingredient.

“Salvinorin A challenges our conception of what psychedelics are,” says Peter Addy, a psychotherapist who has done extensive research on the subjective effects of salvia while working at Yale and wasn’t involved with the Johns Hopkins study. “It’s the only psychoactive substance that is more potent than LSD. Taking an incredibly small amount of salvinorin A produces an incredibly large effect in consciousness.”

Part of the reason for the scientific establishment’s neglect of salvinorin A may have to do with how many people find its effects deeply unpleasant. Compared to LSD and psilocybin, which became emblematic of the 1960s feel-good mindset, salvinorin A comes on fast and can make a person feel like they’ve left their body, which has probably turned many people off from using it recreationally. Indeed, it’s one of the few well-known psychedelics that isn’t a federally controlled substance under Drug Enforcement Administration regulations, although its use is outlawed in several states.

Most of the state laws prohibiting the use of salvinorin A were passed in the mid-2000s after videos of teenagers smoking salvia and going catatonic or losing control of their behaviors and emotions began circulating on the web. This attracted the attention of lawmakers and concerned parents, who sought to ban the substance by comparing it to LSD and other psychedelics. In some states it was the pushback from psychedelic researchers like Addy and Matthew Johnson, a psychiatrist at Johns Hopkins University, that saved the drug from being outlawed. These researchers were concerned that scheduling salvia would make it prohibitively difficult to study its potential therapeutic uses; the fact that salvinorin A acts on an opioid receptor has led some researchers to experiment with it as the basis for a nonaddictive pain management alternative, treatment for cocaine addiction, or an antidepressant.

So far, however, the only evidence for the potential medicinal uses of salvinorin A and related drug analogs is in a limited number of animal studies. Despite some positive results in reducing depressive symptoms and increasing pain tolerance in rats, a lot of work needs to be done before much can be said about any possible medicinal benefits for humans. Doss, for one, isn’t holding his breath. “I don't know if I believe that a kappa opioid agonist is going to be important for the treatment of something like depression or addiction,” he says. “There are not enough reports yet in people. If we believe this activity might be important for the improvement of depression, let’s start running clinical trials.”

The brain imaging study at Johns Hopkins was a first step toward understanding the effects of this bizarre psychedelic. Doss says the study was hampered by several limitations, such as its small sample size and the lack of repeat trials, but it points the way to more comprehensive studies. To get a better handle on what salvia is doing in the brain, in future studies Doss would want to image the brains of individuals on salvia at multiple doses—and cross reference those patterns to the ways their brains behave on classic psychedelics. He says it would also be interesting to compare how people perform tasks while taking salvinorin A versus other psychedelics, rather than just lying still in an fMRI machine, which would help differentiate its effects on specific regions of the brain.

For now, though, salvinorin A remains as mysterious as ever, underscoring how much we have to learn about psychedelics. “There's a lot of information out there on how the brain produces thoughts and behaviors, but much of that is being ignored in psychedelic research,” says Doss. “Instead, what many are doing is simply looking at brain activity and selectively inferring its function, when there's never a clear one-to-one mapping between brain activity observed with fMRI and the consequent mental operations. Not only does this tell me how little we understand psychedelics, it also tells me how little we understand how to study them.”

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