5 Questions for Manoj Doss

Amid the growing popularity of psychedelics as potential medicines, there’s also a boom in interest about the neuroscience of psychedelics: what actually happens in the brain when people use these drugs? For years, the leading theory has focused on what’s called the Default Mode Network, or DMN, a connected web of brain regions thought to be involved with high-level thought, like self-reflection, recalling past experiences, and imagining future events. Some researchers have posited that the DMN is where our ego resides, and that psychedelic experiences disrupt the DMN, which can lead to ego-dissolution and mystical-type experiences.

But not everyone agrees.

Manoj Doss, a cognitive neuropsychopharmacologist and post-doctoral research fellow at Johns Hopkins University, studies the effects of drugs like salvinorin A (the psychoactive molecule in the hallucinogenic plant Salvia divinorum), MDMA, psilocybin, and cannabis on brain function. He and his colleagues’ most recent study on Salvinorin A, published last year in Nature, suggests activity in the DMN can’t fully explain psychedelics’ effects. The Microdose talks to Doss about the neuroscience of mind-altering drugs, and how a combination of brain imaging data and behavioral data might help us better understand how drugs affect the mind. 

What makes you doubt that changes in the DMN are psychedelics’ mechanism of action?

There are many reasons — but often you get stronger effects [in imaging data] outside of the DMN, like in sensory regions of the brain. But also, every drug affects the DMN. I wrote in a paper about Salvia that the strongest and most statistically significant results we got in increases or decreases of functional connectivity were decreases in the DMN. Other researchers have shown this with alcohol, too — but alcohol doesn’t dissolve your ego, it makes you more egotistical!

Are there other, more promising models, in your opinion?

I would say that the theory with the most evidence now is the thalamic gating model. The thalamus is a structure in the brain that takes in sensory information.One thing people noticed is it has this gate; it allows selective information in, so you’re not overloading the rest of the brain. The idea is that psychedelics open up this gate — they remove the gating mechanism.

There has never been a more exciting – or bewildering – time in the world of psychedelics. Don’t miss a beat.

Why hasn’t the thalamic gating model gotten as much attention?

Some of the early work on the thalamic gating model was talked about in terms of psychosis, which doesn’t jive well with people who want to feel good about psychedelics.

You’ve raised issues before about the limitations of imaging work in understanding psychedelics’ mechanism of action or guiding decisions about which therapies are effective. What are the challenges? 

One issue with fMRI is a statistical problem — it’s a very statistically noisy measure, and trying to make sense of it, trying to find reliable signals, is extremely difficult with only 15 subjects. [Editor’s note: In scientific studies, especially those with human subjects, researchers recruit subjects in hopes that they are representative of the population they hope to study, and then draw conclusions from their data using statistics. Those statistics can be skewed if a study includes only a few participants, and it’s a known issue within neuroscience that studies with small participant pools are difficult to interpret. In an ideal world, scientists could test hundreds or thousands of participants for each study, but resources are limited.]

The other thing is that when people are on LSD or psilocybin, they move in the scanner — more so than when they’re given a placebo. People fall asleep when they’re on placebo when they’re sitting in a scanner for 15 minutes! So what are you really comparing — is it people awake versus people asleep, or are you showing psychedelic effects?

It takes cognitive psychology [paired with fMRI data] to actually teach us something about the mind — how the brain operates in a way that results in changes in behavior. And using fMRI is completely useless in psychiatry at the moment. It’s not used for diagnosis, prognosis, or anything — you can’t scan brains and say, “You have this flavor of depression, and we’re going to give you this medication.” It has yet to be used as a psychiatric tool, but I’m hopeful it can be. 

Beyond combining expertise from these various brain science disciplines, what other challenges are there in carrying out solid research on the neuroscience of psychedelics?

A lot of people who come into drug research, in general, are not cognitive psychologists, or they’re not researchers. They’re people who did drugs, and want to study them. And sometimes they feel like their drug experience overrides what people have been doing in experimental psychology — it’s baffling that people don’t look into theories of the mind that have been around for centuries. 

I know only one psychedelic researcher who’s never done psychedelics. I think this means you’ve got some stakes in the game: you did drugs, you liked them, now you’re studying them. You’re going to be tempted to say mostly positive things about them. There’s a conflict of interest.

This interview has been edited and condensed for clarity and length.

Please note we will not be publishing a This Week in Psychedelics post on Friday. We’ll be back with more next week!

Correction: in Friday's newsletter, in our section on the DEA’s Schedule I drug quotas, we originally stated that “ the government produces a certain amount of them each year to be used in research.” The government does not produce the drugs; they permit registered manufacturers to do so.