In F.I.V.E.’s recent webinar, Brain Entropy and 5-MeO-DMT, neuroscientist Manesh Girn, PhD moderated a conversation with Robin Carhart-Harris, PhD and Tommaso Barba, PhD(c) on one of the most fascinating questions in psychedelic science: what happens in the brain during the profound states of consciousness associated with 5-MeO-DMT?
The conversation explored brain entropy, self-dissolution, nondual states, neuroplasticity, and why 5-MeO-DMT may offer researchers such a powerful model for studying consciousness itself.
*This interview has been edited for length and clarity.
Q: How does 5-MeO-DMT appear to affect the brain differently from other psychedelics like N,N-DMT or psilocybin?
Robin-Carhart-Harris: The honest answer is that we don’t fully know yet. One of the clearest clues so far comes from EEG work, where we see slow waves with 5-MeO-DMT that resemble sleep more than a hyper-awake psychedelic state.
That’s part of what makes 5-MeO so fascinating. It is clearly psychedelic, but it is not content-rich in the same way N,N-DMT often is. With N,N-DMT, people commonly describe entering a vivid, elaborate world. With 5-MeO, it seems to be much more about the dissolution of self and content.
One possible reason is 5-MeO-DMT’s strong affinity for serotonin 1A receptors, which are expressed differently in the brain than the serotonin 2A receptors we usually associate with classic psychedelics like LSD, psilocybin, and N,N-DMT. That 1A component may be part of what makes 5-MeO so distinct.
Manesh Girn: There may also be something important happening in how 5-MeO-DMT disrupts the rhythms that maintain our internal narrative and our ordinary sense of self. Serotonin 1A receptors are found in regions like the hippocampus and cortex, which are involved in memory, self-representation, and the maintenance of an internal narrative.
There’s also some evidence from earlier psychedelic research that 1A activity can reduce visual effects. That may help explain why 5-MeO-DMT is less visually rich than other psychedelics, while still being profoundly consciousness-altering.
Q: What are EEG studies revealing about the acute 5-MeO-DMT state?
Tommaso Barba: One of the main findings from the EEG work is that, at peak, 5-MeO-DMT shows a steep increase in ultra-low and very-low brain frequencies… frequencies we usually associate with deep sleep.
But what’s interesting is that this does not look exactly like sleep. In deep sleep, slow waves are usually rhythmic and propagate across the brain. With 5-MeO-DMT, those slow waves appear less rhythmic and more localized. They do not seem to propagate in the same organized way.
We also see some patterns that are familiar from other psychedelics, like a drop in alpha activity. Alpha is often thought of as an inhibitory rhythm that helps hold things together in waking consciousness. When alpha decreases, there may be a release from that inhibition.
But 5-MeO also seems to differ from N,N-DMT in important ways. For example, we found a drop in theta activity, while N,N-DMT studies often show an increase in theta. Theta is associated with spatial navigation, memory, and dream-like world-building. That difference may fit the pharmacology: N,N-DMT often feels like entering another world, while 5-MeO seems more like the dissolution of world and self.
Q: If 5-MeO-DMT is not necessarily visually rich, what does increased brain entropy actually mean?
Robin Carhart-Harris: This is where 5-meO-DMT has pushed the entropic brain hypothesis to evolve. Initially, brain entropy was often discussed as an index of the richness of experience. The richer the experience, the higher the entropy.
But 5-MeO challenges that. We also see increased entropy in certain meditative states, and those states are not usually described as “rich” in the same way a highly visual psychedelic experience might be. So the newer way I think about it is that brain entropy may correspond more to expanded states of consciousness.
With 5-MeO, consciousness may become “bigger” or more spacious, but not necessarily more filled with content. In fact, at higher levels of entropy, you may move past the point where the system can hold form or structure. There may be too much entropy for a world to be constructed.
Tommaso Barba: That fits with what we’re seeing. Entropy appears to be higher with 5-MeO-DMT than with N,N-DMT, and it tracks with the degree of self-dissolution. The stronger the reported self-dissolution, the higher the brain entropy, the higher the delta and gamma activity, and the lower the alpha and theta activity.
So 5-MeO-DMT may show us that increased entropy does not always mean “more content.” It may sometimes mean the breakdown of the structures that normally create self, world, and content.
Q: What can 5-MeO-DMT teach us about nondual states and meditation?
Tommaso Barba: We looked at this through a case study with an experienced Lama meditator who had thousands of hours of meditation practice. We recorded his brain during nondual meditation and also during two different doses of 5-MeO-DMT.
The low dose of 5-MeO seemed closer to the nondual meditation state, at least from a brain-pattern perspective. The high dose was very different. The meditator described the high dose as completely removing the body and the environment, and the brain signal became more chaotic and unpredictable.
It is important to say that this was only a case study, so it is very early and preliminary. But it suggests that we may be able to compare altered states reached through different methods – meditation, psychedelics, and other practices – and begin to map where they overlap and where they are different.
Manesh Girn: One of the most interesting things here is that we may need a more refined cartography of altered states. People may use a term like “nondual experience,” but that could actually refer to many different states that are subjectively and neurologically distinct.
Low-dose 5-MeO, and nondual meditation may share some features, but they are not necessarily the same thing. The differences may be just as important as the similarities.
Q: How could such a short experience lead to long-term changes?
Tommaso Barba: The clinical potential is there. There are programs studying different formulations of 5-MeO-DMT for conditions like treatment-resistant depression, and early reports suggest fast and durable improvements in depressive symptoms.
But the question of why that happens is still open. One possibility is that the changes are not only about what happens during the acute experience, but also about what happens after. How someone spends the time after the dose may be very important.
There is also preclinical research suggesting that 5-MeO-DMT can produce a strong boost in neuroplasticity that lasts long beyond the acute effects, but that evidence is still largely from animal research.
Robin Carhart-Harris: I think a reset or recalibration model is compelling. With 5-MeO-DMT, you get a profound perturbation of the normal organization of brain activity. The system is pushed into a highly altered, entropic state, and then it naturally recalibrates. When you come back to ordinary waking consciousness, you may not come back with the same old weightings, habits, and hang-ups in exactly the same way. There may be a useful disordering that allows the system to reset into something more flexible and more plastic.
I often think about stress and adversity as stripping away possibility – narrowing horizons, reducing freedom, and reinforcing old patterns. Psychedelics may help restore a sense of possibility, even at very low levels of the nervous system.
Manesh Girn: Even though the subjective experience of 5-MeO-DMT may last only 20 or 30 minutes, rodent research suggests it can produce neuroplastic changes that last 30 days or more. In one study, 5-MeO-DMT and psilocybin both increased dendritic growth in the medial prefrontal cortex by around 10 to 15 percent.
That does not mean we have the full answer in humans yet, but it does suggest that a short experience can still be associated with longer-lasting biological changes.
Q: What makes 5-MeO-DMT such an important compound for studying consciousness?
Manesh Girn: 5-MeO-DMT may be one of the clearest models we have for studying what deconstructed consciousness looks like – both subjectively and in the brain.
It disrupts the fundamental rhythms that help create our sense of self, our relationship to the external world, and the construction of experience. That makes it scientifically valuable, not only because of its therapeutic potential, but because it can help us understand what consciousness is made of.
Robin Carhart-Harris: That’s what makes it so exciting. We are still at the beginning. The research is young, the findings are still emerging, and there is a lot we do not understand.
But with 5-MeO-DMT, we may be able to learn something deeply important about the nature of consciousness and how it is encoded by brain activity. It is a fascinating paradox: slow-wave activity that resembles sleep, increased entropy, profound self-dissolution, and yet a person may be awake in one of the most intense experiences of their life.
That paradox is exactly why this field is so interesting.