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How Hallucinogens Can Improve Your Mood and Personality

Two recent studies explain the actions and benefits of LSD and psilocybin.

How do hallucinogens work? The precise mechanisms that are set in motion within the brain after consuming lysergic acid diethylamide (LSD) or psilocybin are unknown. Hallucinogens do not produce perceptions of things that are not actually present; generally, they distort the ability of the brain to represent the perception of objects that are present. For example, hallucinations that alter the function of the visual cortex will distort proportion, form, movement, and the color of objects, however, the objects will likely remain recognizable.

Thus, to understand how your brain can hallucinate, you need to understand how your brain produces a normal sensory experience. A recent study combined the power of three complementary neuroimaging methods, one called diffusion magnetic resonance imaging, the other called functional magnetic resonance imaging, and the third called positron-electron tomography to explain the functional changes, in real-time, of psilocybin. Let’s begin by recognizing a large globular brain region called the thalamus. The thalamus lies deep in the center of the brain and is highly interconnected with the overlying cortex.

All of your sensory information is received, processed, and distributed to reciprocally connected regions of the cortex; the continual cross-talk between these two brain regions is thought to underlie your experience of normal waking consciousness. As these states of functional connectivity change over time, you experienced a stream of consciousness that is dynamic in response to incoming sensory information and always flowing forward. Furthermore, the anatomy of each sensory region of the cortex is designed to keep its processing separate from other sensory regions. For example, visual information is processed within the occipital lobe before being forwarded into the parietal and temporal lobes.

Imagine the chaos that might occur if the cross-talk between usually segregated neocortical regions is disturbed or imbalanced; for example, your visual cortex starts allowing its information to leak into the auditory cortex. Suddenly, the color blue sounds like middle C.

This explanation raises the question of how hallucinogens produce this disturbance of cortical and subcortical integration. All of the known hallucinogens, except one, at doses typically achieved in the brain, interact with at least six different serotonin receptors.

The psychoactive actions of LSD and psilocybin are most likely due to their ability to stimulate one particular serotonin receptors, called 5HT2A. LSD enters the brain within about three minutes after administration; its psychic effects are maximal at about one to three hours later. Radioactively labeled molecules of LSD concentrate within the visual cortex of the occipital lobe, throughout the limbic system, and within the brain stem.

Within minutes of consuming LSD or psilocybin, the activity of serotonin neurons in the brain stem region decreases almost completely. The psychoactive effect of LSD and psilocybin far outlasts the slowing of serotonin neural activity; therefore, the slowed activity of serotonin neurons in the raphe nuclei does not explain why we hallucinate on these drugs. The initial effects of these drugs on serotonin neurons may only be the initial trigger that sets in motion a cascade of complex processes throughout the brain that is ultimately experienced as a hallucination.

In the study by Madsen et al., ten healthy volunteers received a dose of psilocybin and then listened to a standardized music playlist. Eight volunteers reported that they had a “complete mystical experience” based on taking an Altered States of Consciousness questionnaire. One week later, the volunteers were imaged again to look for changes in 5HT2A receptors. Three months later, the subjects were assessed for indicators of mindfulness, personality, and other long-term effects. The researchers found that the volunteers’ levels of mindfulness and openness tended to increase from baseline to follow-up. Changes in 5HT2A receptor binding in two regions of the frontal lobes were inversely correlated with their changes in mindfulness three months after psilocybin.

The authors speculated that the change in neocortical 5HT2A receptor binding may underlie the long-lasting beneficial effects on mood and personality. Their conclusions are consistent with many previous studies that have shown that stimulating the 5HT2A receptor can reduce anxiety.


Luppi AI et al., (2021) LSD alters dynamic integration and segregation in the human brain. NeuroImage Vol 227, 15, 117653

Madsen MK et al., (2020) A single psilocybin dose is associated with long-term increased mindfulness, preceded by a proportional change in neocortical 5-HT2A receptor binding. European Neuropsychopharmacology Vol 33, p, 71-80.