LSD-Tripping Brains Reveal How the Drug Causes the Psychedelic Experience

It’s no secret that LSD causes vivid hallucinations, altered states of consciousness, one-ness with the universe, and a host of other psychedelic effects. But ever since the trippy chemical was discovered by Albert Hofman in 1938, scientists have been trying to figure out how it exerts these overwhelming effects on the brain. An LSD study published Monday in PNAS provides further evidence for a leading theory, suggesting that the brain on LSD trips because it’s experiencing sensory overload.

It’s well established that the brain can’t process all of the sensory information it receives from the outside world. Sometimes those stimuli are redundant, and other times they’re just not useful. The key “filter” for all that information is a ball of neurons in the middle of the brain called the thalamus. When it’s working correctly, the thalamus weeds out unnecessary information so the brain doesn’t get overloaded, much like Twitter’s algorithms try to present only the tweets you want to read.

“Most sensory impressions are routed through the thalamus, which acts as a gatekeeper, determining what’s relevant and what isn’t and deciding where the signals should go,” explained Yale psychiatrist and LSD researcher Andrew Sewell, Ph.D., to LiveScience. Sewell was not involved in the new study.

But LSD and other psychedelics changes the ability of the thalamus to do all this filtering (neuroscientists call it “sensory gating”), according to the theory proposed by Mark A. Geyer, Ph.D., and Franz X. Vollenweider, Ph.D., in 2008. If the thalamus can’t perform its gating duties, the brain suddenly has to deal with a lot more stimuli and goes into overdrive. We experience that flood of information as a psychedelic LSD trip (perhaps analogous to the overwhelming feeling of Twitter overload).

The new PNAS study, led by Katrin H. Preller, Ph.D., of the University Hospital for Psychiatry Zurich and co-authored by Vollenweider, dives deep into the brain to show how LSD exerts its effect on the thalamus. Since, at their peak, LSD trips have similar effects to psychiatric issues like depression and schizophrenia, understanding how the drug works could show scientists how to treat those disorders.

LSD has well-known effects on serotonin, a neurotransmitter involved in many other psychedelic drugs, and it’s been proposed that serotonin is also the key molecule involved in messing with the thalamus’s ability to filter information during an LSD trip, resulting in “an overload of the cortex.” So, Preller and her team tested what would happen if they gave people LSD but blocked their serotonin receptors.

They gave some of their 24 participants both LSD and a drug called ketanserin, which blocks serotonin receptors. And sure enough, when they used the 5-Dimensions Altered States of Consciousness questionnaire to figure out who tripped, they found that “all LSD-induced subjective drug effects were blocked by Ket.” Diving deeper, they showed that LSD interrupts one big circuit of brain regions: The altered serotonin activity reduces the striatum’s influence on the thalamus, which in turn opens up the thalamic filter to a specific part of the cortex called the PCC (posterior cingulate cortex). It sounds like the PCC is going to be a big part of psychedelics research going forward.

“In particular, the present results pinpoint the role of the thalamus–PCC connection for the effects of psychedelics,” they write.

Though the thalamus and PCC seem to be important areas to focus on, other studies have revealed that LSD’s effects ripple through many interconnected parts of the brain. In 2018, scientists in Spain showed that LSD hits “reset” on the brain’s existing connections, offering the potential to treat persistent problems like depression, addiction, and PTSD. In the same year, University of California, Davis, researchers showed that neurons treated with LSD have more “branches” to connect with neighboring cells.

Until we understand LSD more fully, trip on this: Just as people on LSD report feeling a greater sense of connectivity to the universe, the neurons of the brain on psychedelics are likewise increasingly connected, too.

Abstract: Psychedelics exert unique effects on human consciousness. The thalamic filter model suggests that core effects of psychedelics may result from gating deficits, based on a disintegration of information processing within cortico–striato–thalamo-cortical(CSTC) feedback loops. To test this hypothesis, we characterized changes in directed (effective) connectivity between selected CTSC regions after acute administration of lysergic acid diethylamide (LSD), and after pretreatment with Ketanserin (a selective serotonin2A receptor antagonist) plus LSD in a double-blind, randomized, placebo-controlled, cross-over study in 25 healthy participants. We used spectral dynamic causal modeling (DCM) for resting-state fMRI data. Fully connected DCM models were specified for each treatment condition to investigate the connectivity between the following areas: thalamus, ventral striatum, posterior cingulate cortex, and temporal cortex. Our results confirm major predictions proposed in the CSTC model and provide evidence that LSD alters effective connectivity within CSTC pathways that have been implicated in the gating of sensory and sensorimotor information to the cortex. In particular, LSD increased effective connectivity from the thalamus to the posterior cingulate cortex in a way that depended on serotonin2A receptor activation, and decreased effective connectivity from the ventral striatum to the thalamus independently of serotonin2A receptor activation. Together, these results advance our mechanistic understanding of the action of psychedelics in health and disease. This is important for the development of new pharmacological therapeutics and also increases our understanding of the mechanisms underlying the potential clinical efficacy of psychedelics.