5 Ways Psychedelics May Affect the Brain

Here’s what science tells us about these powerful molecules

Austin Perlmutter, MD


Source: Moritz Mentges/Unsplash, Fakurian Design Unsplash

In the last decade, discussions around psychedelics have exploded, driven in part by research showing their safety and efficacy in treating a number of mental health conditions ranging from depression to anxiety to addiction. Psychedelic molecules have obvious, dramatic effects on our thinking and mood. But when it comes to understanding exactly how they exert these effects on our brains, things are a little less clear. Though the mechanisms of each psychedelic may differ, researchers have noted several overarching themes. Here are five of the top ways that psychedelic molecules may influence our brain function.

1. Affecting neurotransmitters and their receptors

Perhaps the most commonly cited effect of psychedelic drugs relates to their influence on neurotransmitters — chemical signaling molecules in the brain. Many psychedelics are thought to work by acting on a site for the neurotransmitter serotonin called the 2A receptor. Psychedelic binding to the 2A receptor on neurons in the brain’s cortex seems to be a major driver of their mind-altering effects.

While the 2A serotonin receptor is key, there’s more to the neurotransmitter story. Other serotonin receptors are involved, and additional neurotransmitters and their receptors (including GABA, dopamine, norepinephrine, and glutamate) also appear to play a role.

2. Changing brain activation patterns

Measuring changes in brain activation patterns has become a popular way to examine the biological effects of psychedelics. In this research, much focus has been on a part of the brain called the “default mode network” (DMN). Activation of the DMN is linked to mind wandering and thinking about the past and future. Psychedelics have repeatedly been shown to change activity and connectivity of this network in the brain. This finding has been proposed by some as a biological correlate to the reorganization of thoughts and opportunity for more insight that accompanies psychedelic use.

A number of other brain activation changes have also been linked to the use of psychedelics. Among the more prominent of these changes are alterations in the connectivity between the prefrontal cortex (a part of the brain involved in emotional regulation and higher-level thinking) and the amygdala (a part of the brain’s temporal lobe involved in the emotional response).

3. Helping the brain rewire itself

The brain is always rewiring itself in response to its environment, a process known as neuroplasticity. One of the ways it does so is by changing the connections between neurons. Issues with neuroplasticity have been linked to worse mental health, especially depression. Interestingly, new research in psychedelics suggests that they might help to reverse this deficit.

Some of the most remarkable evidence for the effect of psychedelics on neuroplasticity relates to ketamine. Though the work is primarily based on animal research, ketamine is thought to help enhance connections between neurons. Further, albeit more limited, research suggests that other psychedelics including MDMA (3,4-methylenedioxymethamphetamine), LSD (lysergic acid diethylamide), and psilocybin may also facilitate new and stronger connections between neurons.

4. Influencing the brain’s immune system

The connection between immune function and mental health has been the subject of considerable research over the last several decades. Elevated inflammation (a form of imbalanced immunity) has been linked to depression and anxiety. It’s also thought that some of the most commonly prescribed antidepressants may work in part through the immune system. When it comes to psychedelics, researchers are now suggesting there may be a similar effect at play.

As previously described, serotonin and its receptors are thought to play a major role in the psychedelic response. It turns out that serotonin itself is involved in multiple aspects of the immune system, and there may be receptors for this neurotransmitter on immune cells and tissues throughout the body and brain. This indicates a potential for widespread immune effects after psychedelic use. Other studies in cells and animals show that psychedelics may have an anti-inflammatory effect. Finally, it has been proposed that psychedelics could directly affect the brain’s own immune cells.

5. Altering gene expression in the brain

One of the most powerful reframes in modern science has to do with the way our genes are expressed. Genes are stretches of DNA that code for proteins and RNA. They influence every aspect of who we are. But though the DNA in our genes is relatively rigid, it has now been shown that our environment, our choices, and even the food we eat can change our genetic expression for the better or the worse. This fascinating discovery may help explain some of the benefits of psychedelics, as preliminary evidence suggests they may change gene expression in the brain.

Research connecting psychedelics and gene expression has been ongoing for several decades. For example, in 2003, scientists showed a rapid change in gene expression after administration of LSD to rats. In an animal study from 2020, a single dose of the psychedelic psilocybin appeared to alter expression of 19 genes in the brain’s prefrontal cortex, especially those related to the immune system. A subsequent animal study found similar brain effects on genes related to neuroplasticity. Finally, very recent (preprint) research suggests a potential effect on thousands of genes after DMT administration. Despite these data points, the overall effect of psychedelics on gene expression and the contribution of this pathway to their subjective effects remains somewhat unclear.

What comes next:

As interest in psychedelics continues to grow, scientists will continue to investigate the myriad ways in which these potent molecules influence our bodies and brains. Like conventional antidepressants, it seems likely that psychedelics act on a range of biological pathways to achieve their effects on mood and cognition, and that different psychedelics may have distinctive effects on the brain.

The climate around psychedelics has changed dramatically over the last several decades, driven in part by books like Michael Pollan’s How to Change Your Mind and research suggesting both efficacy and safety of these molecules when used in the right set and setting. There’s still much to learn about exactly how psychedelics work and how best to leverage them to improve mental health. However, even a slightly richer appreciation for their biological effects could promote understanding of where they might be of value in treatment, as well as helping providers and patients to better anticipate the effects of their use.



Austin Perlmutter, MD

Dr. Austin Perlmutter, co-author of BRAIN WASH, is a board-certified internal medicine physician.