Psilocybin To Treat Addiction?

Psilocybin to Treat Addiction? Psilocybin, Brain Entropy, Brain Modularity, and Social Reward, by Kenneth Anderson, MA

What is Brain Entopy?

Brain entropy is defined by the complexity of the signals produced by the brain. Simpler signals are defined as having lower entropy, and more complex signals are defined as having higher entropy. A sine wave is the simplest type of signal and has the lowest entropy; a tuning fork creates a simple sine wave. The note of a violin, on the other hand, has many higher harmonics superimposed on a simple sine wave, making it a more complex signal with higher entropy. And the signal produced by an orchestra playing a symphony has much higher entropy than a single violin note.

 Figure 1 shows a sine wave and a violin waveform:

To the general public, the word entropy generally has a negative connotation, since it is associated with things slowing down or stopping. However, entropy is neither good nor bad. When we speak of brain entropy, high entropy brain states are associated with the resting state, creativity, and insight. Low entropy brain states are associated with sleep, solving arithmetic problems, and focused repetitive tasks.

There are two ways to measure brain entropy. One way is to record brain waves using an electroencephalograph (EEG) or magnetoencephalograph (MEG). Then, a compression algorithm can be applied to see how much the signal can be compressed. The more that the signal can be compressed, the simpler the wave, and the lower the entropy. Anyone who has ever used a zip file has encountered compression algorithms. The zip program reduces file size by using a compression algorithm to eliminate redundancies. The file can later be unzipped, and all the information is still there. Researchers measure the brain waves from many different parts of the brain at once to get a full picture of the brain activity, then they look at the complexity of signals from different areas in the brain.

Another way to measure brain entropy is to use a functional MRI (fMRI) to measure the BOLD signal. An fMRI takes three-dimensional pictures of the brain every second or two, giving a movie of what is happening in the brain. The three-dimensional pictures are actually comprised of multiple two-dimensional pictures taken from different angles. The word BOLD stands for blood-oxygenation-level-dependent imaging. Whereas EEGs and MEGs look at electromagnetic signals which are the result of neurons firing, BOLD looks at the amount of energy being consumed in different parts of the brain by identifying areas with increased blood flow. Areas with increased blood flow can be identified by measuring the ratio between oxygenated blood and deoxygenated blood; the fMRI can identify this because oxygenated blood and deoxygenated blood have different magnetic properties. Typically, the researchers divide up the areas in the three-dimensional brain movies into hundreds of thousands of different cubes called voxels (like pixels, only for volume) and analyze the different amounts of energy consumption in each voxel. This can be represented as a waveform, whose complexity can be calculated. Calculating the complexity of this waveform allows us to define it as high entropy if it is complex or low entropy if it is simple.

How Psilocybin Affects Brain Entropy

Brain entropy is very relevant to a discussion of psilocybin, because psilocybin results in very high states of brain entropy. A 2026 paper by Lyons and colleagues reported an experiment where subjects were given either a 25 mg dose of psilocybin or a 1 mg dose of psilocybin (essentially a placebo dose) as a control condition. Subjects had never taken psilocybin before. An EEG was used to measure brain entropy before the subjects were given psilocybin (baseline), one hour after, two and a half hours after, and four hours after they were given psilocybin. Subjects who received 25 mg of psilocybin showed large and significant increases in brain entropy while they were tripping on psilocybin compared to baseline brain entropy. Subjects who received 1 mg of psilocybin showed no significant differences between baseline brain entropy and post-dosing brain entropy.

The researchers also measured psychological insight using the Psychological Insight Scale, and mental well-being using the Warwick-Edinburgh Mental Well-being Scale. The researchers found that insight scores were significantly higher after 25 mg versus 1 mg psilocybin one day, two weeks, and one month after dosing. The researchers also found that subjects who had received the 25 mg dose showed significant increases in mental well-being when measured two weeks and one month after being given psilocybin. Subjects who had received the 1 mg dose showed no significant changes in mental well-being.

What Is Brain Modularity?

Many years ago, scientists thought that brain functions were localized in one area of the brain. This is true of some brain functions; for example, Broca’s area is linked to speech production, and the motor cortex controls the movements of our voluntary muscles. However, more recent research has found various pathways and networks in the brain comprised of parts and areas of the brain which are quite distant from each other: one example is the reward pathway, which is involved in habit formation and addiction.

Recent research has identified three brain networks known as the default mode network, the central executive network, and the salience network. According to Chou and colleagues (2023), “The default mode network is a network of brain regions that is active during rest, spontaneous cognition, when thinking about oneself in the past and future, and in relation to others.” The central executive network, on the other hand, is a brain network that is essential for goal-directed behavior, executive functioning, cognitive control, working memory, attention, etc. The salience network functions as a switch between the default mode network and the central executive network. The word “salience” means importance or relevance. So, when the salience network finds external events to be important, it switches the central executive network on, and when it finds internal mental states to be important, it switches the default mode network on.

Many researchers believe that depression is due to the brain being stuck in the default mode network and in rumination. In a person with depression, the three networks are isolated from each other and are functioning as separate modules. Psilocybin is believed to have its antidepressant effect by integrating the three networks and making them function together instead of functioning as three separate modules.

A 2022 paper by Daws and colleagues reported two experiments which used psilocybin to treat depression. The first experiment looked at the effect of psilocybin on treatment-resistant depression. The second experiment compared the effect of psilocybin on depression with the effect of Lexapro.

In the first experiment, subjects were first given the Beck Depression Inventory to measure depression and an fMRI to measure the integration of the three brain networks prior to being given psilocybin. Integration or modularity of the three brain networks was measured using the fMRI to measure the BOLD signals from many different places in the brain. The more synchronous the BOLD signals from the three brain networks are, the more integrated and less modular the three networks are. The less synchronous the BOLD signals from the three brain networks are, the more modular and less integrated the three networks are.

After these baseline measurements were completed, subjects were given a 10 mg dose of psilocybin, then, a week later, they were given a 25 mg dose of psilocybin. The day after receiving the 25 mg dose of psilocybin, the subjects were again given the Beck Depression Inventory and an fMRI to test for brain network integration and modularity. Subjects showed a significant reduction in depression and brain network modularity and a significant increase in brain network integration.

Depressive symptoms were still significantly reduced when subjects were tested six months later.

The second experiment was a randomized controlled trial. Half of the subjects were in the psilocybin group, and the other half were in the Lexapro group. All subjects were given the Beck Depression Inventory and an fMRI to test for brain network integration and modularity before the experiment began. The subjects in the psilocybin group were given 25 mg of psilocybin on the first day of the experiment and one daily capsule of a placebo for the next three weeks. After the third week, subjects were given another 25 mg dose of psilocybin and two daily capsules of placebo for the next three weeks. The subjects were then tested for changes in depressive symptoms and brain network integration and modularity. The subjects in the Lexapro group went through the same procedure, except that their doses of psilocybin were 1 mg instead of 25 mg, and their capsules contained 10 mg of Lexapro instead of a placebo.

At the end of the experiment, both groups showed significant reductions in depressive symptoms compared to baseline; however, symptom reduction in the psilocybin group was significantly greater than symptom reduction in the Lexapro group. Moreover, the Lexapro group showed no changes in brain network integration or modularity, whereas the psilocybin group showed significant increases in brain network integration and significant reductions in modularity.
How does psilocybin work to integrate the three brain networks? The binding target of psilocybin is a type of serotonin receptor known as the serotonin 2A receptor. The default mode network, the central executive network, and the salience network all have large numbers of serotonin 2A receptors. It is believed that when psilocybin binds with these receptors it activates all three networks and gets them to function together, i.e., it integrates the three networks and reduces their modularity.

Social Reward in Mice

If young mice are placed in a cage with other young mice (the social cage), then later placed in a cage where they are all alone (the isolated cage), and still later, given a choice between spending time the social cage or the isolated cage, they will prefer to spend time in the social cage, even though both cages are empty. In technical terms, this is called social reward conditioned place preference. The young mice learn to associate the good feelings they had while playing with other mice with a certain cage and prefer that cage to the one where they were isolated, even when both cages are empty. However, this is only true of young mice. Adult mice no longer learn to prefer the social cage over the isolated cage.

Interestingly, a 2023 study by Romain Nardou and colleagues showed that when adult mice are pretreated with hallucinogens, their behavior reverts back to the behavior of young mice. In other words, the adult mice pretreated with hallucinogens learn to associate good feelings with the social cage and prefer it to the isolated cage just as young mice do. The researchers found that ketamine, MDMA (in a prior experiment), psilocybin, LSD, and ibogaine were all effective at reverting the adult mice back to the behavior of young mice in regard to social reward conditioned place preference. On the other hand, cocaine failed to cause adult mice to revert to the social reward conditioned place preference behavior of young mice. A neutral saline solution also failed to cause this reversion.

This behavioral reversion is an aftereffect of the hallucinogen. In all the experiments, the mice were given the hallucinogens 48 hours prior to their exposure to the social and isolated cages, so the acute effects of the hallucinogens had worn off by the time the experiment started. In fact, this behavioral reversion lasted long after the mice were given the hallucinogens. For ketamine, the behavioral reversion lasted for 48 hours, for psilocybin and MDMA, it lasted for two weeks, for LSD, it lasted for three weeks, and for ibogaine it lasted for four weeks.

What is the mechanism by which hallucinogens have this effect? According to the researchers, oxytocin is the key. Oxytocin is a neurochemical which occurs naturally in the brain, and which has been nicknamed “the love chemical.” Oxytocin plays an important role in social interactions. The researchers found that the hallucinogens had a significant effect on increasing the activity of oxytocin in the nucleus accumbens, which is a part of the reward pathway, and which plays an important role in the development of habits or addictions.

It has been claimed that the opposite of addiction is connection. Although this may be something of an overstatement, it seems clear that social interaction is an aid in overcoming addictions. It is quite possible that one reason why hallucinogens help people overcome addictions is that hallucinogens increase sociability.

Conclusion

A number of studies have shown that hallucinogens such as psilocybin can have a beneficial effect in treating addictions. In fact, studies showing a beneficial effect of hallucinogens such as LSD on alcohol addiction date back to the 1950s. A 2025 study by Xiao and colleagues showed that brain entropy, together with certain other EEG characteristics, accurately diagnosed alcohol use disorder. It will be interesting to see what future research will tell us about the relationships between addictions and brain entropy, brain modularity, and social isolation. It will also be interesting to see if future research shows that the reason that psilocybin and other hallucinogens are beneficial in addiction treatment is due to their effects on brain entropy, brain modularity, and social isolation.