Here's how 4 hallucinogenic drugs transform your brain

Hallucinogenic drugs have a reputation for expanding consciousness, increasing spirituality, and making people, well, hallucinate.

There’s also growing research that the drugs can be effective therapies for treatment-resistant depression and other mental illnesses.

Why do these substances produce dramatic effects? Scientists say it comes down to what happens in the brain when you take them. Here’s what goes down when a brain is tripping on:

• Ketamine
• LSD
• MDMA
• Magic mushrooms

Your brain on ketamine

Ketamine has the distinction of being the only non-Schedule 1 drug on this list.

Schedule 1 drugs are classified by the federal government as having “no medical value” and a “high potential for abuse.” While the federal government permits some research on Schedule 1 drugs, the various hoops and regulations imposed as a result of their status can make clinical trials extremely difficult and impractical. These drugs are notoriously difficult to study in clinical trials because trials can’t receive federal funds As such, we probably have more clinical trials involving ketamine than any of the other “hallucinogenics.”

Ketamine (which is associated with subjective psychedelic effects) was developed in the 1960s as an anesthetic. In the 80s, it became a popular club drug. Now, ketamine has reached its third act: as a medication for treatment-resistant depression.

Ketamine affects the neurotransmitter glutamate. Like all neurotransmitters, glutamate communicates messages between neurons. It’s very prevalent in the brain; some researchers estimate glutamate to be the transmitter at 40 percent of all synapses in the brain. When you learn something or create a memory, connections between neurons (synapses) change. Glutamate is essential to that process. Thus, glutamate is associated with brain plasticity–-the ability of the brain to change physically.

Studies suggest low doses of ketamine can stimulate glutamate production and help repair connections in the brain, especially between the prefrontal cortex and the hippocampus. Extending out of neurons are its “input wires” called dendrites. On dendrites are microscopic tiny spine-like structures that send and receive information. When a person is chronically stressed or depressed, these spines medial prefrontal cortex die. Studies have shown that ketamine facilitates the growth of these spines in mice.

What about K-holes, or the dissociation some people experience when they take the drug? In sheep, ketamine has been shown to change the frequency of the brain waves emanating from the cerebral cortex, which is believed to lead to dissociation.

While there’s still some debate over exactly why ketamine has been such an effective treatment for some people with treatment-resistant depression, the increase in glutamate — and that neurotransmitter’s ability to help neurons communicate — is a leading theory.

Your brain on LSD

Lysergic acid diethylamide (LSD) is a chemical with a very similar structure to serotonin. Serotonin, also called 5-HT because of its chemical structure, is produced by nerve cells. In the brain, serotonin helps brain cells communicate. It also helps regulate mood, sleep, and even digestion.

When a person takes LSD, the body is tricked into thinking the LSD is serotonin, and subsequently sends it where serotonin should go — to the serotonin, or 5-HT, receptors.

There are seven types of serotonin receptors, helpfully classified 5HT-1 through 5HT-7. Each of those receptors has subtypes. LSD stimulates a subtype of the 5HT-2 receptor called 5-HT2A.

5-HT2A receptors are especially concentrated in the frontal cortex of the brain, in the claustrum — an area connected to the visual cortex — and the basal ganglia, one of the brain’s components responsible for motor control, learning, and emotion.

But LSD has an even higher affinity for serotonin receptors than serotonin itself. The regular serotonin signaling is elbowed out of the way, and LSD takes over, stimulating blood flow, electrical activity, and changing communication patterns in the brain. Because the visual cortex and basal ganglia have such a high concentration of 5-HT2A receptors, it’s perhaps not surprising that some of the most significant changes that occur involve information and vision. Barriers between the visual cortex and information-carrying regions are broken down, which leads to hallucinations.

The drug’s ability to stimulate so many areas of the brain tied to consciousness and emotion — like the anterior cingular and insular cortices — is what many researchers think contributes to the “ego dissolution” many people experience when on LSD. By changing these communication patterns in the brain, even temporarily, LSD is thought to help break some of the negative spiraling thoughts characteristic of people with depression and anxiety.

Your brain on MDMA

Experts say there’s a difference between MDMA and ‘classic’ psychedelics — it doesn’t induce a mystical experience or ego dissolution — but it is broadly considered part of the class of psychedelics explored as therapy.

You know that scene in every teen movie where the kid’s parents are out of town, and he thinks he’s going to have a few friends over for a couple of beers? And the moment the door opens, kids from like three different schools pour into the house?

That’s kind of what happens when you take MDMA. Those schools are the neurotransmitters dopamine, norepinephrine, and most importantly, serotonin. MDMA stimulates their release — not just in the metered, organized way the brain does when it’s not on MDMA, but a bunch of it, all at once.

Researchers believe the release of norepinephrine and dopamine contributes to the euphoria, and increased energy MDMA users feel, but that’s just the sideshow. The main event is the massive release of serotonin. Serotonin makes you feel good, as well as increases sensitivity to light, touch, and sound. You can see why music, lights, and face-stroking are commonplace at raves.

MDMA has been shown to acutely decrease activity in the left amygdala, an area associated with fear and memory, as well as increase blood flow to the prefrontal cortex (PFC) in the brain (the area involved in complex decision making and behavior). This reduction of activity in the amygdala might be one reason it’s been shown to be an effective treatment for people with PTSD.

A study published in 2015 in Biological Psychiatry revealed more potential good news for people with PTSD. MDMA increased communication between the amygdala and the hippocampus, areas of the brain known to have reduced communication in people with PTSD.

The same Biological Psychiatry study also found MDMA reduced communication between the medial temporal lobe and medial prefrontal cortex, which is involved in emotional control. These regions of the brain have also been associated with stress and the development of Post Traumatic Stress Disorder, which may be why studies have shown MDMA to be an effective treatment for PTSD.

Your brain on magic mushrooms

While magic mushrooms contain a few different psychoactive substances, the one you’ve likely heard the most about, and has been studied the most, is psilocybin.

You may also have heard of psilocin, a counterpart of psilocybin. Both compounds occur naturally in certain mushrooms and have psychoactive effects when ingested. (Interestingly, psilocybin in and of itself isn’t psychoactive; once it’s ingested, it turns into psilocin, which is.)

Like LSD, psilocybin also stimulates the 5-HT2A serotonin receptors in the brain. Specifically, it decreases activity in the amygdala — and we know high activity in the amygdala is associated with fear. It also reduces activity in the anterior cingulate cortex an area of the brain associated with negative emotion, pain, and depression.

Because this compound quiets these parts of the brain, experts anticipate future research may have radical implications for treating depression and other mental illnesses. But relatively recent research has broadened our understanding of what psilocybin does in the brain even further.

A 2014 study found that psilocybin actually creates new links between previously disconnected brain regions, temporarily changing the organizational networks in the brain.

Typically, the signals in your brain follow the same pathways day after day. They’re a bit like a jogger who runs the same route through the neighborhood every day. When the researchers compared the brains of participants who had received an injection of psilocybin versus A placebo, signals were taking all kinds of new paths and forming different connections.

Essentially psilocybin freed the brain’s activity from being confined to its usual pathways and let it wander freely.

But psilocybin affects more than just serotonin. A 2020 study looked at how the drug affected glutamate levels in the brain. The study, published in Scientific Reports, found psilocybin affected the levels of the neurotransmitter glutamate in certain areas of the brain. The authors concluded that the increased levels of glutamate in the medial prefrontal cortex was associated with ego dissolution – -a reduction in focus on the self and an increase in that zen feeling that we’re all just part of a whole.

The brain is a powerful, and often mysterious web of interconnected communication systems. Despite all we know about this powerful system, there are still mental illnesses we don’t have great treatments for. Hallucinogenic drugs might be the key to understanding some of the brain’s mysteries and alleviating suffering for millions of people.