Could LSD-like Compounds Work As Antidepressants Without Hallucinations?

Depression can kill. It’s a serious mental health disorder characterized by low mood, apathy, fatigue, feelings of hopelessness, and changes in sleep, appetite, and concentration. It’s a leading cause of disability worldwide and can also lead to suicidal thoughts and behaviors.

Current treatments for depression, such as anti-depressants and talk therapy, can be effective, but they don’t work for everyone. Nearly 1 in 3 people with depression don’t respond to current treatments. Moreover, they can take weeks or even months to have an effect.

In the U.S., depression impacts the lives of around 17 million adults, but experts believe the true figures are much higher as many people don’t seek help for their condition. As such, depression is a significant public health issue, and there is an urgent need to find new and effective treatments.

One promising area of research is using psychedelic drugs to treat mental health disorders. However, a significant challenge is that these compounds can cause disturbing and sometimes long-lasting hallucinations.

Now, scientists have developed two compounds targeting the same receptor subtypes that don’t cause mind-altering effects. The findings, published in the journal Nature, suggest that these substances could form the basis of potential treatments for depression.

Continue reading to learn more about these new compounds and their potential implications as mental health therapeutics.

What are psychedelics?

Psychedelics are a class of drugs that produce changes in perception, mood, and cognition. They include lysergic acid diethylamide (LSD) and Psilocybe cubensis — also known as magic mushrooms, or by their active ingredients psilocybin and psilocin.

People use these drugs recreationally — albeit illegally — for their powerful psychoactive effects, which can induce altered states of consciousness, hallucinations, and other changes in perception, known as a ‘trip.’

These potent drugs also have a long history in traditional medicine. The shamans of the Amazon rainforest have used ayahuasca — a plant-based psychedelic brew containing N, N-dimethyltryptamine (DMT) — for centuries to treat a range of physical and mental health issues.

In recent years, there has been a resurgence of interest in the therapeutic potential of psychedelic drugs. Research shows that these substances can effectively treat conditions like depression, anxiety, and post-traumatic stress disorder (PTSD).

However, the distressing and persistent hallucinations these drugs can cause are a significant obstacle to their value as therapeutics.

What did the new study find?

Scientists in the new research successfully developed two compounds that target the same receptor subtypes in the brain as psychedelic drugs — 5-HT2A serotonin receptors. But, unlike psychedelics, the new compounds didn’t cause hallucinations when administered to mice.

The novel compound prompts similar anti-depressant effects to selective serotonin reuptake inhibitors (SSRIs). SSRIs are a class of drugs typically used as anti-depressants but come with a host of side effects, including dizziness, nausea, lethargy, headache, anxiety, and agitation. They may also take weeks or longer to produce a response. Conversely, the new compounds had an immediate and long-lasting effect after only one dose.

The study authors noted that, like ketamine and psilocybin, the compounds had rapid anti-depressant activity. They’re unsure if human subjects would experience similar benefits, but they hope to find out in future research.

A one-dose, long-acting medication that eased the detrimental symptoms of depression without the negative consequences of current drugs would be a significant breakthrough in the field.

How do they work?

When someone consumes psychedelic drugs, they bind tightly to 5-HT2A serotonin receptors on the surface of nerve cells. Serotonin is a neurotransmitter that plays an important role in mood, cognition, perception, and sleep. Its receptors are found in high densities in brain regions associated with these functions.

While the binding of psilocin to 5-HT2A receptors is thought to be responsible for the psychoactive effects of these drugs, the underlying mechanism is not fully understood. It seems that the binding to the receptor can trigger two different signaling pathways — a cascade of chemical signals inside cells — involving the β-arrestin-2 and the Gq protein.

Previous studies show that the hallucinogenic effects of LSD occur through the β-arrestin-2 protein pathway. Therefore, compounds that activate the 5-HT2A receptor but avoid this pathway could potentially treat depression without hallucinations.

SSRIs also modulate serotonin signaling, but they do so indirectly and not in the same way as psychedelic drugs. These anti-depressant meds also boost serotonin levels throughout the body and trigger an immediate increase in serotonin in the brain. Yet, those taking them only feel the benefits weeks later.

These effects prompted the researchers’ interest in creating a compound that targets the 5-HT2A receptor in a way that alters brain chemistry and treats depression but doesn’t activate a ‘trip.’ It was also critical to avoid the side effects associated with SSRIs.

Are they safe?

Not enough is known about the new compounds to say for certain if they are safe. However, non-psychedelic anti-depressants therapies are likely to have a better safety profile than psychedelics, which can cause anxiety and paranoia at high doses. Psychedelic drugs also carry the risk of provoking latent mental health conditions such as schizophrenia.

While more research is needed to determine the safety of the new compounds, the fact that they produce rapid anti-depressant activity with a single dose is promising. Moreover, the findings suggest that developing effective psychedelics-inspired treatments for depression and other mental health conditions is possible.

When will they be on the market?

At this stage, it’s impossible to say when — or even if — these drugs will be available to the public. Psychedelic-based therapies are in the early stages of research, and it could be many years before they’re approved for use.

Psychedelic drugs offer a potential new way to treat depression, but they trigger hallucinations that limit their value as a therapy. Recently, researchers have developed new non-psychedelic compounds that have rapid anti-depressant activity without unwanted side effects.

While more research is needed to determine the safety of these new compounds, the findings suggest that it’s possible to develop safe and effective psychedelics-inspired treatments for depression and other mental health conditions. However, it’s not yet known how these drugs will fit into the current landscape of depression treatments.