Breathing walls, vivid colors, melting faces. The hallucinations that come with psychedelic drugs have been an albatross around the neck of some interested in their antidepressant benefits. Not everyone wants to take a trip if they’re only trying to feel better. It can be the worst part of psychedelics because it holds them back from wider use.
A breakthrough announced Wednesday could go a long way toward changing that paradigm.
Researchers in California have developed a technology that can find and test drugs that can have the same antidepressant effects as psychedelics — without the drug actually producing hallucinations. The breakthrough was made in a study on mice, not people.
In addition, the researchers also think they’ve created a compound that offers the neurological benefits of hallucinogenic drugs without causing the user to hallucinate. Their work is published in the journal Cell. (Here’s the actual paper.)
How we got here — Over the past decade, it’s become increasingly clear that drugs like LSD and psilocybin have enormous therapeutic potential, especially for people whose depression and anxiety aren’t alleviated through traditional drugs.
The bad news is, of course, that LSD and mushrooms are not widely available, as they’re still largely illegal in the United States. There is some hope for science, though. In 2019, the FDA granted psilocybin “breakthrough therapy” to psilocybin therapy, meaning it can be studied in clinical trials.
Despite the piling evidence of their therapeutic benefits, when it comes to drugs that produce hallucinations, policy change rarely moves.
If they do become available, they aren’t likely to be accessible. Because they can produce hallucinations, each drug treatment session requires monitoring by two therapists for the duration of the experience, which can last up to eight hours. There’s also an introductory session and a post-treatment integration session. It’s a lot. With depression estimated to affect 16 percent of people at some point in their lives, new, affordable treatments are needed.
How these drugs help — Psychedelics like psilocybin and LSD have one important thing in common: They all affect a specific subtype of serotonin receptor called the 5-HT2A receptor (2A for short). They bind so well to this receptor because both psilocin (the psychoactive substance psilocybin turns into once ingested) and LSD have a chemical structure very similar to serotonin.
When a psilocybin or LSD molecule binds with a serotonin 2A receptor, it induces a conformational change, which, broadly, means the drug molecule changes its shape to conform to the receptor.
That conformational change sets off a cascade of events. In other words, how the molecule binds with the receptor determines what happens next in the brain.
What’s new — Lin Tian developed a sensor called “psychLight” that can monitor the conformational change that happens between a molecule and the 2A receptor.
Tian is an associate professor in the School of Medicine at the University of California Davis and senior author on the study outlining the research.
“This sensor allows us to image serotonin dynamics in real-time,” Tian says of the genetically encoded fluorescent sensor dubbed the psychLight.
How psychLight works — It’s a bit like an endoscopy. The sensor gives a reading of what’s happening in the body that can be viewed by researchers on a screen.
To put it another way, it’s as though there’s a tiny dimmer switch in the mouse's brain, right in the 2A receptor. When the receptor comes into contact with a hallucinogenic drug, the dimmer switch turns all the way on, showing a bright light to the researchers. When the receptor comes into contact with a non-hallucinogenic drug, the light the researchers see is less bright.
Dave Olson is an assistant professor in the Department of Chemistry at UC Davis and partnered with Tian on the research.
“Previously, we've been trying to measure the effects of drugs as receptors by measuring the cascade of signaling events,” Olson tells Inverse. “What psychLight does is give us a direct optical measure of receptor confirmation.”
In his lab, Olson has been researching compounds that are analogous to hallucinogenics but won’t produce hallucinations. By using the psychLight, the compounds show how hallucinogenic drugs bind with the 2A receptors and try to find other drugs that do the same.
Using psychLight, the researchers hit on a possible winner in their search for a, uhh, non-hallucinogenic hallucinogenic drug. It’s the AAZ-A-154 (AAZ) compound, one that Olson developed in his lab. AAZ is structurally very similar to psychedelics, and the researchers wanted to see if it could produce antidepressant effects without inducing hallucinations.
How they made their discovery — To test the effectiveness of AAZ as one of these pseudo-hallucinogenic drugs, they needed to answer two questions:
- Does the psychLight indicate AAZ is hallucinogenic?
- Does AAZ produce antidepressant effects?
They evaluated the first question by implanting the psychLight sensors in mice. They then looked at what the sensor showed when the mouse was exposed to substances that bind with 2A and produce hallucinogenic effects. They also tested if substances known to bind with 2A do not produce hallucinations.
“Hallucinogenic drugs cause the sensor to glow,” Tian tells Inverse. “Non-hallucinogenic drugs can compete with serotonin in binding to the receptor, showing reduced fluorescence.”
Time and again, they found the sensor did precisely what it was supposed to: glow brightly only when sensing a hallucinogenic drug. They found that AAZ induced the same glow as non-hallucinogenic drugs did.
To further test if the drug was actually hallucinogenic, they looked at the mice for something called the “head twitch response.”
Olson explains: “If you give mice a serotonergic hallucinogen, like LSD or psilocybin, they will rapidly rotate their head for about 15 or 20 minutes or so. And this correlates exceptionally well with human hallucinogenic potency across a wide range of psychedelic compounds.”
The researchers found that AAZ did not induce the head twitch response in mice.
That strongly indicates this compound, which is structurally very similar to a psychedelic, is not causing hallucinations.
To test the antidepressant effects of AAZ, the researchers put the psychLight aside and worked with mice that had been genetically engineered to have anhedonia (the inability to feel pleasure, which closely emulates depression).
“We know in humans if you inhibit this protein called VMAT (vesicular monoamine transporter), you can induce depression. These mice have been genetically engineered to have that protein inhibited and therefore serve as a useful model for depression,” Olson says.
Non-depressed mice will tend to choose a sucrose solution over regular water. But when they become depressed, they’ll choose the water. So all of these VMAT-inhibited mice began by choosing a water solution over a sucrose solution.
“After they’d been given a single dose of AAZ, immediately, they gained a preference for the sucrose solution. And they maintain that preference for about a couple of weeks,” Olson tells Inverse.
The Inverse Analysis — Taken together, the psychLight, the lack of a head twitch response, and a newfound preference for a sucrose solution indicate that Olson and his colleagues may well have developed a compound that can produce the beneficial antidepressant effects of hallucinogenic drugs without actually causing hallucinations.
If that’s right, and a drug like this can get through all the appropriate human safety trials, it could help millions of people.
“What we really need are first-line treatments,” Olson says. “Something that people can take home, put in their medicine cabinet, just like they would aspirin or ibuprofen, to really address this huge unmet medical need because, frankly, the antidepressants that we have currently are pretty ineffective.”
The authors say that more work needs to be done to understand the molecular basis of what’s happening between the compound and the receptor. The psychLight currently tells them whether or not a drug is hallucinogenic, but the specific molecular process is still a mystery.
Perhaps not surprisingly, Tian thinks she can develop sensors for that.
Editor’s note 4/28: An earlier version of this story misstated the psychLight’s response to AAZ. The psychLight indicated that the drug was not hallucinogenic because it responded to AAZ the same way it did to non-hallucinogenic drugs.
SUMMARY: Ligands can induce G protein-coupled receptors (GPCRs) to adopt a myriad of conformations, many of which play critical roles in determining the activation of specific signaling cascades associated with distinct functional and behavioral consequences. For example, the 5-hydroxytryptamine 2A receptor (5-HT2AR) is the target of classic hallucinogens, atypical antipsychotics, and psychoplastogens. However, currently available methods are inadequate for directly assessing 5-HT2AR conformation both in vitro and in vivo. Here, we developed psychLight, a genetically encoded fluorescent sensor based on the 5-HT2AR structure. PsychLight detects behaviorally relevant serotonin release and correctly predicts the hallucinogenic behavioral effects of structurally similar 5-HT2AR ligands. We further used psychLight to identify a non-hallucinogenic psychedelic analog, which produced rapid-onset and long-lasting antidepressant-like effects after a single administration. The advent of psychLight will enable in vivo detection of serotonin dynamics, early identification of designer drugs of abuse, and the development of 5-HT2AR-dependent non-hallucinogenic Q2 therapeutics