A Mouse-Chemical Project for Drugs Designed to Relieve Anxiety and Depression Using a Virtual Library of Ibogaine Molecules
Scientists in Nature report that they have created drugs that doesn’t induce the usual hallucinogen effects but rather relieve anxiety and depression in mice.
It’s the latest involving tripless versions of drugs. One previous effort created a hallucination-free variant of ibogaine, which is made from the root bark of a shrubby plant native to Central Africa known as the iboga tree.
“It’s very encouraging to see multiple groups approach this problem in different ways and come up with very similar solutions,” says David E. Olson, a chemical neuroscientist at the University of California, Davis, who led the ibogaine project.
They had been building a virtual library of 75 million molecules that include an unusual structure found in a number of drugs, including the psychedelics psilocybin and LSD, a migraine drug (ergotamine), and cancer drugs including vincristine.
The team decided to focus on molecules that affect the brain’s serotonin system, which is involved in regulating a person’s mood. But they still weren’t looking for an antidepressant.
There were reports of people getting great results after a few doses of the study, says Brian Shoichet, a professor of pharmaceutical chemistry at the University of California, San Francisco.
“They had the best properties,” Shoichet says. “They were the most potent, and when you gave them to a mouse, they got into the brain at the highest concentrations.”
Scientists have shown that a depressed mouse will give up if it is placed in an uncomfortable situation. If it gets an anti-depressant like Prozac, the mouse will keep struggling.
They didn’t exhibit any signs of a drug that can cause a mouse to twitch in a distinctive way. “We were surprise to see that,” he says.
A double-blind psilocybin therapy study in the UK and Canada: Response to 25 milligrams of COMP360
The team has formulated new molecule that can be tried in people. They have the ability to increase heart rate and blood pressure.
The maximum effect was seen the day after the treatment. Standard antidepressants take several weeks to reach maximum effect, and this is different. He was not involved in the study.
Those results, now published in full in the New England Journal of Medicine, represent the largest randomized, controlled, double-blind psilocybin therapy study ever done. The participants were split into three equal groups, with 22 sites in 10 countries. One group received a very low dose, so low in fact it served as the placebo. The next group received 10 mg and the last group 25 mg. Psychological support was also offered alongside the treatment.
Results of the study, published Wednesday in The New England Journal of Medicine, found “an immediate, fast, rapid-acting, sustained response to 25 milligrams (of COMP360),” said study coauthor Dr. Guy Goodwin, a professor emeritus of psychiatry at the University of Oxford in the United Kingdom.
“This drug can be extracted from magic mushrooms, but that is not the way our compound is generated. It’s synthesized in a purely chemical process to produce a crystalline form,” said Goodwin, who is the chief medical officer of COMPASS Pathways, the company that manufactures COMP360 and conducted the study.
A Study of Response to a Clinical Trial of Antidepressants During the First Three Months after the Treatment-Resistant Treatment
A day after the trip, depression levels were documented five times. Almost half of people who took the 25-milligram dose showed improvement. In fact, 29% were considered to be in remission at week three, the study found.
“If you were in the 25-milligram group, you were nearly three times as likely to respond than if you were in the 1-milligram group,” said Johnson, who coauthored safety guidelines for psychedelic research in 2008.
“The effects did start to wear off by three months, and we need to know how best to prevent the depression returning,” Cleare said, adding that not enough is yet known about potential side effects.
There were 233 study participants who had treatment-resistant depression, which is only reported after a person fails to respond to two courses of antidepressants. There are 9 million people in the US with depression, and 3 million are resistant to treatment. Globally, some 100 million people have treatment-resistant depression, Goodwin said.
“Participants were requested to remain off antidepressant treatment during the first 3 weeks after the trial-drug administration; however, these medications could be started at any time during the trial if deemed clinically necessary by a physician investigator,” the study said.
“The incidence of sustained response at week 12 was 20% in the 25-mg group, 5% in the 10-mg group, and 10% in the 1-mg group,” wrote psychobiologist Dr. Bertha Madras, director of the laboratory of addiction neurobiology at Harvard Medical School’s McLean Hospital in Belmont, Massachusetts, in an accompanying editorial. She did not volunteer for the study.
“This is not a spectacular response rate for a psychiatric treatment … and we would only expect this to worsen over a longer follow-up period,” said Dr. Ravi Das, an associate professor of educational psychology research methods and statistics at University College London via email. He wasn’t involved in the study.
There were 179 adverse events reported by the patients in the trial, but they were not a huge cause for concern. Some patients had serious adverse events. These were defined as displays of suicidal ideation, including self-harm. Five of the patients in the highest-dose group were reported to have displayed suicidal behavior, as well as six in the 10 mg group. One in the placebo group was compared to this.
Headache, nausea, fatigue and dizziness plagued 77% of the study participants and occurred at all dosage levels, which experts say is a typical response on the day of psilocybin administration.
A small percentage of people in the three groups experienced suicidal thoughts or injury over the course of 12 weeks. Two people in the 25-milligram group contemplated suicide within the first three weeks, while two intentionally injured themselves. Two people in the group were suicidal, one was self-injured and one was hospitalized for depression, according to the study.
Most of the time those behaviors occurred less than a week after the session, the company said.
“Remember that this is in people who were assessed not to be at significant risk of suicide when they entered the trial. The numbers were fairly small, but this is something that will need to be taken carefully into account in any later-stage trials,” said Kevin McConway, professor emeritus of applied statistics at The Open University, a British public research university.
The drug results are promising, but there are many unanswered questions, such as if this would work for different types of depression, which was not involved in the study.
The results were promising, if not painting the picture of a miracle cure. After three weeks, 29 percent of patients in the 25 degree group were free of drug toxicity, compared to 8 percent in the placebo group. After time, the positive effects waned: After 12 weeks only 20 percent of the high-dose patients were still responding—an improvement over the placebo group that wasn’t statistically significant.
But given that there is a general reluctance to discuss the downsides of drugs, the fact thatCompass was upfront about the adverse events is a good thing. In August 2022, Breeksema published a review that looked at how adverse events in psychedelics research have been flagged, and found that they have been inconsistently and probably underreported. Many trials looked at reported adverse effects and it was an unlikely reality. The Compass Pathways research “reported adverse effects more rigorously than many of the other trials in our systematic review,” he says.