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Saturday, October 1, 2022

The Search For a Not-so-long, Not-so-strange Trip


As various psychedelics become part of the discussion about wellness and mental health treatment, with psilocybin generally leading the way, researchers are beginning to work with different synthesized formulations to find a way to make psychedelics less, well, psychedelic. 

They want to block the hallucination experience but keep within the psychedelic the natural medicine that helps people with treatment-resistant depression, anxiety, or whatever condition they are seeking to manage.

One preclinical study in January, 2022 used mice to demonstrate how the hallucinatory effect of a psychedelic can be monitored and adjusted—or turned off—where it binds to the serotonin receptor. Researchers designed and tested a new drug, based in part on a study of the active metabolite in psilocybin (psilocin), that would bind to a certain part of the receptor and not create the hallucinatory effect but still help treat depression.

Another group of scientists reported on engineering a water-soluble, non-hallucinogenic, non-toxic analog of ibogaine called tabernanthalog. In tests with lab rats, they were able to neutralize the psychedelic effect, but found that the new analog still promoted neural plasticity, reduced alcohol- and heroin-seeking behavior, and also had antidepressant-like effects. 

The hope is that a still-in-the-lab, non-hallucinogenic psychedelic-therapeutic drug, when fully developed, could become a scaled-up pharmaceutical used by a broader range of people looking for the relief they seek from psychedelics, without the unknown and sometimes frightening hallucinatory experience that comes with it. 

That’s the upside—a broader appeal. But with this trip-no-more option on the horizon, more answers are needed to understand the true value of the complete therapeutic effect of the whole, hallucinogenic psychedelic experience. Will blocking the hallucinogenic experience make it a better or worse therapeutic? 

One article published by the British Psychological Society stated that the brain operates with greater flexibility and interconnectedness under hallucinogens and that the most prominent and intriguing psychological properties of hallucinogens are their ability to produce complex visual hallucinations and ego-disintegration. 

Hallucinogens act within the neurobiology of consciousness, and that is indeed a sticky wicket for researchers sorting out ifs, ands, and buts.

Maybe even bad trips are good. A research paper published in the International Journal of Drug Policy found that bad trip narratives may be a potent coping mechanism, opening “fruitful meaning-making” and enabling users to make sense of frightening experiences. “When even bad experiences become good, an important threshold against psychedelic drug use disappears,” the study concluded.

A cognitive scientist at the University of Minnesota, Link Swanson, explained it this way: If normal perception is a kind of ‘controlled hallucination’ where top-down simulation is constrained by bottom-up sensory input, then psychedelic drugs essentially cause perception to be a less controlled hallucination. “Meeting the challenge of predicting and explaining psychedelic drug effects is the ultimate acid test for any unified theory of brain function,” he concluded.

These are big picture observations to be sure, but they are indicative of the importance of the full, hallucinogenic psychedelic experience in understanding the function of the brain, and helping people adjust to the profound new version of their thinking that usually occurs after treatment.

While the debate goes on, psychedelics companies are stepping up the type and variety of their offerings. Mindset Pharma (OTC: MSSTF) is pursuing both directions—analogs of psilocybin with stronger psychedelic experiences, and another analog of psilocybin with a lower, non-hallucinogenic psychedelic experience. “So what we know preclinically is, the stronger the psychedelic effect of the drug, the greater activation of the serotonin receptor,” Joseph Araujo, chief scientific officer and director at Mindset Pharma, told Psychedealia. “Also, what we’ve seen with our lower psychedelic effect family of compounds is that they stay in the body longer.”

With these new non-hallucinogenic drugs, micro-dosing will be a thing of the past, he said. “We need to determine whether there is a benefit of micro-dosing psilocybin,” he said. “There’s lots of anecdotal data that people feel like there’s a benefit, but we don’t have any really good clinical data to know that today.

“Where people are talking about micro-dosing, we think these low or no hallucinogenic psychedelic drugs will be different,” Araujo said. “You won’t need to microdose them. You can take them with a range of doses, and you won’t have a hallucinogenic effect.”

He said that Mindset is going to be focusing some of their work initially on low or non-hallucinogenic psychedelics by looking at cognitive improvements. “There’s some data pre-clinically, and potentially some anecdotal data, that says if you take very low doses of psilocybin, for example, you can improve attention in animals that have a sort of natural attentional impairments. So we’re going to utilize that pathway to try and develop these drugs,” Araujo said. “And because we’re in the medicinal space, we are looking at treating human diseases with an attention deficit component, such as ADHD and potentially Alzheimer’s disease. Ultimately what we’re trying to do is develop these as new medicines and better medicines than the first generation psychedelic drugs.”

Maybe in the search for a non-hallucinatory psychedelic, researchers will revisit an FDA-approved drug that controls the frequency and severity of hallucinations and delusions for Parkinson’s patients, and formulate a novel therapeutic that can turn a trip off when you have had enough.

Whatever they find out in their labs today, and wherever those findings lead them, will be steps toward bringing psychedelic-assisted psychotherapy out to the masses. It promises to be a long, strange trip. “We think at this stage that the hallucinogenic or psychedelic experience, however you want to refer to it, it’s probably going to remain within a clinical environment for the near future,” Araujo said.


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