Charles D. Nichols, Ph.D.
Medical scientists have found that cannabinoids help fight unwanted inflammation that contributes to many diseases. But the next wonderful anti-inflammatory drug could come from an even more unexpected source: psychedelics.
A team from the University of New Orleans is now working to refine one of the most potent anti-inflammatory molecules known to science, a synthetic psychedelic similar to LSD he called TWO (2,5-dimethoxy-4-iodoamphetamine).1 2 TWO was first synthesized by the famous psychedelic chemist Alexander Shulgin in the 1980s, and is widely used for the study of serotonin receptors in the brain.
Researchers at the University of New Orleans have shown this TWO it is highly effective in preventing and treating widespread inflammation in mice.3 4 Directed by professor of pharmacology Charles Nichols in concert with the life sciences company Eleusis, where Nichols is the scientific founder and director of molecular pharmacology, the team’s current work revolves around reducing behavioral effects TWO, which recreational users report that they include an even longer trip than LSD up to 30 hours, with side effects that can last for days.5 6
Nichols said he has created a variant of TWO, with code name HE-02 by the company, which produces the same anti-inflammatory effect, but two-thirds less behavioral effect. HE-02 should go into drip-shaped clinical trials to treat eye inflammation over the next year, he said.
“While we don’t expect the amount of drug to have behavioral effects, administering it to the eye will reduce exposure to the brain, thus further minimizing the risk of someone stumbling if given a few drops with our drug, ”Nichols said.
5-HT2A Receiver activation
Nichols and Eleusis are in the process of developing third- and fourth-generation psychedelic-derived anti-inflammatory drugs with an even smaller behavioral effect than HE-02 which could eventually be sold, probably in pill form, for the treatment of systemic inflammation and conditions such as arthritis and asthma.
These molecules would be considered standard pharmaceuticals rather than psychedelics, although they are derived from them. TWO and target the same cellular receptor in the brain: serotonin 5-HT2A – which produces hallucinogenic effects.
Interestingly, the behavioral, neuroplastogenic, and anti-inflammatory properties of psychedelic drugs appear to come from this single receptor, a topic of growing interest in the field of neuroscience. The difference is that slightly different molecules, perhaps with only a single atom, can exert unique effects downstream by recruiting different enzymes into the cell.
“When you activate [5-HT2A], indicates inside the cell that it has been activated with a ligand and that it is probably recruiting a dozen or so, if not more, of different enzymes, to do different things in the cell to change- ne physiology, “he explained.” And what we have shown is that the two main pathways that have been associated with behavioral changes do not correlate with anti-inflammatory capacity. “
For example, TWO has both behavioral and anti-inflammatory effects. HE-02 has anti-inflammatory but modest behavioral effects. LSD is an extremely potent psychedelic but only partially effective as an anti-inflammatory, at least compared to TWO and psilocin, a byproduct of psilocybin.
Meanwhile, the endogenous hallucinogen N, N-dimethyltryptamine (DMT), another “classic” psychedelic that activates the 5-HT2A receptor, produces profound subjective effects, but appears to have no efficacy as an anti-inflammatory.7 And the neurotransmitter serotonin, which binds to 15 different 5-HT subtype of receptors, produces no hallucinogenic effects and actually promotes inflammation.
In their search for the perfect anti-inflammatory drug, Nichols and colleagues are working to continue isolating anti-inflammatory pathways from behavioral pathways and then adjusting or modifying them completely by modifying the composition and configuration of the original. TWO molecule.
“The goal is to have a non-psychedelic drug that someone can take and that activates the 5-HT2A receptor to treat something like arthritis, “Nichols said.” Right now it’s really in the early stages, we’re just trying to understand the mechanisms. Once we identify what enzyme we’re recruiting into the receptor, that it will help to better design medicines ”.
LSD for Alzheimer’s
Nichols and Eleusis are also involved in other research projects involving classical psychedelics. One focuses on the use of psilocybin to treat depression, a condition that (such as addiction and post-traumatic stress disorder) is associated with inflammation.
In addition, the company is investigating the use of low doses of LSD to treat Alzheimer’s disease. He recently completed a first-phase safety and tolerability trial with 48 older healthy volunteers.8
Scientists believe that neuroinflammation plays an important role in Alzheimer’s.9 But LSD Nichols says it is promising as a treatment for the disease because of much more than its anti-inflammatory effect.
“LSD it targets almost all serotonin receptors and dopamine receptors, among others, to activate them, “he said.” The activation of several of these receptors has been demonstrated by us and others who use different chemicals individually to have benefits such as improving memory, maintaining cellular health … and reducing stress-related markers.We believe that these multiple positive effects of several different receptors can act synergistically together to be able to to curb neurodegeneration and cognitive symptoms of Alzheimer’s disease. “
Although LSD would be administered in suballucinogenic doses to Alzheimer’s patients, their potential psychoactivity could be interpreted as a safety risk FDA, Nichols acknowledged. This is less worrying HE-02, and should not be a problem with later generations of 5-HT2A anti-inflammatory drugs with little or no behavioral activity that are now being developed in Nichols ’lab.
“With anti-inflammatory drugs … it’s much more of a traditional route,” Nichols said. “We could go to the FDA and they show that there are no adverse effects on behavior, we have effectiveness, we have safety. For the new molecules we are manufacturing, they are not programmed [by the Drug Enforcement Administration]. At this time the FDA will he decide, then, what to do with it? Let’s do it only in list 4 [for prescription drugs with low potential for abuse and low risk of dependence], and now you have a new anti – inflammatory on the market. “
Nate Seltenrich, a freelance science journalist based in San Francisco Bay, covers a wide range of topics such as environmental health, neuroscience and pharmacology.
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