The therapeutic value of LSD, the psychedelic muse behind countless books, music and works of visual art, has hit an altogether more prosaic milestone, albeit toward a still far-out end: A phase I study, sponsored by U.K.-based Eleusis Pharmaceuticals Ltd., found low doses safe and well-tolerated, setting the stage for new tests of the approach as a disease-modifying therapy for Alzheimer’s disease (AD). Results of the healthy-volunteers study, published in the journal Psychopharmacology, support the company’s mission of “unlocking the therapeutic potential of psychedelics at subperceptual, non-psychoactive doses,” said company co-founder and CEO Shlomi Raz, but also sparked new questions.

The potential benefits of low, or micro doses, of LSD have been explored in multiple quarters, but Eleusis said its phase I study is the first double-blind, placebo-controlled, randomized trial of its kind. Over a three-week period, clinicians gave 48 volunteers, with a mean age of 63, either 5 micrograms (µg), 10 µg or 20 µg of LSD, or a placebo every four days. By comparison, standard recreational dosing of LSD is usually around 150 µg, while 20µg is known to be the threshold dose past which psychoactive effects occur.

The top-line readout of the trial found "no deviations from baseline or abnormalities on either safety or cognitive outcome measures." In line with previous studies of low-dose LSD, Eleusis' team also found an "overall lack of detectable cognitive effects (either positive or negative) produced by LSD," a finding that might disappoint fans of micro-dosing and may seem at odds with what researchers would want to see when testing a drug as a potential therapy for dementia, though may be explained by ceiling-effects of cognition testing among healthy volunteers.

Shlomi Raz, CEO and co-founder, Eleusis

"It would be great if this drug would reverse the kind of damage that's been done because of neurodegeneration, but the likelihood of that is uncertain," Raz told BioWorld. "However, from the perspective of modifying the course of the disease, especially treating it early at the mild cognitive impairment stage – that prodromal state where only a small percentage of patients convert to Alzheimer’s – I think it is really kind of a crucial timing for the use of a drug like LSD," he said.

Eleusis is less concerned with the perceptual effects of LSD than with its potential anti-inflammatory effects. "Certain psychedelics are potently anti-inflammatory in variety of translational models," said.

Evidence for that claim has emerged in part from the lab of company co-founder, Charles Nichols, a professor of pharmacology at the Louisiana State University (LSU) Health Sciences Center in New Orleans. Several years ago, Nichols' lab discovered that the drug (R)-2,5-dimethoxy-4-iodoamphetamine, a selective 5-HT2 receptor agonist, "has potent anti-inflammatory activity to prevent TNF-alpha mediated inflammation both in cell culture, and in whole animal models.” Nichols’ continued research on psychedelics made him the most highly cited researcher in the statewide LSU system in 2018, according to a recent analysis by Clarivate Analytics.

Raz said he was further inspired by research published in Nature Reviews Endocrinology in 2018 suggesting that "inflammation is one of the seven evolutionarily conserved mechanistic pillars of ageing that are shared by age-related diseases," a phenomenon the authors called "inflammaging."

"Alzheimer’s disease is an exemplar of inflammaging," Raz said. "It's really distinguished by a complex and multifactorial pathobiology and many researchers believe that it will require a multitargeted approach, rather than the precision-medicine single-target approach that's in vogue," he said. "If there was ever a multitargeted drug suited for such an application, it's LSD."

The advantages of the drug, Raz said, include the ease with which it crosses the blood-brain barrier, its relatively long-lasting effects even at low doses, and its potential to upregulate neuroplasticity and provide neuroprotection, elements that have been pursued in the study of other serotonin 2A receptor (5-HT2A) agonists, but not as part of a bigger package in one drug.

Emergent effects

Neiloufar Family, lead investigator and director of research, Eleusis

During Eleusis's phase I trial, investigators said "mild or moderate" intensity headaches were reported among those participants on drug. But it also gathered reports from active-arm participants of "vigilance reduction," dizziness, and affirmative answers to the question, "Does your body feel different or changed?" Despite those effects, cognition tests found "no significant treatment effects for any dose group on the two dose days it was administered," and no impairment of balance, even during the acute phase of the drug, Neiloufar Family, the study’s lead investigator and director of research at Eleusis, told BioWorld.

"While no impairment of cognitive function was observed, a dose-dependent increase in vigilance reduction, 'feeling bad drug effects,' 'feeling dizzy,' and 'sleepy' suggests that vigilance and alertness will need to be further explored in future trials," Family and her co-authors wrote in the Psychopharmacology article.

Perhaps unsurprisingly, the placebo group in the study had what researchers called "a remarkably high" number of nervous system and psychiatric treatment-emergent adverse events. "The interpretation that we have of this is that it's a psychoactive drug that has a very well-known profile socially, so there was a kind of expectancy bias," Family said. "We didn't find any psychedelic-like effects in any of the participants who had the actual LSD doses," Family said.

The pharmacokinetic profile of the drug was favorable during the trial, she said, with exposure consistent across participants at the two higher doses, adding that the “safety results establish the viability of moving into phase II in a mild Alzheimer’s population."

Supportive regulators

Suggesting the regulatory appetite for the study of psychedelics may be less strident than expected, research is already underway on a different psychedelic, psilocybin, for the treatment of depression in people with mild cognitive impairment or early AD at Johns Hopkins University.

For Eleusis' U.K.-based trial, the MHRA was "very open-minded, progressive, and innovative in their approach," Raz said. The company's team has also informally discussed its development program with the FDA and DEA, finding them to be actively engaged in conversations about psychedelics research in psychiatry and in general. "From a regulatory perspective, there's a clear recognition of the unmet needs that psychedelics could address," he said.

Seeking validation, impact

Eleusis, founded in 2013, has both New York and London-based subsidiaries. As it moves to advance its LSD program for AD, a number of steps lie ahead. It will first focus on developing ELE-02, the lead candidate from what Raz calls the company's "not-so-psychedelic psychedelics" for the treatment of other chronic inflammatory disease. The company will continue to rely on private investors as it pursues its next big milestone, a phase I readout for ELE-02. Success with that program, which targets retinal disease will be necessary to provide both the financial and scientific foundation for advancing LSD into phase II trials for AD and could also prove to be "a very cost-effective proof of concept in humans," he said.

The company's team also wants to design a risk mitigation system to support outpatient use of LSD, which is a Schedule I substance in the U.S., making it illegal to manufacture, buy, possess, process or distribute without a license from the DEA and a Schedule 1 Class A drug in the U.K., where restrictions are also heavy.

There were an estimated 43.8 million people worldwide with AD and other forms of dementia in 2016, according to a systemic analysis published in The Lancet in 2018. So, Eleusis and its competitors big and small, have their work cut out for them. But without doubt, there is substantive need for progress, something that Raz, a former managing director at Goldman Sachs who has personally invested in Eleusis, clearly feels. A key motivator for him, he said, is “the potential to really be of service and to do something that could transform lives and really reduce suffering."

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