New psychedelic-like drugs: All treatment, no trip?

California scientists race to concoct compounds that rewire the brain without euphoria or hallucinations.

Since their creation decades ago, mind-altering drugs have remained as unchanged as bellbottoms, tie-dye and patchouli oil.

Now — full of promise and peril — psychedelics are undergoing a makeover. Chemical neuroscientists, many based in Northern California, are redesigning the structures of psilocybin, ketamine, MDMA and other powerful drugs to concoct compounds that they hope will offer mental health benefits with fewer risks.

With advanced tech tools and a deepened understanding of brain chemistry, scientists say the new drugs might succeed where conventional therapies have failed, treating post-traumatic stress disorder, anxiety, depression, addiction and other devastating mental health problems.

“Our goal is to make medicines that are derived from psychedelics that are safer and gentler, more effective and more accessible,” said Matthew Baggott, former director of data science and engineering at Genentech, whose Palo Alto-based startup Tactogen has patented several novel MDMA, or “Ecstasy,” molecules that offer spiritual and personal insights with less heart-racing anxiety and euphoria.

At the new UC Davis Institute for Psychedelics and Neurotherapeutics, director David Olson is tweaking psychoactive drugs to spur neural growth and rewire the troubled brain without triggering hallucinations or adverse effects. His biotech startup, Delix Therapeutics, has built a portfolio of more than 2,000 non-hallucinogenic compounds.

Stanford University School of Medicine investigators Dr. Boris Heifets and Dr. Rob Malenka have pried apart MDMA’s therapeutic and addictive traits, distinguishing the different molecular pathways behind the drug’s sociability and abuse potential.

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“Can we deconstruct these drugs — basically, take them apart and put them back together — so that they have one of these effects and not the other?” said Heifets, assistant professor of anesthesiology, perioperative and pain medicine.

Separating the agony from ecstasy “would be more helpful and less harmful,” he said.

So far, researchers have managed to demonstrate such decoupling only in rodents. The research in people is embryonic, so we don’t yet know whether drugs can be purely therapeutic.

Compared to modern medicines, the classic psychedelics are elderly. MDMA, or “ecstasy,” was synthesized in 1912 when Woodrow Wilson was president. Swiss chemist Albert Hofmann isolated LSD from grain fungus in 1938 and psilocybin, found in “magic mushrooms,” in 1958. DMT was isolated from the root bark of a tree in 1946. Ketamine, an anesthetic, was made in 1962.

But therapeutic research slowed in the mid-1960s amid President Nixon’s “War on Drugs,” tightened regulations and disappointing clinical trials.

Psychedelic drugs have long been known to be among the most powerful substances to act on the human brain. Emerging science shows why: They stimulate a receptor in the brain known as 5-hydroxytryptamine 2A (5-HT2A), as well as other lesser known brain receptors. There is evidence that they can produce changes in brain architecture by spurring regrowth of damaged neural circuitry and new connections between synapses.

But there are major downsides. Some cause life-threatening heart problems or body overheating. Perception-distorting effects may make them distressing, even dangerous, for people with a predisposition to mental illness. Patients on anti-depressants such as Prozac also risk adverse reactions. Some of the drugs are hard to administer and persist longer than needed.

An off-duty Alaska Airlines pilot charged with trying to shut off the engines of a flight in October told investigators that he had been sleepless and dehydrated since he consumed psychedelic mushrooms about 48 hours before boarding. He had struggled with depression for months, he said.

“They have tremendous potential, but they’re very crude tools,” said Heifets.

Psychedelics are classified as Schedule I substances, illegal except under tightly regulated circumstances, so researchers have faced legal restrictions and professional stigma.

But now, with growing frustration over shortcomings of conventional therapies, there are incentives to innovate.

Private investment into psychedelic research and development has surged, supported by an FDA “breakthrough therapy” designation for clinical trials of psilocybin for depression in 2018. Next summer, the FDA is expected to approve MDMA as a treatment for PTSD, based on clinical trial results at UC San Francisco in a study by the San Jose-based Multidisciplinary Association for Psychedelic Studies.

Philanthropic, institutional and government funding of research has led to the creation of academic centers for psychedelic science across the country. In 2020, the Defense Advanced Research Projects Agency (DARPA) directed $27 million to a 30-person lab at the University of North Carolina at Chapel Hill, where professor Dr. Bryan Roth uses robots, computational chemistry and electron microscopy to identify thousands of new chemical structures.

More than 100 companies are focused on psychoactive drugs, according to patent attorney Graham Pechenik of the San Francisco-based Calyx Law.  Five years ago, only a few dozen patent applications had been submitted for psychoactive-related products, he said. Now his Psychedelic Alpha patent tracker counts more than 1,000.

“I really thought that psychedelics were going to just stay underground forever or maybe stay this weird area of academic research,” said Brom Rector of Empath Ventures, which invests in early stage psychedelic-focused companies. “Over the last few years, all that’s changed.”

Meanwhile, the cultural conversation around psychedelics has begun to shift. Oakland, San Francisco, Santa Cruz and Berkeley have decriminalized “natural” psychedelics. Gov. Gavin Newsom vetoed a bill that would have allowed personal possession of psychedelic mushrooms in California, asking lawmakers to send a version next year with therapeutic guidelines — suggesting that he might be more supportive of medicinal use than decriminalization.

Scientists say research needs to keep up. “The psychedelic landscape is moving very, very quickly. … People are starting to use them without the appropriate guardrails in place,” said Olson. “We still need to understand how they work.”

To make them safer, scientists enlist one of two strategies.

Some are modifying the chemical structures of existing drugs, such as swapping an oxygen atom for a carbon atom. Others are building new drugs from scratch, assembling them like Tinker Toys. They might select the components that are needed to promote neural growth, for instance, but delete those linked to hallucinations.

Updates are long overdue, said Rector.

Existing psychedelics “are the best drugs from almost 100 years ago — the Ford Model T of psychedelics,” he said. “I want to see what the Tesla Model S in psychedelics is going to be like.”