Raised in New Orleans by a mother with untreated bipolar disorder who later killed herself and two others, Tipton said she endured layers of trauma that eventually forced her to seek treatment for crippling anxiety and hypervigilance. For 10 years nothing helped, and she began to wonder if she was “unfixable.”

Then she answered an ad for a clinical trial for MDMA-assisted therapy to treat post-traumatic stress disorder. Tipton said the results were immediate, and she is convinced the drug could help a lot of people. But even as regulators weigh approval of the first MDMA-based treatment, she’s worried that it won’t reach those who need it most.

“The main thing that I’m always concerned about is just accessibility,” the 43-year-old nonprofit project manager said. “I don’t want to see this become just another expensive add-on therapy for people who can afford it when people are dying every day by their own hand because of PTSD.”

MDMA is part of a new wave of psychoactive drugs that show great potential for treating conditions such as severe depression and PTSD. Investors are piling into the nascent field, and a host of medications based on MDMA, LSD, psychedelic mushrooms, ketamine, the South American plant mixture ayahuasca, and the African plant ibogaine are now under development, and in some cases vying for approval by the Food and Drug Administration.

Proponents hope the efforts could yield the first major new therapies for mental illness since the introduction of modern antidepressants in the 1980s. But not all researchers are convinced that their benefits have been validated, or properly weighed against the risks. And they can be difficult to assess using traditional clinical trials.

The first MDMA-assisted therapy appeared to be on track for FDA approval this August, but a from an independent review committee challenged the integrity of the trial data from the drug’s maker, Lykos Therapeutics, a startup founded by a psychedelic research and advocacy group. The FDA will convene a panel of independent investigators on to determine whether to recommend the drug’s approval.

Proponents of the new therapies also worry that the FDA will impose treatment protocols, such as requiring multiple trained clinicians to monitor a patient for extended periods, that will render them far too expensive for most people.

Tipton’s MDMA-assisted therapy included three eight-hour medication sessions overseen by two therapists, each followed by an overnight stay at the facility and an integration session the following day.

“It does seem that some of these molecules can be administered safely,” said David Olson, director of the University of California-Davis Institute for Psychedelics and Neurotherapeutics. “I think the question is can they be administered safely at the scale needed to really make major improvements in mental health care.”

Breakthrough Therapies?

Psychedelics and other psychoactive substances, among the medicines with the , have long been recognized for their potential therapeutic benefits. Modern research on them started in the mid-20th century, but clinical trial results didn’t live up to the claims of advocates, and they eventually got a bad name both from their use as party drugs and from that involved dosing unsuspecting individuals.

The 1970 Controlled Substances Act made most psychoactive drugs illegal before any treatments were brought to market, and MDMA was classified as a Schedule 1 substance in 1985, which effectively ended any research. It wasn’t until 2000 that scientists at Johns Hopkins University were granted regulatory approval to study psilocybin anew.

Ketamine was in a different category, having been approved as an anesthetic in 1970. In the early 2000s, researchers discovered its antidepressant effects, and a ketamine-based therapy, Spravato, received FDA approval in 2019. Doctors can also prescribe generic ketamine off-label, and hundreds of across the nation. A is underway to evaluate ketamine’s effectiveness in treating suicidal depression when used with other psychiatric medications.

Ketamine’s apparent effectiveness sparked renewed interest in the therapeutic potential of other psychoactive substances.

They fall into distinct categories: MDMA is an entactogen, also known as an empathogen, which induces a sense of connectedness and emotional communion, while LSD, psilocybin, and ibogaine are psychedelics, which create altered perceptual states. Ketamine is a dissociative anesthetic, though it can produce hallucinations at the right dose.

Despite the drugs’ differences, Olson said they all create neuroplasticity and allow the brain to heal damaged neural circuits, which imaging shows can be shriveled up in patients with addiction, depression, and PTSD.

“All of these brain conditions are really disorders of neural circuits,” Olson said. “We’re basically looking for medicines that can regrow these neurons.”

Psychedelics are particularly good at doing this, he said, and hold promise for treating diseases including Alzheimer’s.

A number of psychoactive drugs have now received the FDA’s “breakthrough therapy” designation, which expedites development and review of drugs with the potential to treat serious conditions.

But standard clinical trials, in which one group of patients is given the drug and a control group is given a placebo, have proven problematic, for the simple reason that people have no trouble determining whether they’ve gotten the real thing.

The final clinical trial for Lykos’ MDMA treatment showed that 71% of participants no longer met the criteria for PTSD after 18 weeks of taking the drug versus 48% in the control group.

A March report by the Institute for Clinical and Economic Review, an independent research group, questioned the company’s clinical trial results and challenged the objectivity of MDMA advocates who participated in the study as both patients and therapists. The institute also questioned the drug’s cost-effectiveness, which insurers factor into coverage decisions.

Lykos, a public benefit company, was formed in 2014 as an offshoot of the Multidisciplinary Association for Psychedelic Studies, a nonprofit that has invested more than $150 million into psychedelic research and advocacy.

The company said its researchers developed their studies in partnership with the FDA and used independent raters to ensure the reliability and validity of the results.

“We stand behind the design and results of our clinical trials,” a Lykos spokesperson said in an email.

There are other hazards too. Psychoactive substances can put patients in vulnerable states, making them potential victims for or other types of abuse. In Lykos’ second clinical trial, two therapists were found to have spooned, cuddled, blindfolded, and pinned down a female patient who was in distress.

The substances can also cause shallow breathing, , and hyperthermia.

To mitigate risks, the FDA can put restrictions on .

“These are incredibly potent molecules and having them available in vending machines is probably a bad idea,” said Hayim Raclaw of Negev Capital, a venture capital fund focused on psychedelic drug development.

But if the protocols are too stringent, access is likely to be limited.

Rachel del Dosso, a trauma therapist in the greater Los Angeles area who offers ketamine-assisted therapy, said she’s been following the research on drugs like MDMA and psilocybin and is excited for their therapeutic potential but has reservations about the practicalities of treatment.

“As a therapist in clinical practice, I’ve been thinking through how could I make that accessible,” she said. “Because it would cost a lot for [patients] to have me with them for the whole thing.”

Del Dosso said a group therapy model, which is sometimes used in ketamine therapy, could help scale the adoption of other psychoactive treatments, too.

Artificial Intelligence and Analogs

Researchers expect plenty of new discoveries in the field. One of the companies Negev has invested in, Mindstate Design Labs, to analyze “trip reports,” or self-reported drug experiences, to identify potentially therapeutic molecules. Mindstate has asked the FDA to green-light a clinical trial of the first molecule identified through this method, 5-MeO-MiPT, also known as moxy.

AlphaFold, an AI program developed by Google’s DeepMind, has identified thousands of potential psychedelic molecules.

There’s also a lot of work going into so-called analog compounds, which have the therapeutic effects of hallucinogens but without the hallucinations. The maker of a announced in March that the FDA had granted it breakthrough therapy status.

“If you can harness the neuroplasticity-promoting properties of LSD while also creating an antipsychotic version of it, then that can be pretty powerful,” Olson said.

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Out of desperation, her husband scraped together $600 for the first of six rounds of intravenous ketamine therapy at Ketamine Clinics Los Angeles, which administers the generic anesthetic for off-label uses such as treating depression. When Gutilla got into an Uber for the 75-mile drive to Los Angeles, it was the first time she had left her home in Llano, California, in two years. The results, she said, were instant.

“The amount of relief I felt after the first treatment was what I think ‘normal’ is supposed to feel like,” she said. “I’ve never felt so OK, and so at peace.”

For-profit ketamine clinics have proliferated over the past few years, offering infusions for a wide array of mental health issues, including obsessive-compulsive disorder, depression, and anxiety. Although the off-label use of ketamine hydrochloride, a Schedule III drug approved by the FDA as an anesthetic in 1970, was considered radical just a decade ago, now between have cropped up across the nation.

Market researcher Grand View Research pegged industry revenues at $3.1 billion in 2022, and projects them to more than double to $6.9 billion by 2030. Most insurance doesn’t cover ketamine for mental health, so patients must pay out-of-pocket.

While it’s legal for doctors to prescribe ketamine, the FDA hasn’t approved it for mental health treatment, which means that individual practitioners must develop their own treatment protocols. The result is wide variability among providers, with some favoring gradual, low-dosage treatments while others advocate larger amounts that can induce hallucinations, as the drug is psychedelic at the right doses.

“Ketamine is the wild West,” said Dustin Robinson, the managing principal of Iter Investments, a venture capital firm specializing in hallucinogenic drug treatments.

Ketamine practitioners stress that the drug’s emergence as a mental health treatment is driven by a desperate need. Depression is the in the United States for individuals ages 15-44, according to the National Institute of Mental Health, and experience a diagnosable mental disorder in any given year.

Meanwhile, many insurance plans cover mental health services at lower rates than physical health care, . Thus many patients with disorders receive little or no care early on and are desperate by the time they visit a ketamine clinic, said , chair of psychiatry and the behavioral sciences at the University of Southern California’s Keck School of Medicine.

But the revelation that died in part from a large dose of ketamine, along with , has piqued fresh scrutiny of ketamine and its regulatory environment, or lack thereof.

Commercial ketamine clinics often offer same-day appointments, in which patients can pay out-of-pocket for a drug that renders immediate results. The ketamine is administered intravenously, and patients are often given blankets, headphones, and an eye mask to heighten the dissociative feeling of not being in one’s body. A typical dose of ketamine to treat depression, which is 10 times lower than the dosage used in anesthesia, costs clinics about $1, but clinics charge $600-$1,000 per treatment.

Ketamine is still shadowed by its reputation as the party drug known as “Special K”; Siegel’s first grant from the National Institutes of Health was to study ketamine as a drug of abuse. It has the potential to send users down a “K hole,” otherwise known as a bad trip, and can induce psychosis. Research in animals and has shown chronic use of the drug impairs both short- and long-term cognition.

Perry’s death in October raised alarms when the initial toxicology screening attributed his death to the acute effects of ketamine. A December report revealed Perry received infusion therapy a week before his death but that the fatal blow was a high dose of the substance taken with an opioid and a sedative on the day of his death — indicating that medical ketamine was not to blame.

A Variety of Protocols

Sam Mandel co-founded Ketamine Clinics Los Angeles in 2014 with his father, Steven Mandel, an anesthesiologist with a background in clinical psychology, and Sam said the clinic has established its own protocol. That includes monitoring a patient’s vital signs during treatment and keeping psychiatrists and other mental health practitioners on standby to ensure safety. Initial treatment starts with a low dose and increases as needed.

While many clinics follow the Mandels’ graduated approach, the dosing protocol at MY Self Wellness, a ketamine clinic in Bonita Springs, Florida, is geared toward triggering a psychedelic episode.

Christina Thomas, president of MY Self Wellness, said she developed her clinic’s procedures against a list of “what not to do” based on the bad experiences people have reported at other clinics.

The field isn’t entirely unregulated: State medical and nursing boards oversee physicians and nurses, while the FDA and Drug Enforcement Administration regulate ketamine. But most anesthesiologists don’t have a background in mental health, while psychiatrists don’t know much about anesthesia, Sam Mandel noted. He said a collaborative, multidisciplinary approach is needed to develop standards across the field, particularly because ketamine can affect vital signs such as blood pressure and respiration.

The protocols governing Spravato, an FDA-approved medication based on a close chemical cousin of ketamine called esketamine, are illustrative. Because it has the potential for serious side effects, it falls under the FDA’s Risk Evaluation and Mitigation Strategies program, which puts extra requirements in place, said Robinson. Spravato’s REMS requires two hours of monitoring after each dose and prohibits patients from driving on treatment days.

Generic ketamine, by contrast, has no REMS requirements. And because it is generic and cheap, drugmakers have little financial incentive to undertake the costly clinical trials that would be required for FDA approval.

That leaves it to the patient to assess ketamine providers. Clinics dedicated to intravenous infusions, rather than offering the treatment as an add-on, may be more familiar with the nuances of administering the drug. Ideally, practitioners should have mental health and anesthesia expertise, or have multiple specialties under one roof, and clinics should be equipped with hospital-grade monitoring equipment, Mandel said.

Siegel, who has researched ketamine since 2003, said the drug is especially useful as an emergency intervention, abating suicidal thoughts for long enough to give traditional treatments, like talk therapy and SSRI antidepressants, time to take effect. “The solutions that we have and have had up until now have failed us,” Mandel said.

The drug is now popular enough as a mental health treatment that the name of Mandel’s clinic is a daily sight for thousands of Angelenos as it appears on 26 Adopt-A-Highway signs along the 405 and 10 freeways.

And the is accelerating. A drug containing MDMA, known as ecstasy or molly, is expected to receive FDA approval in 2024. A drug with psilocybin, the active ingredient in “magic mushrooms,” could launch as early as 2027, the same year a stroke medicine with the active ingredient of DMT, a hallucinogen, is expected to debut.

Robinson said many ketamine clinics have opened in anticipation of the expanded psychedelic market. Since these new drugs will likely be covered by insurance, Robinson advises clinics to offer FDA-approved treatments such as Spravato so they’ll have the proper insurance infrastructure and staff in place.

For now, Sarah Gutilla will pay out-of-pocket for ketamine treatments. One year after her first round of infusions, she and her husband are saving for her second. In the meantime, she spends her days on her ranch in Llano where she rescues dogs and horses, and relies on telehealth therapy and psychiatric medications.

While the infusions aren’t “a magic fix,” they are a tool to help her move in the right direction.

“There used to be no light at the end of the tunnel,” she said. “Ketamine literally saved my life.”

This article was produced by ºÚÁϳԹÏÍø News, which publishes , an editorially independent service of the .Ìý

ºÚÁϳԹÏÍø News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about .

USE OUR CONTENT

This story can be republished for free (details).