Freedom Biosciences Develops Ketamine Combination Therapies

A startup company guided by some of the world’s leading ketamine researchers says it is studying a promising treatment for  extending the antidepressant effects of the drug, making it potentially less expensive and easier for patients to access.

Freedom Biosciences says that in a small clinical trial, patients who were given a drug called rapamycin two hours before their ketamine infusion saw their depression lift for as long as two weeks. 

The antidepressant effects of ketamine alone often fade after two to seven days, clinicians say. New patients are typically given the drug twice a week for at least four weeks.

Longer lasting effects will benefit providers and patients, according to Dr. John Krystal, a founder of Freedom Biosciences and chair of the psychiatry department at the Yale School of Medicine.

 “We reduce the cost…and we provide a greater flow through the clinic, so that more people can get access to the treatment,” Krystal says. 

Freedom Biosciences says that its first program, called FREE001, will extend ketamine’s  antidepressant effects by combining it with rapamycin, which suppresses inflammation and is used in cancer treatment.

To follow up on the first clinical trial, which had just 23  patients, Freedom Biosciences has hired a contract research organization to conduct a trial with at least 100 patients that will take a couple of years to complete.

Dina Burkitbayeva, who is Freedom Biosciences’ CEO, says the first trial had what’s called a crossover design, meaning each patient was his or her own control. Every one did better with the combination of rapamycin and ketamine than with ketamine alone.

Because the FREE001 protocol combines two existing drugs that already have FDA approval, Burkitbayeva believes that the regulatory process should be more straightforward and less expensive than the process of bringing a new chemical entity to FDA. “We have an incredibly high probability of success,” Burkitbayeva says. 

As first reported by Psychedelic Alpha, the company also applied  in 2018 for a patent for a combination therapy that uses mTORC1 inhibitors to augment the effects of antidepressants.  Freedom Biosciences employs about 20 people, most of them part-time. 

The company has other medicines in pre-clinical development that it is not yet ready to discuss. Among them are efforts to make ketamine less addictive.

 “People have undersold the addictive risks of ketamine,” Krystal said. “Ketamine abuse carries risks that have to be taken very seriously, all the way from drunk driving to really high-dose ketamine use.” 

Freedom Bioscience Raises $10M In Seed Funding

Freedom Biosciences was founded in 2021 by Krystal and Burkitbayeva, a partner at PsyMed Ventures, a venture capital firm. Dr. Robert Berman, who with Krystal and others discovered ketamine’s antidepressant effects in the late 1990s, is the startup’s senior medical advisor. The two psychiatrists, with Yale Med school colleagues, have studied ketamine ever since.

They are “the most knowledgeable group there is when it comes to ketamine’s potent antidepressant potential,” said Gurdane Bhutani, a managing partner of MBX Capital, an early investor in Freedom Bioscience. The company said last year that it had raised $10.5 million in seed financing from MBX Capital, PsyMed and Village Global, among others. 

Ketamine is, of course, not a new drug. The FDA approved ketamine as an anesthetic in 1970.  It was deployed as a battlefield painkiller during the last years of the Vietnam War and remains in wide use today as an anesthetic for people and animals. While ketamine is not a classic psychedelic, it produces what are called “dissociative” effects, enabling people to feel separated from their bodies or surroundings.

Krystal and Berman were doing basic research into the biology of depression when they stumbled upon ketamine’s healing power. They wanted to study the role of  glutamate, a chemical that carries electrical impulses between nerve cells in the brain, in depression. To do so, they gave ketamine which triggers glutamate production, to seven patients with major depression.

To the amazement of the researchers, patients given ketamine felt better right away. Their study, titled Antidepressant Effects of Ketamine in Depressed Patients, was published in 2000 in a journal called Biological Psychiatry. 

Not much happened at first. “There was an enormous amount of skepticism in the field,” says Krystal. The study “definitely needed replication,” says Berman, its lead author. But after scientists at the National Institute of Mental Health replicated their findings in a study in JAMA Psychiatry in 2006, doctors began to give  ketamine to people with depression. They prescribed the drug off label, meaning that it is used to treat a condition other than the one for which was approved.

Since then, ketamine has shaken up the world of psychiatry. It has brought fast-acting relief to people with depression, especially those who do not respond to the established medicines that have been go-to treatments for the disease since the introduction of Prozac in 1987.  It has also spawned an industry that includes hundreds of providers in the U.S., including at least a half dozen small companies that operate clinics or train therapists. Startups including Nue Life, Mindbloom, Field Trip Health, Delic and Journey Clinical all offer ketamine treatments, as they await FDA approval of other psychedelic medicines. The research into ketamine at Yale and elsewhere also has upended conventional wisdom about the underlying neurobiology of depression, scientists say. 

Today, ketamine is distributed through three distinct channels:

FDA-sanctioned Antidepressant

The FDA  gave ketamine a stamp of approval in 2019 when regulators authorized a version of the drug, called esketamine and branded as Spravato. It’s available by prescription, administered as a nasal spray and often covered by insurance, for people for whom other treatments have failed. 

Spravato is expensive. It costs between $4,720 to $6,785 for the first month of treatment and $2,360 to $3,540 per month after that, according to the Institute for Clinical and Economic Review, a nonprofit that studies drug pricing. Britain’s National Health Service won’t pay for Spravato, citing concerns about its costs and effectiveness.

Nevertheless, Spravato is a big financial success for Janssen Neuroscience, a unit of Johnson and Johnson. Sales are growing rapidly–an indication that it brings relief to patients. Dr. Robert Hough, who led the team that took Spravato through the FDA for Johnson & Johnson, is now chief medical officer for Freedom Biosciences.

Generic Drug, Given Off-label

No one knows just how many doctors and clinics offer ketamine to patients, but indications are that the market is growing and crowded. Startups including Nue Life, Mindbloom, Delic,  Journey Clinical and Stella,  all offer ketamine treatment, as they await FDA approval for other psychoactive drugs.

There’s no standard protocol for administering ketamine. It is offered with or without psychotherapy, and by various pathways–intravenously, by injection into a muscle, through the nose or as a lozenge, which is sometimes given at home. No independent authority  monitors the outcomes of these practitioners, so it’s impossible to learn from their successes or mistakes. Some clinics claim to be able to treat anxiety, PTSD and obsessive-compulsive disorder with ketamine.

Recreational Drug, Underground

Sometimes called Special K, ketamine is sold on the black market and the dark web and it’s been part of the nightclub and musical festival scenes since the 1980s. It’s typically taken through the nose, but ketamine lozenges were diverted to the unregulated market during the Covid-19 epidemic, when some clinics dispensed ketamine for at-home use. 

In an interview with Lucid News and during an exhaustive three-hour and 54-minute podcast with author Tim Ferriss, Krystal said that he is troubled by the widespread abuse of ketamine and by  exaggerated claims that some practitioners make about the drug.

“I’m concerned when treatments are delivered which are not supported empirically,” Dr. Krystal says. “I try to be very clear about the boundaries of what we have learned.”

That said, there’s little doubt among researchers that ketamine can effectively treat  depression, with or without talk therapy.  In a systematic review of studies looking at ketamine and mental health, researchers found “support for robust, rapid and transient antidepressant and anti-suicidal effects of ketamine.” 

Interestingly, ketamine research has also opened up new pathways for understanding and treating depression. The research is “overturning the received wisdom regarding the underlying neurobiology” of depression, Dr. Krystal and colleagues write in an essay titled, Ketamine: A Paradigm Shift for Depression Research and Treatment published in 2019 in the journal Neuron.

For decades, scientists believed that commonly-prescribed antidepressants such as Prozac, Paxil and Cymbalta worked by increasing the  levels of neurotransmitters – serotonin, norepinephrine and dopamine –  in the brain by blocking their reuptake or reabsorption. These drugs can improve mood and emotions, but they can take days or weeks to affect moods and they don’t work for many patients. 

By contrast, a single dose of ketamine can have an immediate impact. Precisely how that happens is not entirely clear, but indications are that the glutamate release set off by ketamine prompts the brain to create new neural connections and strengthen existing ones. These new connections enable patients to develop more positive thoughts. 

Whether the dissociative effects of ketamine contribute to its effectiveness as an antidepressant remains an unsettled question. (Krystal says it’s not essential.) Nor do clinicians agree on the role, if any, that psychotherapy plays in its effectiveness. Questions remain about the optimal dose of ketamine as well.

“The biology of depression is unspeakably complicated,” says Krystal.

Looking back at his quarter-century of working with Ketamine, Krystal says he’s been moved by hearing from patients who have benefitted from the drug. “It’s been enormously meaningful,” he says. His goal now, he says, is to find ways to make it less addictive and even more effective.