New Treatment Update: FDA Approves Non-psychedelic Ketamine for Clinical Trials

Woman with depression speaks to her doctor.

KatarzynaBialasiewicz / Getty Images

Key Takeaways

  • Ketamine is sometimes prescribed off-label to treat depression in a clinical setting.
  • Recently, researchers have been exploring whether the drug could be used safely at-home for treatment-resistant depression.
  • The results of the largest real-world study of ketamine outcomes was recently published, and the FDA has approved one form of ketamine for clinical trials in the US.

Ketamine, a dissociative anesthetic that was developed in the early 1960s, is primarily used for human and veterinary anesthesia. But in recent years, scientists have explored the possibility of using ketamine to treat mental illness, in particular treatment-resistant depression (TRD). 

Ketamine is sometimes prescribed off-label for depression, under medical supervision and in a clinical setting. But if proven in clinical trials, R-ketamine could be a safe antidepressant for people to use at home. 

With more than 30% of adults with major depressive disorder affected by treatment-resistant depression, potentially millions of people could be helped by ketamine therapy. 

FDA Approval for R-ketamine

One form of ketamine has recently been approved by the Food and Drug Administration (FDA) for use in a life science study, to be carried out by German psychedelics startup Atai Life Sciences. Their clinical trial will use R-ketamine, a non-psychedelic form of ketamine, to look at whether it is effective for TRD. 

“For these patients, currently available front-line treatments do not offer sufficient relief,” says Atai Life Sciences’ co-founder and chief scientific officer, Srinivas Rao. “So far, we have reason to be optimistic that our R-ketamine formulation, PCN-101, could have potential as an effective, at-home treatment for people with treatment-resistant depression.”

Another form of ketamine, S-ketamine, has been shown to reduce depression symptoms in people with treatment-resistant depression in clinical trials used to support the registration of Spravato in the U.S.

Srinivas Rao

So far, we have reason to be optimistic that our R-ketamine formulation, PCN-101, could have potential as an effective, at-home treatment for people with treatment-resistant depression.

— Srinivas Rao

“S-ketamine is rapid-acting, offering relief from depressive symptoms within hours (as opposed to weeks or even months, as can be the case with SSRIs),” Rao explains.

But when compared to S-ketamine, PCN-101 has demonstrated the potential for greater potency, longer duration of effect, and reduced abuse potential in pre-clinical studies. “These characteristics could potentially position R-ketamine as a rapid-acting antidepressant with a more favorable safety and tolerability profile than S-ketamine,” Rao says. 

Furthermore, R-ketamine could offer the potential for at-home use, which could revolutionise the patient’s therapeutic journey, by potentially increasing access and ease-of-use.

Alongside the first U.S. study, a drug-drug interaction (DDI) trial which will begin in early 2022, Atai’s Phase 2 proof-of-concept trial in treatment-resistant depression is ongoing in Europe. 

Studying Real World Patients

In January 2022, the largest real-world study of ketamine outcomes, conducted by Stanford University School of Medicine, was published in the Journal of Affective Disorders.

“This study represents outcomes on more patients than have ever been studied in academic trials of ketamine intravenous therapy (KIT) for depression,” says L. Alison McInnes, MD, MS, vice president of medical affairs at Osmind, a healthcare technology company and public benefit corporation (PBC) dedicated to empowering clinicians and researchers to bring innovative mental health treatments to those who need it most. 

While academic trials study carefully groomed patients without comorbidities, studying real-world patients that have comorbidities enable a true picture of how a particular treatment performs in the community, Dr. McInnes adds. 

L. Alison McInnes, MD, MS

Ketamine intravenous therapy (KIT) is relatively safe and is a rapid and very effective treatment for depression.

— L. Alison McInnes, MD, MS

The study found that in a subset of 537 people receiving KIT across 178 clinics, there was a 54% response rate and a 29% remission rate.

“KIT is relatively safe and is a rapid and very effective treatment for depression,” explains Dr. McInnes, adding that only 8% of people experience worsening symptoms. It’s also durable—80% of people were still responding to their initial intravenous treatment at one month and 60% at two months, without any maintenance infusions. 

“We were surprised at how durable the antidepressant effect is, and that most patients only get 2-3 maintenance treatments before exiting care,” Dr. McInnes says. However, there’s still a lot to learn about the patient experience. “We need to understand what happens to these patients,” Dr. McInnes adds. “Do they leave because of the expense and/or because they feel better? How long till they relapse?” 

Dr. McInnes hopes the findings will improve treatment options for people with depression by persuading insurers to pay for KIT therapy. "This will increase access to care for people of all races and socioeconomic levels," she says. "For now, KIT is only available to those fortunate people who can pay out of pocket."

What This Means For You

If antidepressant medication and other therapies haven't improved your symptoms of depression, you might want to speak to your doctor about ketamine infusion therapy. A good starting point is the American Society of Ketamine Physicians, Psychotherapists & Practitioners (ASKP) directory.

It's important to consider various factors before going ahead with ketamine therapy. Your doctor will tell you whether you're eligible for this type of treatment and what to expect.

4 Sources
Verywell Mind uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
  1. Jelen LA, Young AH, Stone JM. Ketamine: A tale of two enantiomersJ Psychopharmacol. 2021;35(2):109-123. doi:10.1177/0269881120959644

  2. Zhdanava M, Pilon D, Ghelerter I, et al. The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United StatesJ Clin Psychiatry. 2021;82(2). doi: 10.4088/JCP.20m13699

  3. Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: Results of a randomized, double-blind, active-controlled study(TRANSFORM-1)Int J Neuropsychopharmacol. 2019;22(10):616-630. doi:10.1093/ijnp/pyz039

  4. McInnes LA, Qian JJ, Gargeya RS, DeBattista C, Heifets BD. A retrospective analysis of ketamine intravenous therapy for depression in real-world care settingsJ Affect Disord. 2022:S0165032721014142. doi: 10.1016/j.jad.2021.12.097

By Claire Gillespie
Claire Gillespie is a freelance writer specializing in mental health. She’s written for The Washington Post, Vice, Health, Women’s Health, SELF, The Huffington Post, and many more.