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  • A large-scale analysis of real-world ketamine intravenous therapy showed promise for treating depression.
  • Symptoms improved in 50% of subjects with a 30% remission rate, but worsened in 8% of subjects.
  • More than 70% of people with suicidal ideation benefited from ketamine therapy.
  • Off-label ketamine treatments are available at community clinics and administered by psychiatrists.

Ketamine is an FDA-approved anesthetic that’s gaining popularity in psychedelic research for its effectiveness in treating depression.

Depression is notoriously challenging to treat, and a growing body of evidence suggests that ketamine may help reduce symptoms.

A pivotal new study published in January 2022 analyzed the effectiveness of ketamine therapy in real-world community care settings — the largest analysis of its kind.

Findings suggest that ketamine infusion therapy (KIT) produced “robust, rapid, and durable results” for individuals with depression, according to lead researcher Alison McInnes, MD, Vice President of Medical Affairs at Osmind, a platform designed for treatment resistant mental health practices.

The observational study was conducted by Osmind researchers and physician-scientists at Stanford University School of Medicine.

Researchers analyzed a sample of 537 people with depression receiving KIT across 178 clinics. They observed that:

  • around 54% of people responded positively to the treatment
  • around 30% achieved remission from their depression symptoms
  • 40% of people with suicidal ideation no longer experienced this symptom following ketamine treatment, with more than 70% experiencing overall improvement; 2017 research produced similar results
  • the antidepressant effects of KIT remained for 4 weeks in 80% of subjects
  • the effects lasted for 60% of subjects at 8 weeks, even without maintenance infusions

“This is the largest real-world study of intravenous ketamine therapy outcomes ever performed, and it also represents more patients surveyed than ever studied in academic trials to date,” McInnes told Psych Central.

Though the study had its limitations, it’s the first in a series of follow-up ketamine studies that will include larger demographics and a wider range of clinical histories across a larger number of subjects over a longer period of time.

“Having real-world data on these treatments is really valuable because you don’t know if it’s going to generalize,” said Keith Heinzerling, MD, an addiction medicine specialist and director of the Pacific Treatment & Research in Psychedelics Program for the Pacific Neuroscience Institute in Santa Monica, California.

Heinzerling told Psych Central the new findings are encouraging since depression can be so difficult to treat. “Although there’s a variety of medications, there are limitations,” he said.

Ketamine is not technically a psychedelic, but it has dissociative effects that can cause hallucinations, confusion, and euphoria.

While researchers do not yet fully understand how ketamine helps manage depression, Heinzerling said there are some biological explanations, such as how it affects brain chemicals involved in mood, like serotonin, norepinephrine, and the opioid and dopamine systems.

Heinzerling said that ketamine could also produce neuroplasticity and neurotrophic effects that may trigger brain and nerve growth and generate new neural pathways.

Heinzerling explained that intravenous ketamine is typically dosed based on an individual’s weight: 0.5 milligrams per kilogram as a starting dose, infused over 40 to 60 minutes.

“The nice part about that is you can turn it off, or turn it up or turn it down,” Heinzerling said.

The clinician can also determine the exact number of milligrams to administer and gauge the amount of time it will take for ketamine’s acute effects to kick in, which can happen in minutes.

These include:

  • increased blood pressure
  • elevated heart rate
  • moderate sedation

“It’s very reassuring from a safety standpoint,” Heinzerling said. “I like to know that the patient’s on track and the vital signs are fine.”

Ketamine can also be administered intramuscularly, producing a psychedelic effect at the immediate onset, compared to an equivalent dose given slowly by IV over an hour.

“[Intramuscular injections are] a steeper up and down,” Heinzerling explained. “The infusion is more of a gradual up and down.”

Heinzerling, who treats individuals at his clinic with ketamine-assisted psychotherapy (KAP), explained that absorption and bioavailability are reliable in both methods (Heinzerling administers intramuscular injections in his practice).

The new research examined intravenous ketamine therapy, which is a slow IV drip provided in a clinical setting.

The FDA has not yet approved intravenous or intramuscular ketamine therapies for depression. However, the FDA has approved a different form of ketamine therapy — intranasal esketamine — for people with treatment resistant depression.

But McInnes explained that intravenous and intramuscular therapies are widely used in psychiatry to treat depression as off-label treatments.

“Clinicians are legally allowed to prescribe treatments off-label, and in fact, clinicians across all medical specialties do this regularly in all types of care settings,” McInnes said.

“Ketamine infusion therapy is legal and available to anyone with depression who can afford to pay for it at this time,” McInnes added.

The observational study noted that depressive symptoms worsened in 8% of subjects, suggesting that in some cases, ketamine therapy could backfire.

“Some patients experienced increased depressive symptoms or increased suicidal ideation — or both,” McInnes said. “We cannot say what caused those or what specific experiences were associated with those phenomena. These are important avenues for future study that we will undertake.”

As with any psychoactive drug, ketamine has its risks.

“I worry most about cardiovascular effects that occur when you give the person the medication,” Heinzerling said. “Their blood pressure and their heart rate will increase pharmacologically.”

Other possible risks of ketamine therapy include:

  • headaches
  • nausea
  • throat spasms
  • difficulty breathing
  • urinary tract issues
  • addiction and substance misuse
  • anxiety and fear

“The biggest problem with the experience is if you’re not prepared for some of the effects and they come on, you think: Am I losing my mind?” Heinzerling said.

What is intravenous ketamine therapy?

Intravenous ketamine is administered in community clinics, like those observed in McInnes’ study. It may be prescribed in conjunction with other antidepressant medications.

Heinzerling said that in some cases, stricter procedures may pre-medicate individuals with Valium to help them remain calm during ketamine therapy.

What is ketamine-assisted psychotherapy?

The ketamine-assisted psychotherapy method, according to Heinzerling, is more integrated. He said the presence of a therapist while a person is under the influence can provide comfort and reassurance.

“Our clinic is set up more like a living room compared to an infusion center,” he said, adding that music and dim lights can help enhance treatments.

“We’re using the medication as a tool to augment, accelerate, or amplify the psychotherapy process,” he said.

What is intranasal ketamine therapy?

The FDA has approved Spravato (intranasal esketamine) for adults who have not benefited from other antidepressants, i.e., people with treatment resistant depression.

Spravato comes with a risk of sedation and dissociation, so a healthcare professional will monitor the person for at least 2 hours after they receive a dose of the medication.

While intravenous ketamine is traditionally the most studied method in clinical settings, Heinzerling expects more research on psychedelic-assisted therapy is on the horizon.

In future studies, McInnes said she plans to more closely explore the side effects of ketamine therapy, comorbid medical and psychiatric conditions, and dosing, among other factors.

As ketamine therapy goes mainstream, whether the medical or psychedelic-assisted model is more effective will ultimately depend on the individual.

The medical model is unlikely to produce powerful hallucinations, but Heinzerling said you don’t always need to have an emotional or spiritual experience for the treatment to be effective.

“I think there’s plenty of room for both,” he said. “I’m grateful to be in a position to work with these medicines and with the therapists that work with us — and for the people from Indigenous cultures who figured out that plants could do this for us.”