Ketamine, Psilocybin, and Depression: Hope For Those Running Out of It

Illicit drugs elicit relief for treatment resistant depression.

This article is part of a Wise & Well Special Report: The United States of Depression.

I have witnessed many patients undergoing electroconvulsive therapy, or “ECT,” for treatment-resistant depression. Notwithstanding Jack Nicholson’s portrayal of Randle McMurphy’s ECT treatment in One Flew Over the Cuckoo’s Nest, a modern ECT treatment — performed under anesthesia — is as undramatic an event as one can imagine.

ECT remains the gold standard for treating depression in patients who have not responded adequately to other forms of treatment, and response rates in this group of patients are at least 40%, possibly higher.

But what about the remaining 50–60% of people suffering from depression that simply won’t budge no matter what treatment they try? Or what if someone has failed conventional antidepressant therapy and is concerned about the side effects of ECT?

New treatment options for treatment-resistant depression are quickly emerging, the most promising of which are ketamine and psilocybin.

Ketamine

Ketamine is widely used for sedation during brief medical procedures. But it wasn’t until the year 2000 when researchers led by John Krystal, MD, professor of psychiatry at Yale School of Medicine, connected the dots between several lines of research and published the first clinical trial demonstrating the effectiveness of ketamine in treating depression.

Years later, his colleague Ronald Duman, MD, said in a statement, “The rapid therapeutic response of ketamine in treatment-resistant patients is the biggest breakthrough in depression research in a half-century.”

(Presumably, the breakthrough a half-century earlier he had in mind was the establishment of ECT under anesthesia as a treatment for depression.)

Since then, multiple studies have confirmed the therapeutic effects of ketamine for some patients with depression. The most recent of these trials, led by Colleen Loo, MD, professor of psychiatry at the University of New South Wales, was published in July of this year.

Loo’s study was unique in a couple of ways. First, it analyzed a subcutaneous injection of ketamine — similar to the insulin shots individuals with diabetes give themselves. This method of administration is much more convenient than the intravenous infusion used in prior studies. (There is also a nasal spray under investigation in separate research.)

Secondly, Loo’s study included patients who had failed to respond to ECT. Patients with this especially resistant form of depression have typically been excluded from prior studies.

“Most studies exclude people who have had ECT because it is very hard for a new treatment to work where ECT has not,” Loo said in a statement.“We found that in this trial, ketamine was clearly better than the placebo — with 20% reporting they no longer had clinical depression compared with only 2% in the placebo group. This is a huge and very obvious difference and brings definitive evidence to the field.”

An additional 10% of patients receiving ketamine experienced a significant decrease in their depressive symptoms while not meeting the threshold for “remission.”

Another study published just weeks earlier demonstrated that intravenous ketamine may be even more effective, with 55% of patients responding to ketamine. However, these studies were not identical in implementation, and the two methods of administration have not yet been compared directly.

It is important to emphasize, though, that one of the major lessons from these studies is that neither ketamine nor ECT work for everyone, and what works for one person does not necessarily work for another.

So patients should discuss their options with their doctors to determine what treatment modality might be best for them.

A major concern with ketamine is that it is unclear how long a positive response lasts.

“Our study deliberately followed people up for another four weeks after the end of the four-week treatment course, to see how well the benefits lasted in those who improved with ketamine,” Loo told me. “Up to now, there has been minimal published data on how long people stay well after treatment has ceased. Study results show that some maintained their improvement, but for the majority, the depression tends to gradually return after treatment is ceased.”

But, she also told me that repeated dosing of ketamine can sustain the beneficial effects of the treatment. So while not a cure, prolonged response with maintenance doses is possible.

But if neither ketamine nor ECT work, are there other options? Indeed there are, and one option experiencing a resurgence is psilocybin.

Psilocybin

Chryss Cada was ahead of the curve. The Colorado-based writer and journalist has been using psilocybin-containing mushrooms (both small daily “microdoses,” and a couple full-send “macrodoses”) to treat her anxiety for the last couple of years. A brave ambassador for the benefits of the practice, she wrote about her experiences before hallucinogenic mushrooms were legalized in Colorado.

She admitted to me that talking about it now is a bit less nerve-wracking after the passage of Colorado’s Proposition 122 (passed in November of 2022) decriminalizing possession and use of the fungi.

I asked her what microdosing felt like.

“You are supposed to take such a small amount that you don’t even feel it,” she said. “But you will catch yourself not feeling anxious. Like, ‘Oh wow! I can handle this.’”

As opposed to a quick and temporary fix like a glass of wine or a Xanax, Cada describes microdosing as bringing a long-lasting change of perspective.

“It sort of builds up over time,” she said. “You remember what it feels like to not be anxious, to not be depressed. In the long term, you have this reminder in your head. You remember what it feels like to not react a certain way, and think, ‘Maybe I could react differently this time.’”

Hallucinogenic mushrooms have been used in religious rituals for thousands of years. One of the common active ingredients — psilocybin — was first identified in the 1960s. Soon after, considerable research was conducted into the effects of psilocybin on the brain.

But by the 1970s, widespread recreational use of psilocybin and other hallucinogenic drugs had led to strict limitations on access to the compound, making research on the compound difficult.

By the 1990s, however, interest in the potential medical uses of psilocybin was rekindled, and government agencies began taking steps to lower the barriers to entry for research — including clinical trials — related to psilocybin and mental illness.

Psilocybin has now been legalized (for use under specific circumstances) in Colorado, Oregon, and some parts of Washington, California, Michigan, and Massachusetts. Meanwhile, the drug remains classified as a Schedule I drug by the federal government in the US, making possession and use illegal under federal law. It is important to note that in localities like Colorado and Oregon where state or local laws permit use of psilocybin, federal agents can still enforce the federal prohibition. Whether that is likely to happen to any given individual is another question.

And while I am a doctor, I am most certainly not a lawyer, so that is a question I will not even attempt to answer. However, it is notable that what used to be an underground network of mental health professionals facilitating use of psilocybin is becoming increasingly overground.

Macrodoses

Medical research into the benefits of psilocybin has enjoyed a resurgence over the past decade. The US Federal Drug Administration is fast-tracking some clinical trials related to depression and psilocybin, and taking other steps to facilitate additional research moving forward.

While the experiences like those related by Cada are compelling, research into the benefits of microdosing for mental health conditions is still in its early days. The evidence related to macrodoses is quickly becoming more clear.

Just in the last couple of weeks, the largest psilocybin clinical trial to date was published. The study, led by Charles Raison, MD, director of clinical and translational research, demonstrated that more than 40% of patients showed sustained (40-day) response to a single macrodose of psilocybin.

“The data suggest a benefit which is truly encouraging,” Raison said in a statement. “It could provide hope for those who have not responded to other treatments, and it could also present a viable option for individuals seeking to avoid long-term treatment with standard antidepressants.”

Is the trip the destination?

Research is emerging looking into how to get the benefits of psilocybin without the hallucinations. Strategies include chemically modifying the drug to eliminate the hallucinations, or administering the medication under anesthesia.

But I can’t help but wonder if it is really possible to arrive at the mental health destination without the trip.

Michael Pollan, best-selling author of multiple books on the role of food in our lives and culture, turned his attention to psychedelics in his 2018 book How To Change Your Mind. Ever the committed researcher, he tried magic mushrooms himself under the watchful eyes of two guides.

“I found myself in this place where I could no longer control my perceptions at all,” he said while discussing the experience with Fresh Air’s Terry Gross. “I felt my sense of self scattered to the wind, almost as if a pile of Post-its had been released to the wind, but I was fine with it…And what I brought back from that experience was that I’m not identical to my ego, that there is another ground on which to plant our feet.”

Cada agrees. While microdosing has been a huge help with her anxiety, it was a full fledged trip that brought her closure on the death of her brother 41 years prior. “That’s what a large dose of mushrooms brought me once again,” she wrote in her 2022 article. “Seeing my brother’s face. Kinetic with the little lines at the corner of his mouth pushing out a fold against his high cheekbones as he smiles. Mark is OK, he is at peace. So now, at last, I can be too.”

I asked what she thought about efforts to eliminate the hallucinogenic experiences that accompany psilocybin use.

“The power of this medicine is to bring up trauma and past pain that has been stored up in your brain and bring a little comfort along the way,” she said. “The medicine will put you back into that place, what it felt like. That is obviously really uncomfortable and painful. The hallucinogenic qualities help you swallow that bitter pill.”

Research will ultimately answer the question, but for now I find it hard to believe that hallucination is just a side effect of psilocybin. When I hear people like Pollan and Cada talk about their experiences, the hallucinations sound like at least part of the cure.

Moving forward

While the developments in new treatment options for individuals with treatment-resistant depression is encouraging, it is apparent there is still no magic pill that will work for everyone.

Is there anything else on the horizon of depression treatment?

“It is a rapidly developing field and we have had several important developments in new treatment approaches for treatment-resistant depression in recent years,” Loo told me.

“These include improvements in treatment approaches for transcranial magnetic stimulation, ECT, other new brain stimulation treatments (e.g. transcranial direct current stimulation) and we are still looking at optimizing the way we give ketamine treatment. There are other new technologies in the research pipeline, e.g. using ultrasound-based brain stimulation approaches.”

Reflecting on her experiences with psilocybin, Cada concluded our conversation saying, “This has just been such a gift and I am so grateful that it is available.” Researchers like Loo, Raison, and many others continue to work to make available an ever wider spectrum of therapies for those suffering under the weight of depression.

This article is part of a Wise & Well Special Report: The United States of Depression. If you or a loved one is depressed, it’s vital to talk about it. Because depression increases the risk of suicide, consider calling the confidential National Suicide Prevention Lifeline at 1–800–273-TALK (8255) for English, 1–888–628–9454 for Spanish, or call or text 988. Global support in 44 languages is available from Befrienders Worldwide.

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