On a Monday afternoon in March 2019, 62-year-old Bob Hyne settles into a recliner, his Timberland boots propped up. Sunlight pours in from the window next to him, which overlooks Main Street in the village of Port Jefferson. He watches an IV line deliver ketamine straight into his bloodstream. For years he unsuccessfully sought treatment for chronic depression — he finally found it here, with this drug, nicknamed “Special K” by partiers who recreationally revel in its euphoric effects.
Hyne and others like him are proving what clinicians have suspected for decades: that psychotropic partying drugs, sometimes viewed as dangerous when abused, are actually quite effective in treating mental health conditions in a clinical setting under the care of health professionals. Drugs such as ecstasy and psilocybin, the active ingredient in what is most commonly known as “magic mushrooms,” are also now seen as effective in treating other conditions like post-traumatic stress disorder and anxiety. Their medicinal virtues are helping to reverse 50 years of federal criminalization, which is promising for millions of people like Hyne. The FDA also clearly favors broadening the use of these drugs, as evidenced by its recent approval of a nasal spray version of ketamine in March of 2019.
All sorts of antidepressant drugs failed to help Hyne’s battle with chronic depression, which grew worse with the death of his wife. After consulting with psychiatrists, his family doctor eventually suggested ketamine infusions.
“It takes all your problems away,” Hyne said, at one of several clinics that have opened on Long Island to use Special K for treatment. “It kind of puts your brain back in perspective — it reconnects you to where you were prior to being in this position. You feel good.”
Hyne is among nearly 4 million Americans treated for depression annually who fail to respond to available medications. According to the National Institute of Mental Health, roughly 17 million people in the U.S. suffer from some kind of depression. Nearly 20 different antidepressant medications and several well-established forms of talk therapy effectively treat most of them. But those who try these methods and find no relief have to walk away from treatment, still depressed. Too many commit suicide.
Drug makers have been trying to find a way forward for these patients, in an attempt to curb growing national suicide rates. Most states, including New York, have seen a roughly 30% increase in suicides since 1999, according to a June 2018 report by the Centers for Disease Control and Prevention.
Administering infusions of ketamine for people like Hyne are part of the daily duties at Dr. Rena Ferguson’s posh and modern Port Jefferson office. The infusions are pricey — at Ferguson’s office, they cost $600 each, and aren’t covered by insurance. This is because depression treatment is an unapproved use for ketamine by the FDA, but doctors can still prescribe it “off-label.” This is when the drug is prescribed for a purpose unspecified in the FDA’s approved packaging label, a practice that is legal and common. Ketamine is FDA-approved as an anesthetic, but to approve it for depression, like any drug, the FDA needs evidence that it works, and is unharmful. The FDA gets that evidence from clinical trials and studies that can cost millions of dollars, involving hundreds or thousands of people. But because ketamine is a generic drug, pharmaceutical companies are unable to patent it and earn their money back, meaning they have little interest in investing in these trials, or investing in ketamine for depression.
But new hope for people like Hyne emerged when the FDA approved the nasal spray in 2019. Janssen Pharmaceuticals Inc., a branch of Johnson & Johnson, found a way around the generic-drug dilemma by making a slight variation to the ketamine molecule and devising a new delivery system — the nasal spray. This made the drug patentable and, with FDA approval, eligible for insurance coverage. The intent is for it to reach more people and help reduce rising suicide rates.
“You needed a little bit of research, you needed a drug company that was interested in investing, and on top of that, the issue of suicidality becoming more in the social mainstream,” said Dr. Edward Rubin, who offers ketamine infusions at his Infusion Therapy Center in Garden City. “It’s all kind of pushing to get [ketamine] as a treatment for more people.”
The spray, called esketamine, was put on the FDA’s fast-track to approval, and was given the designation of a “breakthrough therapy.” The track and the designation give new drugs, which treat serious and life-threatening conditions such as treatment-resistant depression, expedited review based on need, according to the FDA.
“[The data] was hard to ignore, when people were getting better so quickly,” Ferguson said of the ketamine studies that led to the fast track and “breakthrough therapy” designations. The National Institute of Mental Health reports that depression is responsible for up to 70% of psychiatric hospitalizations and about 40% of suicides, underscoring the need for effective treatments like esketamine.
Like ketamine infusions, the nasal spray is no small fee either — the cost for a one-month course of treatment will be between $4,720 and $6,785, according to Janssen. But now, after approval, it will likely be covered under many insurance plans.
Today, over 150 clinics in the U.S. provide ketamine infusion treatments and are listed in the American Society of Ketamine Physicians directory. Long Island is home to at least four others along with Ferguson’s; one in Hewlett, Medford, and two others in Garden City. Some are run by anesthesiologists like Rubin, who can legally administer the infusions off-label for depression, usually after patients are referred to them by their doctor.
“I knew that even though I had other ways of treating depression, they weren’t working,” said Ferguson, whose niche is caring for patients with treatment-resistant depression. “As ketamine came along, I told my patients I was going to be doing this ketamine thing… and at first, they said, ‘Isn’t that an animal tranquilizer?’ It’s taken a lot for people to wrap their heads around the idea.”
Ferguson’s patients were almost right; the history of ketamine has a place in animal treatments. It’s used as an anesthetic in veterinary and some human surgeries. That’s where Special K’s beginning lies, along with the synthesis of phencyclidine, better known as PCP. In the 1950s, PCP was as a general anesthetic for humans, and then used in veterinary medicine as a tranquilizer, according to the Center for Substance Abuse Research. Ketamine, an analog of PCP with a structure at one-tenth the potency, was created in 1962, and approved by the FDA in 1971 as a general anesthesia, used to put patients to sleep for surgery. But the drug’s out-of-body and hallucinogenic sensations led to its abuse during the late 1960s and early 1970s, when it came to be known as Special K. By 1999, the U.S. Drug Enforcement Administration listed it as a Schedule III drug, classified as those that can lead to abuse or addiction, but are less dangerous than drugs in Schedules I and II. Evidence that this drug helped with depression was finally tested in the late 1990s, and in 2000, a study by Dr. Dennis Charney and his team was published in the journal Biological Psychiatry that showed seven subjects with major depression showed significant improvement in depressive symptoms within 72 hours after receiving ketamine, but not placebo infusion.
“[Ketamine] is better than all these pills that psychologists and psychiatrists would keep pushing on you,” said Hyne, a soft-spoken man who was a union truck driver for Long Island newspaper Newsday for 33 years, before leaving with a back injury. “They take so long to affect you, and they didn’t really affect me at all. I really just thought they were worthless. I feel this almost immediately.”
Ketamine’s quick effect caught the attention of the psychiatric field, but more still needs to be understood about it, said Dr. Lucian Manu, clinical assistant professor of psychiatry and director of neuromodulation at Stony Brook School of Medicine. Manu was the principal investigator of Janssen’s trial of esketamine at Stony Brook University Hospital, which began in 2017 and ended in early 2019.
“It’s complicated and it’s still not fully elucidated yet,” Manu said. “We don’t 100% know how ketamine works. Just [in August] of 2018, there was a blockbuster piece of information that revealed the mechanism of action may not be what we thought — this was very intriguing.”
Manu is referring to a Stanford study published in The American Journal of Psychiatry in August that showed that ketamine’s antidepressant effects require activation of opioid receptors in the brain. The finding overturns previously held beliefs that the drug’s antidepressant effects are caused by its impact on the glutamate system. Glutamate is a powerful action-firing neurotransmitter, like dopamine or norepinephrine, that is released by nerve cells in the brain. It is responsible for sending signals between nerve cells, and under normal conditions, it plays an important role in learning and memory.
The researchers of the study said in a press release published in Stanford Medicine the findings may explain why ketamine works so quickly as an antidepressant. It activates the brain’s opioid receptors during its first phase of activity, then the glutamate system may maintain the effects after ketamine is metabolized. Revealing how the opioid system plays a role is critical in the effort to develop new antidepressant drugs, the authors said, as it could help reshape how they are developed and administered in order to try and reduce the risk of related opioid dependence.
“Psychiatry used opioids, barbiturates and high doses of stimulants to treat depression 50 or 60 years ago,” Alan Schatzberg, M.D., a leading psychiatry professor at Stanford, said in the release. “We have to properly examine the risks associated with using drugs of abuse — even in low doses — to treat depression. It’s not limited to ketamine; other antidepressant drugs that target the opioid system are in development now, too.”
Currently, SPRAVATO, Jannsen’s brand name of esketamine, is only available through a restricted program called the SPRAVATO Risk Evaluation and Mitigation Strategy Program. It can be administered at certified healthcare clinics and to patients enrolled in the program, because of the risks for sedation, dissociation and abuse and misuse, according to the medication’s guidelines. Data will be entered into the FDA’s Approved Risk Evaluation and Mitigation Strategies registry, meant to further define the risks of the drug and support safe use, according to the FDA. Infusions of ketamine lack similar controls because of its status as an “off-label” treatment for depression.
Dr. Rubin is board certified in anesthesiology and pain medicine and offers ketamine infusions at his Infusion Therapy Center in Garden City for mental health issues. Rubin, who only provides the infusions if the patients’ psychiatrists are on board, said that he feels resistance from the psychiatric community toward anesthesiologists providing ketamine treatments, and the drug in general.
“The feeling I’m getting is that a lot of psychiatrists don’t see this yet as a legitimate treatment modality,” Rubin said. “They kind of roll their eyes at you. The intent is for us as the anesthesiologist to provide the service, but for the psychiatrist or psychologist to keep treating the patient. We’re not trying to take people away from their psychiatrists, but I wish more of them would be open-minded to letting their patients try it..”
Because of its similarities to ketamine, the nasal spray has the potential for abuse. Both drugs can induce psychotic episodes in people who are at high risk for them and can cause sedation and out-of-body experiences in high doses. Psychiatrists like Manu believe that restricting the use of this drug to in-office visits makes it safer for at-risk patients because they will receive closer monitoring and care from a mental health professional.
Researchers have also been working with other recreational drugs of the past to explore treating mental health disorders. In 2016, a paper published in the Journal of Psychopharmacology showed that the “magic mushroom” drug psilocybin produced substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer. The drug known by the street name ecstasy or Molly could also be a promising treatment for post-traumatic stress disorder, a 2018 study published in the British journal The Lancet Psychiatry showed. The study found that after two sessions of psychotherapy with the party drug officially known as MDMA, a majority of 26 combat veterans and first responders with chronic PTSD who failed to be helped by traditional methods saw dramatic decreases in symptoms.
“I think society is coming around a little bit in looking at these other drugs and not inherently labeling them as good or bad, based on how they were used 40 years ago,” Rubin said. “If you go back even 20 years, oxycodone was good, and marijuana was bad. Today, it’s the exact opposite. These drugs are not inherently good or bad things, it’s how people are using them or misusing them.”
Ferguson said she was very open to the possibility of using other psychoactive drugs in her practice.
“I do think there are so many untapped things there,” she said. “For me, I’m very interested in all of these psychogenics. I think they have value.”
On his success with ketamine infusions so far, Hyne said: “Hopefully it’s going to last forever. And they say you can come back for more sessions, but I’m going to see how this plays out.”