Prying open the third eye

Ketamine’s long, strange trip to becoming the next revolution in mental health medication

Ketamine’s use as a sort of end-of-the-line treatment for people suffering from treatment-resistant forms of depression (including PTSD, bipolar disorder, post-partum depression and, after some recent research, obsessive compulsive disorder) has been gaining notoriety in the U.S. for the past 17 years or so.

This summer, Cameron McArthur sat in a clinic in Denver, an infusion pump slowly introducing ketamine to his bloodstream. As the drug worked its way through his veins to his brain, Cameron experienced a sensation of unfurling, “like a time lapse video of a flower blossoming,” he says. As minutes passed, his eyes closed, geometric shapes formed with machine-like precision. They moved in a perfect symphony of motion, silently relaying information — about Cameron, about life — back and forth.

There was no fear, only a sense of openness Cameron had never known.

The 43-year-old is fairly reserved until he’s asked to describe his first ketamine treatment, and then it’s as though by simply talking about the experience he’s expanding again, a flower in bloom.

Before his treatment earlier this year, years of depression and anxiety from post-traumatic stress disorder (PTSD) had slowly consumed Cameron. Nothing lifted the fog; no medicine, no exercise, no amount of meditation allowed light to pierce the darkness.

So his therapist suggested ketamine infusions.

“All of this stuff that you knew was there and that you didn’t know was there presents itself simultaneously,” Cameron says. “I don’t care if it was something trivial like getting new tires on the car next week or the deepest level of pain and confusion that brought you there, it’s addressed in a way that’s the equivalent…” He pauses.

“I would say it’s like you are interacting with a higher intelligence.”

Like prying open the third eye?

“Exactly,” he says. “It’s a universal consciousness that you’re connecting to, but at the same time it’s intimately personal.”

He knows how this might sound, but he doesn’t care.

“It was… profound.”

Ketamine’s use as a sort of end-of-the-line treatment for people suffering from treatment-resistant forms of depression (including PTSD, bipolar disorder, post-partum depression and, after some recent research, obsessive compulsive disorder) has been gaining notoriety in the U.S. for the past 17 years or so. Treatment centers have popped up from coast to coast, including here on the Front Range. When patients have found no relief using everything else modern medicine has to offer, mental health professionals are beginning to point them toward ketamine.

It’s not a new drug by any means. With some help from a pharmaceutical consultant, a chemistry professor at Wayne State University in Michigan first synthesized ketamine in 1962. It quickly proved to be a better alternative to PCP (yes, angel dust) as a dissociative anesthetic, and in 1970 the Food and Drug Administration (FDA) approved it for medical use. It was soon used to anesthetize wounded soldiers during the Vietnam War, and became a go-to drug in operating rooms across the country.

It didn’t take long for psychonaunts to discover ketamine and incorporate it into America’s growing psychedelic drug culture. As a dissociative drug, ketamine distorts perceptions of sight and sound and creates a sense of being detached from the body and its surroundings. At high doses the effects become aggressive, leaving the user immobilized, confused and susceptible to amnesia.

In the 1990s, ketamine found its way to the rave scene, where it became known as Special K. Despite its decades-old, government-approved use as a human anesthetic, rumors ran rampant that ketamine was a horse or cat tranquilizer. Ask a few people on Pearl Street Mall about ketamine and chances are someone will bring up horses.

In 2000, a research group led by Robert M. Berman of Columbia University blazed a new path for ketamine. They conducted the first placebo-controlled, double-blind trial to measure ketamine’s ability to improve symptoms of depression. The test was small, just seven subjects hooked up to either an IV of low-dose ketamine (far lower than use for anesthesia) or saline solution, but the results were compelling.

“Subjects with depression evidenced significant improvement in depressive symptoms within 72 hours after ketamine but not the placebo infusion,” the team wrote.

A team led in 2006 by Carlos Zarate of the National Institute of Mental Health was able to replicate Berman’s work.

The takeaway here is that relief in three days is significantly faster than the four to six weeks it takes to see improvement from the current gold standard treatments in depression, those well-known and well-worn SSRIs (selective serotonin reuptake inhibitors) and MAOIs (monoamine oxidase inhibitors). When someone is experiencing suicidal thoughts, the difference between a few days and a couple of weeks becomes even more significant. 

“I would actually argue that we know more about ketamine than we do about SSRIs,” says Steven Levine, founder of Actify Neurotherapies (formerly Ketamine Treatment Centers), a network of clinics around the U.S., including the center in Denver where Cameron McArthur received his treatment. “We actually have no idea about how SSRIs work. We don’t have a clue. The party line about chemical imbalance and SSRIs restoring that balance of neurotransmitters is — pardon my language — bullshit. Everybody in the field who knows better knows that.”

More diplomatically, a lot of what we think we know about antidepressants is speculative. Despite years of use and years of study, scientists still don’t know if low levels of neurotransmitters like serotonin cause depression, or if raising those levels resolves it. To Levine’s point, we simply don’t know enough about brain chemistry to say what’s balanced or unbalanced. 

Here’s what we do know about the brain: up until a couple of decades ago it was believed that the human brain only developed new neurons — those nerve cells that carry messages throughout the body — to a point in our early 20s and after that we only lost them. Now we know our brains make neurons throughout our lifespan (a phenomenon called neural plasticity), albeit slower than it did before our 20s.

We now know that depression is a neurodegenerative condition. If left untreated, depression can lessen the number and quality of neurons, but with treatment the connections can be repaired. Part of what drives the repair of neural connections is a group of proteins called neurotropic factors. One of the main proteins is BDNF, or brain derived neurotropic factor. Things like exercise and SSRIs increase BDNF, as does ketamine, only much faster.

We also know that there are multiple neurotransmitters in the brain and body. People are most familiar with serotonin, dopamine and norepinephrine, but glutamate is the most abundant. Recent research has shown that depressed people with systemic inflammation have high levels of glutamate in regions of the brain that affect motivation. Big Pharma is currently fixated on ketamine’s ability to target glutamate and lessen its production.

And finally we know that ketamine activates a pathway called the mammalian target of rapamycin, which produces those neuron-building proteins like BDNF.

“In the case of ketamine, all of this happens very quickly, within hours,” Levine says. “It has this really beneficial effect on the plasticity of the synapses, the spaces between cells where information is transmitted.”

Even before we knew all of that, Berman’s work in 2000 set the stage for ketamine’s use as an antidepressant and gave physicians a set of guidelines — like how many milligrams of ketamine to deliver intravenously per kilogram of body weight over what period of time — that are still standard practice today.

But “standard” is a thorny word to use when talking about ketamine treatment. For starters, doctors administering ketamine for depression are engaging in off-label use of the drug. Sounds shady, but it’s not. In the FDA’s words, once the Administration approves a drug for a specific use — anesthesia in the case of ketamine — “healthcare providers generally may prescribe the drug for an unapproved use when they judge that it is medically appropriate for their patient.”

Why? Because “you may have tried all approved treatments without seeing any benefits.”

Ultimately, humans are one organism made of many systems, and so a medicine used in, say, cardiology, is going to have some effects on other systems, and so it can potentially be leveraged therapeutically for other systems.

While the FDA lays out guidelines for how to deliver a drug for best results for its approved purpose, they don’t provide guidance for delivery in off-label uses.

This is where some questions arise about ketamine’s use for depression.

Ketamine can be delivered in four ways: intravenously, intramuscularly, intranasally and sublingually. 

“The biggest difference among them is what is most bioavailable, what’s most absorbed,” explains Levine.

“Intravenous is 100 percent bioavailable. Intramuscular is about 90 percent. With nasal and oral there is tremendous variability, and that can be within one person over time and certainly from person to person. Those are more difficult to control and difficult to know how much medicine people are getting.”

Actify Neurotherapies s only administer intravenous ketamine. But other physicians, like psychiatrist William Van Derveer of the Integrative Psychiatric Healing Center of Boulder, sees marked improvement in his patients via intramuscular shots of ketamine.

“There are definitely differences [between methods of delivery,]” he says. “I think there are settings and situations and people where one would be better than the other. I have seen people do really well on intranasal ketamine but also seen people not get any benefit at all. So far I’m not ready to say this is better or this is worse, it’s just a different tool for a different situation.”

Van Derveer has been involved in a long-term study of another pyschotropic drug, MDMA, and its use in psychotherapy for PTSD, which Boulder Weekly covered in March of this year. (The rave scene also commandeered MDMA, but the drug used in Van Derveer’s research is free of adulterants, unlike “molly” or “ecstasy.”) Part of the protocol for the MDMA research involved more than a dozen non-MDMA sessions — just regular talk therapy.

“I think if I gave somebody MDMA without psychotherapy it would maybe make them feel better for a few hours or a day, maybe, but I don’t think it would last like the results that we saw,” he says.

He sees the same necessity in ketamine-assisted treatment.

“When it goes well that’s what you see — people being able to access things that they really wouldn’t touch in ordinary states of consciousness. Disassociation from the body, which is regarded as a side effect, is a way of being able to see that their mind doesn’t have to be dominated by the physical inputs from their body.

“For example, in PTSD you oftentimes have a huge body component to it, where there’s a lot of tension, fear, fight or flight chemicals going on. So the ketamine can help for a brief period of time, help people disconnect and gain a different perspective, but you have to do integration work to make that real in your life.”

Van Derveer’s clinic is currently looking to set up intravenous ketamine delivery in the near future, and they have partnered with other clinics to collect informal data about how ketamine affects their patients.

Which brings us to another problem with ketamine: the limited size of research trials thus far.

“We only have what we call phase II studies on ketamine,” Van Derveer says. “So we’ve got double-blind, randomized controlled trials, which is good, but small, on the order of 20 to 30 participants. If someone wants to take a drug to the market to get FDA indication [for a specific use], they have to go through phase III trials, which require hundreds of participants. So a multi-center, phase III, randomized trial is the gold standard for establishing FDA approval. That never happened for ketamine with depression because 2001 (at the time of Berman’s research) was I think 35 years after it came to the market as an anesthetic. It was way off patent by that time, so nobody stands to gain the profit that you would get from getting FDA indication.”

However, in what comes as no surprise to anyone in America, Big Pharma is finding a way to take ketamine all the way to the bank. Janssen, the pharmaceutical arm of Johnson and Johnson, is moving into phase III trials with a nasal spray spin-off of ketamine called esketamine.

Van Derveer uses SSRIs Celexa and Lexapro as examples.

“Celexa is what in organic chemistry they call a racemic mixture,” he says. “So if you take the molecule and put it in front of a mirror you see the mirror image looking back at you. One is called the left-handed and one is the right-handed molecule. Celexa is 50 percent right-handed and 50 percent left-handed. Lexapro is only the left-handed version of Celexa.

“I don’t know why you are allowed to make a profit and bring another patent to market when you’ve already shown the previous drug, which was just a mixture of the left- and right-handed molecules, was effective, why you get another turn to, if you ask me, profiteer off of people,” he says. “The only difference is that you took off the right-handed part and you’re calling it a new drug and put a new name on it. That what’s happening with ketamine. The ketamine that I use, that all people use, is 50 percent left- and right-handed and esketamine is a left-handed version of ketamine.”

He laughs from frustration.

“It’s great because you can make a ton of money doing it.”

Even at that, Van Derveer and Levine hope that more regulation will come as the FDA begins to consider ketamine’s potential to combat depression. Not so much regulation that ketamine becomes difficult to access for the millions of people who might benefit from it, but enough to keep people from being able to take ketamine out of the clinical setting and into their homes — which is a distinct possibility with Janssen’s nasal spray in the pipeline.

While ketamine isn’t addictive in the same way opioids are, dependence can still arise. Excessive prolonged use of ketamine can damage the bladder. Rampant non-medical use in the U.K. and Asia has led to surges in bladder removal. Early ketamine researcher Marcia Moorse, who explored self-injection in the ’70s, wandered into a field in a ketamine-induced stupor and froze to death.

It’s a fine line to walk between accessibility and safety, as the opioid epidemic has shown us.

Ketamine treatments are currently fairly pricey, between $300 and $400 per session on average, but some clinics will charge $700 or more. Most insurance companies don’t currently cover ketamine treatment, but Levine has been working to change that. He’s had meetings with the Center for Medicare and Medicaid Services as well as officials at the Deptartment of Veteran’s Affairs. Kaiser Permanente, which has a large presence in Colorado, already provides coverage for ketamine treatment to members at eight locations in Northern California. This might be a first step in getting other branches of Kaiser to follow suit.

Ketamine isn’t the panacea of mental health treatment, but it’s the first real breakthrough the field’s had in years.

And while the experience is mildly hallucinogenic — there’s no way around describing it as such — that’s not really how Cameron McArthur sees it.

“Anyone who undergoes this treatment, it is not a physical sensation that will last for a long period of time. This is an emotional journey. A month out you’re going to have realizations from your treatment from when you breached the veil. There is another side,” he says. “Six months down the road you’re going to have more realizations than you had when you were underneath the ketamine.

“The devil is in the details. It’s nuanced, massive… profound.”

Editor’s note: This article originally referred to Actify Neurotherapies as Ketamine Treatment Centers. This is a misnomer as the network is changing their name. Also, Steven Levine is the founder of Actify, not the cofounder. We apologize for any inconvenience. 

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