A new study shows that weekly ketamine infusions are associated with continued and maintained reductions in depressive symptoms among patients with treatment-resistant depression.
The findings, which are considered novel among studies assessing ketamine administration for patients with treatment-resistant depression, evidence the promising role the controversial drug could play in psychiatric care.
A team of investigators, led by Jennifer L. Phillips, PhD, an associate scientist in the Mood Disorders Research Unit at The Royal’s Institute of Mental Health Research, conducted a randomized, double-blind crossover comparison of single ketamine infusion versus active placebo control midazolam. The assessment, held with 41 participants with treatment-resistant depression at single treatment center, observed patients receive 6 open-label ketamine infusions 3 times per week over 2 once patients had a relapse of depressive symptoms.
Patients who reported a decrease of at least 50% in the Montgomery-Åsberg Depression Rating Scale (MADRS) received another 4 additional infusions once weekly in a maintenance phase.
Those administered a single ketamine infusion reported significantly reduced depressive symptoms at the primary efficacy endpoint of 24 hours post-care versus those treated with midazolam. The therapy showed cumulative antidepressant effects over repeated infusions, as well a doubling of antidepressant response rate in patients, according to linear mixed models.
Investigators found that 59% of patients met the response criteria following repeated infusions, with 3 infusions serving as the median dosage required to reach achieved response. In patients receiving weekly maintenance infusions, no further improvement in MADRS scores were reported.
The first-of-its-kind findings come just 1 month following the US Food and Drug Administration (FDA) approval of esketamine nasal spray (Spravato) for the treatment of patients with treatment-resistant depression. At the time, the therapy made history as the first novel treatment indicated for depression in 30 years—and headlines as one of the first hallucinogenic drugs to reach indication for a common condition.
Dennis Charney, MD, Dean of Icahn School of Medicine at Mount Sinai and a member of the Yale University team that led pioneering antidepressant ketamine trials in the 1990s, told MD Magazine®that microdosing or implementing controversial therapies for psychiatric care require what any other trial requires: control, safety, and a carefully-assessed standard for efficacy.
“No matter what treatment is being assessed, you have to follow those scientific approaches,” Charney said. “For conditions that don’t have effective treatments available, there should be an open mind.”
For the majority of individuals that benefit from it, it will be essentially buying them time for other treatments—be them pharmacotherapies or device-based treatment, or psychotherapies, because those are beginning to work much more slower than ketamine does,” he said.
Whatever its marketed use entails, Phillips and colleagues concluded positively that ketamine showed both initial and repeated benefits for antidepressant effects as a once-weekly infusion.
“These findings provide novel data on efficacious administration strategies for ketamine in patients with treatment-resistant depression,” they wrote. “Future studies should further expand on optimizing administration to better translate the use of ketamine into clinical settings.”
On Tuesday (March 5), the U.S. Food and Drug Administration (FDA) approved a ketamine-like nasal spray for patients with depression who haven’t responded to other treatments.
But what makes this newly approved treatment so different?
The drug, called Spravato and made by Janssen Pharmaceuticals, contains the active ingredient esketamine. This substance has the same molecular formula as ketamine but a different chemical structure. (In other words, it contains the same type and number of elements but in a different configuration.) Ketamine is typically used as an anesthetic, but it’s also been used as an illicit party drug.
One reason experts are excited about the nasal spray is that its effects can be seen within several hours to days. Other antidepressants, meanwhile, can take weeks to start working
Antidepressants work by regrowing brain cells and the connections between them, and ketamine appears to have the same effects, said David Olson, an assistant professor of chemistry, biochemistry and molecular medicine at the University of California, Davis. But, these effects likely start much sooner than with other antidepressants, he said.
Still, it’s not entirely clear how the drug works.
Ketamine-like drugs are “dirty”, meaning they likely hit a variety of targets in the brain, Olson told Live Science. “There are a lot of very interesting hypotheses out there, [and] many of them are probably partially valid.”
One idea is that ketamine treats depression by blocking a neurotransmitter called glutamate from binding to the NMDA receptor, and stopping signals from cascading across the brain, Dr. Alan Schatzberg, a professor of psychiatry and behavioral sciences at the Stanford University School of Medicine, told Live Science.
Glutamate is a chemical that brain cells use to send signals to other brain cells. But high levels of it can cause over-excitement in the brain, which can, in turn, damage brain cells.
A more controversial idea is that ketamine binds to opioid receptors, causing a release of naturally occurring opioids in the body. Schatzberg and his team published a small study on this last summer in which they gave patients with depression ketamine twice — once after receiving an opioid-blocking drug, and once after receiving a placebo in place of the opioid blocker. The two treatments took place about a month apart, and neither the participants nor the researchers knew whether patients received the opioid blocker or the placebo. The study found that the patients responded well to the ketamine treatment if they didn’t receive the opioid-blocking drug, but ketamine had no effect on those that did, suggesting an opioid-like role.
“My concern about this compound is that it is a disguised form of opiates,” said Dr. Mark George, a distinguished professor of psychiatry, radiology and neurosciences at the Medical University of South Carolina. While George said he is “overjoyed” for the prospect of a new treatment option, “I’m alarmed that there is pretty clear evidence [that] the way ketamine works is through the opioid system.”
If this is the mechanism that ketamine acts through to treat depression, its effects won’t last and people might develop a tolerance to the drug, possibly even becoming addicted, George told Live Science. But if its antidepressant effects come from other mechanisms, such as blocking the NMDA receptor, then “that’s good,” he said.
Olson, however, said that he is less convinced by the opioid hypothesis and thinks more work needs to be done before ringing the alarm bells.
What’s more, the new drug will see limited use. The medication comes with a risk of sedation and dissociation, such as difficulty with judgment, attention and thinking. Because of that, the nasal spray was approved to be used only under a “restricted distribution system,” according to a statement from the FDA.
This means that only patients with severe depression who haven’t responded to at least two antidepressant treatments can receive the drug. In addition, the treatment is administered only in doctor’s offices, and patients must stay in the office and be monitored for several hours after receiving the treatment.
Ultimately, despite some potential problems with the newly approved drug, experts are hopeful it will come through strong.
“I think that the FDA approval of ketamine is a huge landmark in the history of treating neuropsychiatric diseases,” Olson said. “Ketamine really represents a leap forward in terms of new ideas for attacking depression and related neuropsychiatric diseases.”
A decades-old anesthetic made notorious as a party drug in the 1980s is resurfacing as a potential “game-changing” treatment for severe depression, patients and psychiatrists say, but they remain wary about potential long-term problems.
The Food and Drug Administration earlier this month OKd use of Spravato for patients with depression who have not benefited from other currently available medications. Spravato, the brand name given to the drug esketamine, is a molecule derived from ketamine — known as Special K on the club scene.
Ketamine has been shown in some studies to be useful for treating a wide variety of neurological disorders including depression. Regular, longtime use of it isn’t well understood, psychiatrists say, but the need for a new drug to treat depression is so great that the FDA put Spravato on a fast-track course for approval.
The drug likely will be commercially available in a few weeks, and patients already are requesting it. Restrictions around its use, though — the drug must be administered in a doctor’s office by providers who are certified with the company making it — mean it may be months before it’s widely available, and longer than that before insurers start paying for it.
“I don’t think we know at this point how effective it’s going to be,” said Dr. Craig Nelson, a psychiatrist at the UCSF Depression Center. “There have been a number of studies of ketamine, sometimes showing effects in people who were resistant to other drugs. If we can treat a different group of people, it would be a great advantage.”
Ketamine was developed in the 1960s as a surgical anesthetic for people and animals. The drug can cause hallucinations and a feeling of “dissociation” or unreality, and in the 1980s it took off as a party drug among people seeking those effects. It remained a common anesthetic, though, and in the early 2000s doctors began to notice a connection between ketamine and relief from symptoms of depression and other mood disorders.
Spravato is delivered by nasal spray, which patients give themselves in a doctor’s office. Patients must be monitored while they get the drug and for two hours after to make sure they don’t suffer immediate complications. At the start, patients will get the nasal spray twice a week for four weeks, then taper to regular boosters every few weeks for an indefinite period of time.
Studies of ketamine — and specifically of Spravato — have produced encouraging but inconsistent results. Psychiatrists say that, like most other antidepressants, the drug probably won’t help everyone with difficult-to-treat depression. But there likely will be a subset of patients who get substantial benefits, and that alone may make it an incredible new tool.
About 16 million Americans experience depression every year, and roughly a quarter of them get no benefit from antidepressants on the market. Thought scientists haven’t determined exactly how ketamine works on the brains of people with depression or other mood disorders, it appears to take a different path of attack than any drug already available. That means that people who don’t respond to other antidepressants may find this one works for them.
But a concern among some psychiatrists is that studies have suggested that ketamine may affect the same receptors in the brain that respond to opioids. Ketamine and its derivations may then put patients at risk of addiction — but research so far hasn’t explored that kind of long-term effect.
“There might be some potential problems if you used it too aggressively,” said Dr. Alan Schatzberg, director of the Stanford Mood Disorders Center, who led the research that identified a connection with opioid receptors. “The issue is not so much the short-term use, it’s the repetitive use, and the use over time, as to whether there are going to be untoward consequences.
“It would be hard for me to recommend the use of this drug for chronically depressed people without knowing what the endgame is here,” he added.
Dr. Carolyn Rodriguez, a Stanford psychiatrist who was part of the studies of ketamine and opioid receptors, said she shares Schatzberg’s concerns. But she’s been studying the use of ketamine to treat obsessive-compulsive disorder, and for some patients the results have been so remarkable that the benefits may exceed the risks.
“When I gave ketamine to my first patient, I nearly fell off my chair. Somebody said it was like a vacation from their OCD, and I was just, ‘Wow, this is really possible,’” Rodriguez said. “I want to make sure patients have their eyes wide open. I hope (the FDA approval) spurs more research, so we can really inform consumers.”
Though the new nasal spray is the first formal FDA approval of a ketamine-derived drug, psychiatrists have been using the generic anesthetic for years to study its effect on depression and other mood disorders.
In recent years, clinics have opened around the country offering intravenous infusions of ketamine to people with hard-to-treat depression and other problems. These treatments aren’t specifically FDA-approved but are allowed as off-label use of ketamine. The clinics have faced skepticism from some traditional psychiatrists, but there’s a growing ream of anecdotal evidence that the ketamine IVs work — for some people.
Aptos resident Mary, who suffers from depression and other mood disorders and asked that her last name not be used to protect her privacy, said the already available antidepressants weren’t keeping her symptoms at bay, and she frequently felt “one step away from the abyss.” When she first heard about ketamine, from a support group for people with depression and other mood disorders, she was hesitant.
“I kind of hemmed and hawed, because I’d heard that K was a street drug,” Mary said. “But then I said, ‘What do I have to lose?’ So I went and did it.”
The results were quick: Within four days, “the cloud had lifted,” she said. More than a year later, she is still feeling good with regular infusions every three or four weeks. During the ketamine infusion, Mary said she’ll feel the dissociation, which she described as feeling like she’s viewing the world around her as though it were a movie and not her own life.
She said she’s pleased the FDA approved Spravato, though she hasn’t decided whether she’ll switch from the IV ketamine to the nasal spray. She hopes that the FDA approval will give some validation to ketamine and encourage others to try it.
Mary gets her infusions at Palo Alto Mind Body, where Dr. M Rameen Ghorieshi started offering ketamine two years ago. He’s certified with the maker of Spravato — Janssen Pharmaceuticals, a branch of Johnson and Johnson — to provide the drug, though he doesn’t know when he’ll actually start giving the nasal spray to patients.
Ghorieshi said that although he’s been offering IV ketamine for more than two years, he shares his colleagues’ wariness of the long-term effects of regular use of the drug. He hopes FDA approval will encourage further research.
“At this point we’ve done 1,000 infusions. The outcomes have exceeded my own expectations,” Ghorieshi said. “But anecdotes are not clinical trials. I approach this very cautiously. What I don’t want is 20 or 30 years from now to look back and say, ‘What did we do?’”
Ketamine’s remarkable effect bolsters a new theory of mental illness.
A Vaccine for Depression?
Ketamine’s remarkable effect bolsters a new theory of mental illness.
One sunny day this fall, I caught a glimpse of the new psychiatry. At a mental hospital near Yale University, a depressed patient was being injected with ketamine. For 40 minutes, the drug flowed into her arm, bound for cells in her brain. If it acts as expected, ketamine will become the first drug to quickly stop suicidal drive, with the potential to save many lives. Other studies of ketamine are evaluating its effect as a vaccination against depression and post-traumatic stress. Between them, the goal is nothing less than to redefine our understanding of mental illness itself.
Depression is the most common mental illness in the United States, affecting 30 percent of Americans at some point in their lives. But despite half a century of research, ubiquitous advertising, and blockbuster sales, antidepressant drugs just don’t work very well. They treat depression as if it were caused by a chemical imbalance: Pump in more of one key ingredient, or sop up another, and you will have fixed the problem.
But the correspondence between these chemicals (like serotonin) and depression is relatively weak. An emerging competitive theory, inspired in part by ketamine’s effectiveness, has it that psychiatric disease is less about chemical imbalance than structural changes in the brain—and that a main cause of these changes is psychological stress. “I really do think stress is to mental illness as cigarettes are to heart disease,” says Gerard Sanacora, the psychiatry professor running the ketamine trial at Yale.
The theory describes stress grinding down individual neurons gradually, as storms do roof shingles. This, in turn, changes the nature of their connections to one another and the structure of the brain. Ketamine, along with some similar molecules, acts to strengthen the neuron against that damage, affecting not just the chemistry of the brain but also its structure.
Mental hospitals don’t usually see patients until they break: a brain shaped by vulnerable genes, wrecked by the stress of loss or trauma. This isn’t how it works with other sicknesses: heart disease, cancer, AIDS. Detected early, these conditions can often be managed. Crises averted.
If Sanacora and like-minded researchers are right, we may be on the cusp of a sea change that allows for a similar approach to mental health. The new approaches may prevent mental illness before it hits, by delivering a vaccination for the mind.
The need for progress could hardly be more urgent: Of all illnesses, neuropsychiatric diseases are estimated to put the heaviest burden on society. Nearly half of Americans are affected by some sort of mental disorder at some point in life. Suicides, 90 percent of them among the mentally ill, take 40,000 Americans every year—more than murder or car crashes. Since 2005, the suicide rate among U.S. war veterans has nearly doubled; in the first half of 2012, more service members died by suicide than in combat. Few medical failures are more flagrant than psychiatry’s impotence to save these people.
At the same time, treatment can be woefully ineffective. Less than a third of depression patients respond to a drug within 14 weeks, according to the 2006 STAR*D trial, the largest clinical test of antidepressants. After six months and multiple drugs, only half of patients recovered. Thirty-three percent don’t respond to any drug at all. When the pills do work, they are slow—a deadly risk, given that people with mood disorders kill themselves more often than anyone else.
Our treatments work so poorly in part because we don’t really understand what they do. Serotonin, the most common target for current antidepressants, is a neurotransmitter, a chemical that carries messages in the brain. But it was first found, in 1935, in the gut. Serotonin’s name comes from blood serum, where Cleveland Clinic scientists discovered it in 1948, noting that the chemical helps with clotting.
When Betty Twarog, a 25-year-old Ph.D. student at Harvard, later found serotonin in neurons, she wasn’t taken seriously. At that time, brain signals were thought to be purely electrical impulses that leapt between cells. Twarog called this old idea “sheer intellectual idiocy,” as Gary Greenberg reports in his book Manufacturing Depression. Working at the Cleveland Clinic in 1953, she found serotonin in the brains of rats, dogs, and monkeys.
Twarog didn’t know yet what serotonin was doing there, but a clue came soon from D.W. Woolley, a biochemist at Rockefeller University, in New York. In 1954 Woolley pointed out in a paper that lysergic acid diethylamide, or LSD, is chemically similar to serotonin and is processed similarly in the brain. Since LSD “calls forth in man mental disturbances resembling those of schizophrenia,” he wrote, another drug affecting serotonin might be used to treat schizophrenia. Twarog’s original paper would take years to percolate through the male-dominated field, but her work and Woolley’s would become accepted as evidence of how important chemicals like serotonin could be to brain signaling. The discovery was a breakthrough for neuroscience—but it also birthed a misleading, long-lived belief about mental illness. “The thesis of this paper,” Woolley wrote, “is that … serotonin has an important role to play in mental processes and that the suppression of its action results in a mental disorder. In other words, it is the lack of serotonin which is the cause of the disorder.”
Around the same time, other researchers stumbled on the first antidepressants, iproniazid and imipramine. Intended to treat tuberculosis and schizophrenia, respectively, these drugs also happened to make some patients “inappropriately happy.” Researchers found that the drugs elevated levels of serotonin, along with related neurotransmitters.1 This began a huge search to find chemically similar drugs that worked better as antidepressants.
Drug companies often say mood disorder is caused by a “chemical imbalance.” But the evidence for this story is slim.
Iproniazid was the first of a class of medicines that block an enzyme from breaking down serotonin, as well as dopamine and norepinephrine, two other neurotransmitters. The chief downside of these drugs, called monoamine oxidase inhibitors (MAOIs), is that they require a strict diet: no aged cheeses, wine, beer, or cured meats. Combined with these foods, the drugs can cause deadly spikes in blood pressure, a hassle that often inclines patients to ditch them. (The novelist David Foster Wallace took an MAOI for decades; in part to escape the food restrictions, he got off the drug months before his suicide.) On the other hand, tricyclic antidepressants, like imipramine, work by blocking the re-absorption of serotonin and norepinephrine. The cost is a host of side effects, from dry mouth to weight gain to erectile dysfunction and loss of libido.
The next generation of drugs focused on fine-tuning the same mechanisms, and had somewhat improved side effects. A new class of drugs known as selective serotonin reuptake inhibitors, or SSRIs, arrived in the ’80s, bringing huge commercial successes like Prozac, Zoloft, and Paxil. Since SSRIs are more specifically focused on serotonin, they were heralded as cleaner options; but they are not much more effective at lifting mood than the older drugs. We often take for granted the diabetes analogy for depression: If you are depressed, it is because you need serotonin, just as a diabetic person needs insulin. Drug companies often say that mood disorder is caused by a “chemical imbalance” in serotonin or a signal like it. One ad for Zoloft, the blockbuster antidepressant, featured a sad white circle crawling cutely beneath a gray cloud; the voice-over boasted that depression may be “related to an imbalance of natural chemicals in the brain. Zoloft works to correct this imbalance.”
But the evidence for this story is slim. Prozac raises serotonin levels within hours yet doesn’t change mood for weeks. When scientists deplete serotonin in healthy people, it does not make them sad. And when doctors measure serotonin levels in the cerebrospinal fluid of depressed people, they do not find a consistent deficiency; one 2008 study even found increased levels of serotonin in depressed people’s brains. The drug tianeptine, discovered in the late ‘80s, decreases serotonin levels yet relieves depression. And studies have shown that people falling in love show lower, not higher, levels of serotonin.
Serotonin is clearly not just a feel-good chemical. If a serotonin-based drug like Zoloft makes you happier, it works in some other, indirect way. As psychiatrist Ronald Pies, editor of Psychiatric Times, put it in 2011, “The ‘chemical imbalance’ notion was always a kind of urban legend—never a theory seriously propounded by well-informed psychiatrists.”
Stress in moderation is not harmful, but motivating. Cortisol, a stress hormone, cycles daily; synchronizing with sunlight, it helps arouse us for the day. In health, the hormone spikes when we need to pay attention: a test, a job interview, a date. Studies on rodents and humans confirm that brief, mild increases in stress are good for the brain, particularly for memory. During these spikes, neurons are born and expand in the hippocampus, the seahorse-shaped finger of tissue responsible for forming new memories and understanding three-dimensional space, and rodents learn better. The student who gets stressed while studying is more alert and remembers more than the one who feels no urgency—up to a point. The problem comes when stress is either too intense at one moment, as in a rape or violent attack, or too sustained, as in long-term poverty, neglect, or abuse.
Stress changes brain architecture differently, depending on how long it lasts. After chronic stress, like childhood trauma, the effect of hormones on brain cells inverts: Neurons in the hippocampus and the prefrontal cortex, which is responsible for mood and impulse control, start to shrink, while those in the amygdala, the almond-shaped seat of fear and anxiety, expand like overgrown shrubbery. But people are differently vulnerable, depending on genes and on prior life experience. “If you take two people and subject them to the same stressful event, for one of them it will be harmful and for the other, no,” says Maurizio Popoli, a professor of pharmacology at the University of Milan. “It is because they perceive the stress differently.”
Stress hormones’ most important effect is to flood parts of the brain with glutamate, the brain’s “go” signal. Used by 80 percent of neurons in the cortex, this key neurotransmitter drives mental processes from memory to mood. Glutamate triggers neurons to generate sudden bursts of electricity that release more glutamate, which can in turn trigger electrical bursts in nearby neurons.
This cellular signaling is called excitation and is fundamental to how information is processed in the brain. Like sexual excitability, it ebbs and flows; a “refractory period” follows each neural firing, or spike, during which the neuron cannot be excited. Other neurotransmitters, like serotonin, are called “modulatory,” because they change the sensitivity of neurons that secrete glutamate (among others). Less than 1 percent of neurons in the cortex signal with these modulators. As Popoli puts it, these modulators are “very important for fine-tuning the machine. But the machine itself is an excitatory machine,” driven by glutamate.
Glutamate moves like a ship between neurons. The sea it sails is called the synapse, the shore it departs from is the presynaptic neuron, and the destination, on the synapse’s far side, is the postsynaptic neuron. Another component, called a glial cell, works to remove glutamate ships from the synapse and recycle them. The glutamate system is affected at each of these points by stress hormones: They push the first neuron to send more ships, interfere with the glial cell’s recycling, and block the docks on the distant shore. All of these changes increase the number of glutamate ships left in the synapse, flooding the cell with aberrant signals. Indeed, depressed people’s brains, or at least animal models of depression, show all three of these problems, leading to long-lasting excesses of glutamate in key portions of the brain.
This superabundance of glutamate makes a neuron fire sooner than it should and triggers a cascade of signals inside the cell, damaging its structure. Glutamate binds to the neuron and allows in a flood of positively charged particles, including calcium, which are vital to making a neuron fire. But in excess, calcium activates enzymes that break down the neuron. Each neuron has tree-like branches, called dendrites, which are used to communicate with other neurons. When overdosed in glutamate, this canopy of branches shrinks, like a plant doused with herbicide. First the “twigs,” called spines, disappear. After prolonged stress, whole branches recede.
This harmful process, called excitotoxicity, is thought to be involved in bipolar disorder, depression, epilepsy, and neurodegenerative diseases like Alzheimer’s, Huntington’s, and Parkinson’s. In depressed brains, many areas are shrunken and underactive, including part of the prefrontal cortex and the hippocampus. The brain changes that cause mood disorders, Sanacora and his colleagues believe, come in part from chronic stress overexciting neurons with glutamate.
Ketamine works faster than any other drug, and for up to 65 percent of patients who don’t respond to existing treatments.
We usually think of our brains’ adaptability as a good thing. Just as neurons grow during development, the wiring in the adult brain can change. After strokes or other brain injuries, neural signals re-route themselves around damage, allowing even very old people to re-learn lost skills. Psychotherapy and meditation can change patterns of brain activity in ways that persist after treatment.2
But the neuroplasticity hypothesis of mental disorder highlights the drawback of such neural liberalism: The human brain’s flexibility allows regeneration, but also renders it vulnerable to being altered by stress. Subjected to the trauma of war, a bad breakup, or a bout of homelessness, a person with a genetic predisposition may find his mind stuck in a loop of chronic fear or depression.
The mood drugs in wide use now focus on modulatory neurotransmitters like serotonin. Ketamine, however, works directly on glutamate signaling. If ketamine is tapping into the root of the problem, this might explain why it works faster, better, and more often than more popular antidepressants.
Not everybody accepts the idea that glutamate and stress are central to depression. Some experts see the effects of stress as downstream effects, not the root cause of mood disorder. “The mechanism of action of a good treatment does not have to be the inverse of a disease mechanism,” says Eric Nestler, an expert on addiction and depression at Mt. Sinai Hospital. Serotonin drugs and ketamine may affect depression indirectly, without a serotonin or glutamate abnormality at the root of depression. Nestler also points out that depression probably includes a diversity of subtypes, without any single cause. He treats depression not as a unified disease, but a constellation of symptoms, each with discrete neural roots.
Even so, we do know that ketamine works faster than any other drug, and for up to 65 percent of patients who don’t respond to existing treatments.
If ketamine turns out to be a psychiatric savior, it will be one with a surprising history. Since 1962 it has been a go-to anesthetic for children in emergency rooms, because it kills pain, muffles consciousness, and rarely causes breathing or heart problems. Children given ketamine enter “a trance like state of sensory isolation” free of pain, memory, and awareness, as one review put it. Emergency room doctors rely on ketamine to make sure kids have no awareness or memory of, say, the trauma of having a shattered arm set back into place.
On the other hand, ketamine is a well-known recreational drug with potential for abuse. The dissociative trip caused by a moderate dose of ketamine has made it popular in clubs and raves since the 1970s, especially in Asian cities like Hong Kong. Its sedative effect made “special K” a date-rape drug. Doctors, patients, and the government agencies that fund research are often suspicious of a drug known to cause hallucinations, as they have been of psychedelics like psilocybin and ecstasy, despite their potential for treating depression or anxiety. Each tends to show fast results after a single dose, like ketamine.
In 1999, the same year ketamine was declared a controlled substance in the United States, Yale researchers happened upon its antidepressant power. A team co-led by Dennis Charney, now dean of the Icahn School of Medicine at Mt. Sinai, in Manhattan, and John Krystal, now chair of the department of psychiatry at Yale, used ketamine to study glutamate: Since ketamine was known to block glutamate receptors, it might show what role the excitatory neurotransmitter plays in the depressed brain. To their surprise, they found that the drug made patients feel better, often within hours. A single dose, much smaller than what’s used for anesthesia, tended to last for weeks.
Since 1999, a dozen studies have replicated the results, often on patients who failed to respond to other drugs. Ketamine also works for bipolar people in depressive phases, without triggering mania, as classic antidepressants sometimes do. The majority of depressed people studied have responded to ketamine. For patients who are often suicidal, this fast response can be lifesaving. Some 50 doctors in the U.S. now offer ketamine infusions for depression.
The first evidence in humans that ketamine might work to prevent mood disorder came from the battlefield.
Many leaders in the field see the emergence of ketamine, and future fast antidepressants based on glutamate, as a great leap forward for the field. “In my mind,” Sanacora told NPR recently, “it is the most exciting development in mood-disorder treatment in the last 50 years.”
Ketamine and the old antidepressants both result in fuller neural “trees,” but by different routes, at different speeds. Prozac and other serotonin-based drugs take four to six weeks to kick in. A landmark 2003 Science study by Columbia University’s René Hen and Ronald Duman, now at Yale, found that serotonin-based antidepressants only work if they spur birth of new neurons in the hippocampus.3 These new neurons take four to six weeks to mature, roughly the same amount of time that conventional antidepressants take to lift a depressed person’s spirits. A 2010 paper argued that SSRIs like Prozac may work by dampening glutamate release in response to stress. So even old-school antidepressants, when they work, may act on the glutamate system.
Ketamine, on the other hand, seems to act directly on mature neurons, fertilizing them to grow branches more robustly, or protecting them against damage. Ketamine’s key effect is to block glutamate receptors of one type. This causes less calcium to flow into the neuron, reducing the risk of the neuron shrinking or self-destructing.
Today ketamine is offered by psychiatrists and anesthesiologists, at prices ranging from $300 to $1,000 per dose, for people who are morbidly depressed or have chronic pain. Insurance doesn’t usually cover the cost of an infusion, because even though it is FDA approved as an anesthetic, it has not been approved as an antidepressant. Each new use of a drug requires multiphase clinical trials for FDA approval, usually funded by pharmaceutical companies, which have little incentive to invest in a drug they can’t monetize. Ketamine got its original patent in 1966, and that expired long ago. So even if drug companies steered ketamine through the expensive approval process as an antidepressant, doctors could still prescribe the cheap, generic versions already available for anesthesia instead of pricier, patented versions intended for depression. This is an old story. Lithium carbonate, which also acts on glutamate receptors, is still one of the most reliable drugs for treating bipolar disorder. But lithium, which is an element, can’t be patented. So, despite their effectiveness, these generic pills do not attract many corporate dollars.
One tough truth about mood disorder is that not all forms may ever be curable. Brain-imaging studies have shown structural differences between the white matter in healthy versus bipolar brains. Differences in personality and sleep patterns also persist in bipolar people, even between manic or depressed episodes. The structural changes likely have genetic roots, and once they arise, are difficult or impossible to reverse.
Nevertheless, if a drug prevents a mood disorder from manifesting, it might prevent harmful anatomical changes from ever taking place. Just as a vaccine triggers the body to arm itself against a particular virus, a drug like ketamine, given before the crisis that triggers a breakdown, might protect the brain against the effects of stress. Like a vaccine, the drug might only need to be given once for lasting resilience.
The first evidence in humans that ketamine might work to prevent mood disorder, not just treat it, came from the battlefield. U.S. soldiers injured in Iraq were treated with various anesthetics, including ketamine. Since ketamine can cause hallucinations, surgeons worried that it might make trauma worse: Scary combat-related hallucinations could put soldiers at higher risk of mental illness.
But they found the opposite. Out of 25,000 service members wounded in Iraq between 2002 and 2007, the data showed, veterans treated with ketamine for burns had lower rates of post-traumatic stress disorder. Among civilians and soldiers hospitalized for burns, as many as 45 percent end up with PTSD. But soldiers treated with ketamine on the battlefield got PTSD about half as often—even though they had more severe burns requiring more surgeries and longer hospital stays.
Mental hospitals don’t usually see patients until they break: This isn’t how it works with other sicknesses.
Rebecca Brachman, a neuroscientist and recent doctoral graduate from Columbia University, and her supervisor, Christine Denny, tried giving ketamine to mice and then exposing them to stressors.4 The researchers tested several types of stress, including one in which subject mice are “bullied” by more aggressive mice for two weeks. After this daily hazing, mice ordinarily develop the rodent equivalent of PTSD and depression: freezing in a new space, refusing to interact with other mice, and not moving in a forced swim test. But the mice “vaccinated” before the bullying fared far better: They didn’t act depressed afterward. Brachman and Denny found that the protection from a single dose lasted for weeks, even though ketamine only stays in the body for a few hours. Though they haven’t tested it yet, it is possible that, like a vaccine, this protection could last for much longer. Their rodent research suggests ketamine may work even better as a prophylactic than as an antidepressant.
Denny says that we may eventually routinely use ketamine to prevent PTSD in combat veterans, rape victims, or survivors of car crashes or mass shootings. Ketamine seems to be most strongly protective in mice when given before stressful events, Brachman says. Since we can’t predict most traumatic life events, this would limit the drug’s utility. But if injected after a trauma yet before the psychological damage sets in—as with the burned soldiers—ketamine may still be protective. Denny is investigating this possibility now.
And in some situations, violent shock is predictable. “You don’t know when an earthquake will happen,” Brachman says, “but we do know when we’re about to send U.N. workers into an area devastated by a disaster.” When people know they are going into an acutely traumatic situation, she imagines, a preventive drug given ahead of time might protect their brains from the long-lasting effects of stress. Think of earthquake aid workers, fire fighters, or rescue workers in Syria, dragging mangled people from rubble.
The idea that a single injection could prevent mood disorders is a radical departure from current psychiatric thinking. But there are some precedents: Talk therapy and mindfulness meditation have long focused on building resilience to stress. Bipolar patients take “neuroprotective” drugs like lithium not to treat current symptoms, but as a protection against future breakdowns, for instance.
Not everyone is confident that ketamine is a safe bet, to be sure. Ketamine’s long-term safety is not known, says Nestler. No lasting ill effects are seen in anesthesia patients, who take much larger doses, but they haven’t received routine treatments, the way it is administered as an antidepressant.
Plus, ketamine’s reputation as a street drug is tough to shake. Many doctors consider the hallucinogenic an unacceptable risk for patients, who they fear may develop a taste for the high. Yale’s Sanacora points out that patients in his trial, who are screened for drug or alcohol abuse, often find the trip feeling unpleasant or disturbing. The psychedelic experience is surreal, he points out, not the mellowing pleasure of a drug like alcohol, Xanax, or heroin. Extreme ketamine trips, referred to as falling in a “K-hole,” are often compared to near-death or unsettling out-of-body experiences; they hardly sound like fun to most people.
But since the antidepressant dose is far lower than the one taken to get high, many patients don’t even notice. Drug companies are also competing to develop a less trippy alternative. Johnson & Johnson is testing a nasal spray form of esketamine, a version of ketamine with less psychoactive impact. A company called Naurex has finished phase II trials of Rapastinel, an injected drug that partially blocks the same glutamate receptors as ketamine, but is not psychedelic.
The ketamine pioneers emphasize that their prevention research is the beginning of a new road, raising hopes, rather than offering an immediate cure. Brachman and Denny stress that ketamine may not be the drug that ultimately makes it into widespread use; like the anti-tubercular drugs in the 1950s that spawned the antidepressant era, it is the first to trail-blaze this new class of psychiatric prophylactics. “What this work shows us is that we can intervene beforehand and create some sort of self-reinforcing stress resilience,” Brachman says. “We didn’t know that before; that’s what’s important. Everything else—should we use it, how should we use it—that all comes later.”
Taylor Beck is a journalist based in Brooklyn. Before writing, he worked in brain imaging labs studying memory, aging, and dreams.
1. Maxwell, R.A. & Eckhardt, S.B. Drug Discovery Humana Press, New York, NY (1990).
2. Kennedy, S.H., et al. Differences in brain glucose metabolism between responders to CBT and venlafaxine in a 16-week randomized controlled trial. American Journal of Psychiatry 164, 778-788 (2007).
3. Vogel, G. Depression drugs’ powers may rest on new neurons. Science301, 757 (2003).
*Images reprinted from Popoli, M., Yan, Z., McEwen, B., & Sanacora, G. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nature Reviews Neuroscience 13, 22-37 (2011).
The anesthetic ketamine, used in both humans and animals, is perhaps best known as an illegal party drug due to its hallucinogenic effects. However, a growing body of research indicates that the drug may have a powerful new medical use: as a fast-acting antidepressant without the side effects seen in most prescription antidepressants.
As Nature reports, in many clinical trials to date people who have not responded to standard antidepressant treatment — such as SSRIs including Prozac — seem to respond to ketamine. And while it can take weeks to feel better after starting a prescription antidepressant, the therapeutic effects of ketamine are seen in a matter of hours.
Despite the seemingly “miracle drug” nature of ketamine, there are serious concerns about its use in depression. First, it is unclear how the drug works to alleviate depression. Second, there are no long-term studies on its long-term use. Studies that have already been done indicate the antidepressant effects of ketamine can last from between a few days to a few weeks.
And due to the addictive nature of ketamine itself, there are worries that sustained use of it may lead to dependence.
On May 4, Nature published the results of the latest trial involving ketamine, bolstering its potential as an antidepressant treatment. Researchers, examining the drug in mice, found that that the mood boosting effects may not be caused by ketamine itself, but instead by one of the metabolites ((2R,6R)-hydroxynorketamine) formed when the drug is broken down into smaller pieces.
Even more promising, the ketamine given to the rats did not increase side effects, even though the dose was much stronger than what would be given to humans for depression. The researchers say they want to take the metabolite into testing in humans, though that is likely years away.
Despite the lack of clear-cut evidence of its benefits and unknowns about its long-term risk, many doctors are already offering ketamine as a depression treatments to patients, though this is an off-label use.
Side effects of ketamine can include confusion, lucid daydreaming, fuzzy vision, and a “high” feeling, though they tend to go away quickly, according to these doctors. Patients, who are usually given ketamine via infusion, are carefully monitored and must have pre-arranged transport home. They can’t drive or use heavy machinery for 24 hours.
Drug companies are even trying to cash in on the ketamine craze. Janssen Pharmaceutical is testing a form of ketamine it developed, called esketamine, in 5 clinical trials. It would be given via a nasal spray. Another is rapastinel, under development by Allergan. Both drugs had “breakthrough therapy designation” from the FDA, meaning they will go through the regulatory process at a much quicker rate.
By Tracie White Illustration by Kotryna Zukauskaite
Geuris “Jerry” Rivas, a native of New York, was diagnosed with severe obsessive-compulsive disorder when he was 15. Obsessions with organizing and reorganizing the belongings in his bedroom — posters, comic books, videos — took over most of his life.
Forced by germ obsessions to compulsively wash and rewash his hands, he started wearing gloves all day to both protect him from the germs and stop him from washing his hands raw. Now, at 36, OCD symptoms continue to cost him jobs and relationships. He’s managed to turn his organizational skills into a profession — he’s a home organizer and house cleaner — but still he struggles daily with his obsessions.
“It’s caused me a great deal of suffering,” Rivas says. “I’ve tried many, many medications. I’ve wasted so much of my life.”
In 2012, running out of answers, Rivas took part in the first clinical trial to test ketamine as a treatment for OCD. While ketamine is approved by the U.S. Food and Drug Administration as an anesthetic, it is also an illicit party drug known as “Special K,” with hallucinogenic effects and the potential for abuse. Over the past 10 years, dozens of small studies of ketamine’s ability to treat a variety of mood and anxiety disorders have reported remarkable results — including the sudden alleviation of treatment-resistant depression, bipolar disorder and post-traumatic stress disorder. And these effects lasted days, sometimes weeks, after the hallucinogenic effects of the drug wore off.
With a single infusion of the drug, Rivas experienced for two weeks what it was like to live without the compulsions and obsessions that had for years controlled his life.
“I felt like, for the first time, I was able to function like a regular person,” he says.
Pros and cons
Ketamine has brought hope to a psychiatric field desperate to find new treatments for severe OCD, a chronic condition marked by debilitating obsessions and repetitive behaviors. Current treatments, which include antidepressants such as Prozac, can take months to have any effect on the disease, if they work at all.
“Severe OCD takes such a toll on patients,” says Carolyn Rodriguez, MD, PhD, who as a researcher at Columbia University ran the OCD trial. Now an assistant professor of psychiatry and behavioral sciences at Stanford, she has continued to explore the pros and cons of using ketamine to treat OCD. “The constant, intrusive thoughts that something is contaminated, the checking and rechecking, the repetitive behaviors. It interferes with your life, your jobs, your relationships.”
Ketamine was developed in the 1960s and has been used for decades as an anesthetic during surgery. It remains a mystery just how the drug works in the brain, and there are safety concerns. There is evidence from people who take the drug routinely — in much higher doses — that chronic, high-frequency ketamine use may be associated with increased risk of bladder inflammation and cognitive impairment, Rodriguez says. And if taken regularly, it can lead to dependence.
But researchers like Rodriguez are intrigued about the drug’s potential to help them identify a whole new line of medicines for fast-acting treatment of mental health disorders.
“What most excites me about ketamine is that it works in a different way than traditional antidepressants,” Rodriguez says. “Using ketamine, we hope to understand the neurobiology that could lead to safe, fast-acting treatments. I feel that is part of my mission as a physician and researcher.”
‘Right out of a movie’
Rodriguez’s interest in ketamine as a treatment for OCD was sparked about a decade ago when she was starting out as a research scientist at Columbia. A small, placebo-controlled study published in 2006 by a mentor of hers, Carlos Zarate, MD, now chief of the section on neurobiology and treatment of mood disorders at the National Institute of Mental Health, had shown that ketamine induced dramatic improvement in treatment-resistant depression within two hours of infusion. It was a landmark study, drawing attention among the psychiatric community and launching a new field of research into the use of ketamine to treat various mood and anxiety disorders.”What most excites me about ketamine is that it works in a different way than traditional antidepressants.”
Rodriguez, intent on searching for better, faster treatments for her patients like Rivas with OCD, took note. There was an emerging theory that ketamine affects the levels of the neurotransmitter glutamate in the brain and increasing evidence that glutamate plays a role in OCD symptoms, she says. Perhaps ketamine could help regulate OCD symptoms as well as depression.
In 2013, Rodriguez and colleagues published their results from that first clinical trial of ketamine in OCD patients. The trial randomized 15 patients with OCD to ketamine or placebo.
In those patients who were given ketamine, the effect was immediate. Patients reported dramatic decreases in their obsessive-compulsive symptoms midway through the 40-minute infusion, according to the study. The diminished symptoms lasted throughout the following week in half of the patients. Most striking were comments by the patients quoted in the study: “I tried to have OCD thoughts, but I couldn’t,” said one. Another said, “I feel as if the weight of OCD has been lifted.” A third said, “I don’t have any intrusive thoughts. … This is amazing, unbelievable. This is right out of a movie.” And while nearly all initially had dissociative effects like feelings of unreality, distortions of time or hallucinations, they were gone within two hours after the start of the infusion.
“Carolyn’s study was quite exciting,” Zarate says, adding that there were a number of similar, small but rigorous studies following his 2006 study that found fast-acting results using ketamine to treat bipolar disorder and post-traumatic stress disorder.
“We had no reason to believe that ketamine could wipe out any symptoms of these disorders within hours or days,” he says.
So how does it work?
Virtually all of the antidepressants used in the past 60 years work the same way: by raising levels of serotonin or one or two other neurotransmitters. Ketamine, however, doesn’t affect serotonin levels. Exactly what it does remains unclear.”There’s a recognition that people like me and others are using the drug to treat patients now. There’s an incredible need for something.”
Since coming to Stanford in 2015, Rodriguez has been funded by the National Institute of Mental Health for a large clinical trial of ketamine’s effects on OCD. This five-year trial aims to follow 90 OCD patients for as long as six months after they’ve been given a dose of ketamine or an alternative drug. Rodriguez and her research team want to observe how ketamine changes participants’ brains, as well as test for side effects.
Ultimately, Rodriguez says, she hopes the study will lead to the discovery of other fast-acting drugs that work in the brain like ketamine but without its addictive potential.
Recent research in the field indicates that the glutamate hypothesis that triggered her pilot study might be further refined.
“Ketamine is a complicated drug that works on many different receptor sites,” she says. “Researchers have fixated on the NMDA receptor, one of the glutamate-type receptors, but it might not be the only receptor bringing benefit.”
In May 2016, researchers from NIMH and the University of Maryland — Zarate among them — published a study conducted in mice showing that a chemical byproduct, or metabolite, created as the body breaks down ketamine might hold the secret to its rapid antidepressant actions. This metabolite, hydroxynorketamine, reversed depressionlike symptoms in mice without triggering any of the anesthetic, dissociative or addictive side effects associated with ketamine, Zarate says.
“Ideally, we’d like to test hydroxynorketamine and possibly other drugs that act on glutamate pathways without ketamine-like side effects as possible alternatives to ketamine in OCD,” Rodriguez says.
Beyond the clubs
Meanwhile, dozens of commercial ketamine clinics have popped up across the country, making treatments available to patients who are searching for help to stop their suffering now. Medical insurance companies usually cover ketamine’s FDA-approved use as an anesthetic but won’t cover its use for other purposes, such as mental health disorders. So patients who have run out of treatment options are paying hundreds of dollars a dose for repeated ketamine infusions.
“The fact that these clinics exist is due to the desperation of patients,” says Rodriguez.
She and other researchers are calling for guidelines to protect patients and more research to learn how to use the drug safely.
“I think it’s a game changer, and it’s here to stay,” says David Feifel, MD, PhD, professor emeritus of psychiatry at UC-San Diego, who studies the effect of ketamine on clinical depression. Feifel began prescribing the drug for patients with treatment-resistant depression in 2010.
“I’ve found it to be very safe,” Feifel says, adding that the American Psychiatric Association this year issued safety guidelines on how to use ketamine clinically for treatment of depression.
“There’s a recognition that people like me and others are using the drug to treat patients now,” he says. “There’s an incredible need for something.”
The drug hasn’t worked for everyone he’s treated, Feifel says, but for many it’s been “life-changing.”
Rodriguez says she understands what motivates the clinicians to prescribe the drug now to patients in dire straits — those who are suicidal or who have tried every possible medication and therapeutic option and continue to suffer each day.
“I see it as a way to treat people whose OCD is very, very severe,” she says. “People who can’t come out of the house, who are suicidal, who have no other options.
“I just don’t like the idea of people being in pain,” Rodriguez adds. “I want to see science translated into treatments now.”
Meanwhile, researchers are learning more about the drug. Janssen Pharmaceutical is testing the efficacy of a version of ketamine, known as esketamine, as a therapy for treatment-resistant depression and for major depressive disorder with imminent risk for suicide. The FDA has fast-tracked both investigations. At Stanford, Alan Schatzberg, MD, a professor of psychiatry and behavioral sciences, along with other faculty including Rodriguez, is studying the mechanism of action for ketamine in treating depression.
Rodriguez is also interested in using ketamine to kick-start a type of cognitive behavioral therapy called exposure and response prevention, an evidence-based psychological treatment designed to help patients overcome OCD. The therapy involves teaching patients with OCD to face anxieties by refraining from ritualizing behaviors, then progressing to more challenging anxieties as they experience success.
Relaxation and other techniques also help patients tolerate their anxiety — for example, postponing the compulsion to wash their hands for at least 30 minutes, then extending that time period.
“My goal isn’t to have people taking ketamine for long periods of time,” Rodriguez says. But perhaps a short-term course of ketamine could provide its own kind of exposure and response prevention by allowing patients to experience that it is possible not to be controlled by their OCD, she says.
Rivas well remembers that infusion of ketamine he received during Rodriguez’s first clinical trial to test the drug. The rush made him feel “like Superman.”
“I felt like my body was bigger, that I was more muscular, that I could tackle anything,” he says. But that feeling only lasted the duration of the 40-minute infusion. His OCD symptoms disappeared immediately and were still gone for two weeks after.
“I was amazed that something like that would work and work so fast,” he says. His OCD symptoms today are still intrusive, but he manages to keep them under control by taking antidepressants and seeing a therapist. Still, each day when he comes home from work, he has to put gloves on before he enters his apartment building, and as soon as he enters his apartment, he must wash his hands.
“It’s a ritual now,” he says. “There has never been a time that I haven’t done that, except those two weeks after the ketamine.”
When he heard that certain private ketamine clinics are now offering the drug as treatment for OCD, he said he understands why patients take the risks and pay the high prices. As more research has become available, he’s begun considering it himself.
“I’ve been suffering through my OCD for so long, I’ve gotten to the point where I’d try anything,” he says.
NOVA Heath Recovery Ketamine Treatment Center | Call 703–844-0184 for a Ketamine Treatment | Alexandria, Va 22306 | 7 days a week and evening appointments as well! We also evaluate depression, ADHD, PTSD. Intranasal Ketamine available. The email is EMAIL@novahealthrecovery.com
Learn How Ketamine Can Treat Post Traumatic Stress Disorder
For decades, ketamine has been used as a medicinal intervention for treating depression, anxiety, mood disorders, and post-traumatic stress disorder (PTSD). While most ketamine advocates recognize its therapeutic potential for treating depression, the many benefits available to those suffering from PTSD are less understood.
Do you or a loved one suffer from post-traumatic stress disorder? If so, ketamine infusion therapy may be able to help alleviate your symptoms and provide the relief you need. However, public knowledge about medicinal ketamine is lacking. In this article, we go over everything there is to know about ketamine for treating PTSD.
PTSD 101: What You Need to Know
Post-traumatic stress disorder has a medical diagnostic code of ICD-10, which is the code used for reimbursing treatment through your insurance provider. PTSD, unlike other mental illnesses, is characterized by its triggering from a single or series of traumatic events. This explains why PTSD is common among military veterans and first responders.
According to a summary article from Mayo Clinic, PTSD is a mental health condition triggered by a terrifying experience. The sufferer subsequently experiences flashbacks, night terrors, and anxiety attacks that they cannot control as a result of the event. It takes a significant amount of time, therapy, and self-care to overcome the trauma of PTSD.
There is no known cure for PTSD. However, many experimental medicinal interventions are breaking ground when it comes to finding a cure. For example, the psychoactive drugs MDMA and ketamine have both been studied for their potential to alleviate the negative effects of PTSD.
Ketamine Infusion Therapy
Since the early 2000s, ketamine has gained popularity among medical providers for its application in infusion therapies. In recent years, clinics all around the world have embraced the healing power of ketamine by offering ketamine infusion therapy. This unique therapy involves one or more intravenous injections of ketamine under the supervision of an anesthesiologist.
What Is Ketamine?
Although ketamine has garnered a reputation as a party drug, its primary value is in its ability to provide fast-acting and potent relief for those with chronic pain issues. Ketamine was first synthesized in the 1960s and was later adopted as an anesthetic in veterinary medicine by the end of the decade. However, use in humans was initially sparse.
Ketamine is both an analgesic and anesthetic drug, which means its primary quality is to reduce or prevent pain. This makes ketamine highly effective for treating major depressive disorder, chronic back pain, and PTSD.
Ketamine and PTSD
Ketamine infusion clinics across the United States are now offering specialty treatments for those suffering from PTSD. For example, the renowned Ketamine Clinics of Los Angeles has treated hundreds of PTSD patients over the years. Led by Dr. Steven Mandel, M.D., the team at Ketamine Clinics of LA has a proven track record of helping relieve the pain of PTSD.
An increasing amount of scientific research has proven that ketamine is effective in treating PTSD. Most notably, a breakthrough 2014 study in JAMA Psychiatry discovered that a single intravenous subanesthetic dose of ketamine resulted in “significant and rapid reduction in PTSD symptom severity.”
Over the past few years, many articles and news reports have heralded ketamine as a potential wonder drug for treating PTSD. A recent article published by Medscape discussed how a team of researchers at the Icahn School of Medicine at Mount Sinai in New York City used ketamine to fight depressive symptoms in patients with PTSD and severe depression.
Is Ketamine Safe for PTSD?
There is no doubt that ketamine is a novel treatment for many PTSD sufferers. Since it is a relatively new medicinal intervention, there is some skepticism within the medical community regarding whether it is safe for human use. However, many of these doubts have been quelled over the years thanks to numerous studies and experiences that have proven its safety.
The most compelling evidence suggesting that ketamine infusion is safe in humans comes from a 2014 clinical study. This study managed to safely administer low doses of ketamine to treat neuropathic pain states in adults. Over the two-week monitoring period, the patients exhibited numerous benefits while experiencing only marginal or negligible side effects.
It should be noted that ketamine is not safe if taken recreationally. Since its inception, ketamine has gained a reputation as a party drug for its ability to induce dissociative states and euphoria. However, ketamine is not safe to use unless administered by a licensed physician. It is possible to overdose on ketamine, and the side effects of using high doses of ketamine can be fatal.
Ketamine: A PTSD Prevention Tool?
Interestingly, ketamine has found success as a tool for preventing the onset of PTSD. In one case, a research team gave a family of mice a low dose of ketamine before exposing them to electric shocks. Usually, mice exhibit symptoms of PTSD after being exposed to such a severe stressor. However, the mice that were given ketamine did not exhibit these symptoms at all.
Typically, traumatized mice freeze up when they are placed back in the cage in which they were shocked. In this case, the mice who were sedated with ketamine did not freeze when placed in the cage or froze for a significantly reduced duration. This led the research team to believe that ketamine may have value in both preventing and treating PTSD in humans.
Is Ketamine Right for You?
Ketamine may be an appropriate treatment option for you if you have treatment-resistant PTSD. In other words, you must first be diagnosed with PTSD and have sought the traditional frontline treatments for the condition before considering ketamine infusion therapy. We recommend speaking with your doctor about your PTSD symptoms and the appropriate therapies available to you. Usually, SSRIs or benzodiazepine pharmaceutical drugs, in conjunction with cognitive behavioral therapy (CBT) is the first method of treatment. However, if you do not respond well to this treatment option you should consider seeking ketamine therapy.
NOVA Heath Recovery Ketamine Treatment Center | Call 703–844-0184 for a Ketamine Treatment | Alexandria, Va 22306 | 7 days a week and evening appointments as well! We also evaluate depression, ADHD, PTSD. Intranasal Ketamine available. The email is EMAIL@novahealthrecovery.com
Ketamine for Depression: Does it work?
What is Ketamine?
Ketamine, also known as Ketalar, Ketaset, and Ketanest, is a medication that’s currently FDA approved only as an anesthetic but it’s showing great potential as a treatment for severe depression. In fact, numerous Ketamine Clinics have begun to appear throughout the United States to solve this problem. Depressed patients with stubborn symptoms get relief within hours rather than weeks with conventional anti-depressants. Doctors can only prescribe ketamine for depression off-label because studies are relatively new, but experts are saying that ketamine is one of the biggest breakthroughs in severe depression treatment to come along in decades .
Ketamine is a powerful pain reliever and a relaxant, but at higher doses it can also induce unconsciousness and disturbances in how a person experiences sight and sound. In high doses, it can produce hallucinations and delusions and its ability to create strong dissociative experiences have made it popular in the club scene where it’s known as “Special K”. An overdose of ketamine can be fatal and it can be addictive if patients don’t follow their doctor’s prescription guidelines. Currently, ketamine is scheduled as a class III drug and it’s created a lot of controversy among experts who disagree about whether it’s safe for doctors to prescribe it as a treatment for chronic depression. Despite the intrigue and the need for additional research to establish its safety and efficacy, ketamine clinics are now offering infusion treatments to patients all over the United States .
Effects of Ketamine
As a street drug, ketamine creates a sense of dissociation and can change a person’s sense of hearing and sight, but for patients with severe depression, ketamine relieves mood problems within hours or sometimes moments for about 85% of those treated. While conventional anti-depressants can take several weeks to take effect, studies have shown that ketamine often improves depression symptoms almost immediately. Patients typically feel better within hours .
Doctors, dentists, and psychiatrists prescribe ketamine to help their patients achieve a variety of different health goals. Doctors often use ketamine in FDA approved situations such as procedures involving cardiac catheterization, orthopedics, skin grafting, or diagnostics involving the eye, ear, nose, and throat. Surgical dentists may also use ketamine as an anesthesia during tooth extractions. After other treatment options have been attempted and failed, doctors may use ketamine to treat certain types of seizures in patients with status epilepticus .
Researchers demonstrated in 2014 that ketamine reduced symptoms of post-traumatic stress disorder in 41 patients and there are other exciting possibilities on the horizon in terms of PTSD treatment. Treatment-resistant depression and substance use disorders could both be treated with this drug, though many medical professionals view ketamine treatment for these mental health issues as controversial .
Ketamine for Pain Management (CRPS)
Central Sensitization is a process the central nervous system goes through which causes Complex Regional Pain Syndrome (CRPS/RSD) and other types of chronic pain. In central sensitization the number of NMDA receptors increases which amplifies a patients’ experience of pain. Ketamine interferes with NMDA receptors which puts a damper on pain signaling, providing pain relief and a desensitization to pain for patients affected by CRPS .
At low doses, ketamine can relieve chronic pain and potentiate the effects of sedatives. Researchers believe that ketamine could provide an alternative to more addictive painkillers like morphine if the FDA approves it for this use .
Ketamine for Anesthesia
In the 1960’s doctors used ketamine as an anesthetic on the battlefields in Vietnam because administration lends itself well to use in disaster zones; doctors don’t need electricity, an oxygen supply, or even highly trained staff to give patients ketamine. Since that time, the FDA has only approved ketamine for use as an anesthetic in hospitals and medical settings. As an anesthetic, ketamine doesn’t lower the patient’s breathing rate or blood pressure, which makes it safer than other anesthesia options. It’s for this reason that veterinarians use ketamine more than any other type of anesthetic for surgery on animals .
Ketamine for Depression
Depression is a major issue in the United States and though there are many anti-depressants on the market, about one-third of patients don’t experience any relief from their symptoms using the drugs that are currently available. Ketamine acts on depression by rebalancing a different set of neurotransmitters and receptors (the NMDA/glutamate receptors and GABA receptors) than the old-school Selective Serotonin Reuptake Inhibitors (which function by blocking reabsorption of serotonin). By blocking glutamate receptors in the brain, the majority of patients with ‘Treatment Resistant Depression’ are able to experience relief from their symptoms using ketamine .
Even though ketamine has yet to be approved by the FDA for use in treating depression, patients are flocking to ketamine clinics to receive the treatment off-label. It provides fast relief, which is vitally important in cases where patients feel suicidal and for depressed patients who have tried all of the other anti-depressants available with no luck, ketamine offers new hope. Infusion treatments take about 1 hour at a clinic, but the results are long-lasting with most patients returning only once every one to two weeks over a specified period of time. The treatment is expensive, but the results are promising enough that patients are willing to pay out-of-pocket for it .
The FDA hasn’t yet approved ketamine for use as an anti-depressant, but both Esketamine and Rapastinel (developed by Johnson & Johnson and Allergan respectively) have been fast-tracked as breakthrough drugs. The demand for these two medications is projected to grow rapidly in the coming years. Still, doctors can only prescribe ketamine for depression off-label since ketamine has been FDA approved for use as an anesthetic, not as an anti-depressant. Researchers have cautioned doctors to avoid over-prescribing this drug because the long-term health and well-being of patients could be at risk. Ketamine has a high potential for abuse, after all and experts claim that the evidence does not exist to prove that this drug is safe .
Ketamine as Drugs of Abuse
Ketamine is abused as a recreational drug and it has effects that are similar to Phenylcyclidine (PCP), LSD, dextromethorphan (DXM) and nitrous oxide (laughing gas). Ketamine is a dissociative anesthetic that can alter one’s sense of sight and sound and also produce profound relaxation, hallucinations, and delusions for about an hour. The effects of the drug come on almost immediately. It has been used as a rape drug that can render women unable to speak or to move .
People who abuse ketamine have developed serious bladder and kidney problems such as ulcerative cystitis, stomach issues, and memory loss. In fact, street users even risk developing depression as a result of addiction and dependence on the drug .
How is Ketamine used for depression?
Doctors may prescribe ketamine by itself or in tandem with other anti-depressants . Many experts on depression recommend that ketamine only be used as a short-term depression treatment option while other anti-depressants are taking effect. Though there are convenient ketamine nasal sprays in research and development by Johnson & Johnson, the high-potential for abuse of this drug has made many doctors and psychiatrists wary of using this drug to treat depression long-term. Further, some medical organizations are concerned that the long-term effects of chronic ketamine use is not well-understood. According to these organizations, more research is needed to establish the safety of this drug .
Promising Remedy for ‘Treatment Resistant Depressions’
Thomas Insel, the director of the National Institute of Mental Health says, “Recent data suggest that ketamine, given intravenously might be the most important breakthrough anti-depressant in decades.” Conventional anti-depressants aren’t able to help about one-third of patients with major depression, but new ketamine drugs such as esketamine (in development by Johnson and Johnson) may offer new hope. Infusion therapies available through ketamine clinics across the United States report a high success rate of 60% to 70% treating Treatment Resistant Depression as well as Major Depression with risk of suicide .
Fast-Tracked by FDA
Two drugs, Johnson & Johnson’s Esketamine and Allergan’s Rapastinel, were both upgraded to ‘fast-track’ status by the FDA in 2016 due to their importance and promise in treating treatment resistant depression.
Depression is the leading cause of disability in the world and currently, 12% of Americans (about 29 million people) are taking anti-depressant medications. The suicide rate is higher now than it has been in over 30 years. And about one-third of depressed Americans don’t experience relief taking conventional anti-depressants. In the interest of capitalizing on the market value of depression, which is projected to almost double by the year 2024, the FDA will review the use of these new ketamine-based depression drugs in 2018 and 2019, allowing Johnson & Johnson and Allergan to go through an abbreviated version of the normally lengthy FDA approval process for new drug therapies .
Drug trials have shown that 60% to 70% of patients with Treatment-Resistant Depression have been responsive to ketamine. Esketamine, a nasal spray developed by Johnson & Johnson, is in Phase III clinical trials right now. They are expected to receive FDA approval later in 2018, and once that happens, it will open doors for administering ketamine outside a clinic setting.
Rapastinel, which was developed by Allergan, is out of Phase III and awaiting FDA approval. The drug can be administered within 30 seconds intravenously and Allergan is working to develop an oral version of the drug as well .
How Ketamine Therapy Works
Ketamine therapy is usually performed at a ketamine clinic. Patients receive an intravenous infusion of the drug with relief from depression symptoms that can last for several weeks.
Ketamine Infusion or Intravenous Therapy (Infusion Process)
Ketamine can be injected directly into muscle tissue or it can be given intravenously. Researchers for Johnson & Johnson have also recently developed new treatment protocol called Esketamine that’s awaiting FDA approval. Using Esketamine, patients will be able to self-administer the drug as a nasal mist .
Patients must receive a referral from a doctor to go to a ketamine clinic. There, patients can receive an intravenous infusion of ketamine. On the first visit, a doctor will assess the patient before hooking the patient up to a ketamine IV. Patients then experience a variety of sensations during the infusion and for up to 2 hours following the infusion. Many patients report feeling a sense of deep relaxation and the ability to reflect on past traumas and anxieties calmly .
How does it work?
Researchers have demonstrated that a deficiency in certain vital connections between certain neurons in the brain may cause depression. Ketamine works as an NMDA receptor antagonist (NMDA is a glutamate receptor also known as N-methyl-d-aspartate) and an AMPA receptor stimulator. As such, ketamine stimulates the development of new receptors and synapses in the brain which helps patients regulate their mood, sleep better, and experience better focus .
Ketamine works by interfering with and rebalancing the glutamatergic system (glutamate and GABA) to stimulate new synaptic connections, better memory, and brain plasticity . During ketamine infusions, patients may feel capable of exploring traumatic memories more calmly to reframe the past or they may feel a pleasant sensation of relaxation or floating . Effects from an infusion can last for up to a week or two.
Intranasal ketamine formulas work by binding to a receptor called N-methyl-d-aspartate. In the brain, ketamine blocks the neurotransmitter glutamate which causes communication between the conscious mind and other parts of the mind (such as mood centers) to be blocked. In low doses, it relieves depression, but in higher doses, it can cause patients to feel an uncomfortable sense of dissociation from the body similar to a near death experience .
While most anti-depressant medications must build up in the body over the course of several weeks in order to have an effect, ketamine’s mood-altering benefits happen as the drug leaves the body. Researchers don’t know why this is the case, or even exactly how the drug achieves its strong anti-depressant effects but the fact is, ketamine works quickly to relieve depression symptoms in 85% of patients who are resistant to other forms of therapy . Standard anti-depressants target the neurotransmitters serotonin, norepinephrine, and dopamine, but ketamine is different. Ketamine blocks glutamate and stimulates synaptic plasticity or the ability of the brain to change and grow .
Doctors don’t fully understand how ketamine works or the potential effects that patients may experience from taking tiny doses of this drug over and over again. What is known is that recreational users can suffer ulcerative cystitis or cognitive issues as a result of prolonged use .
Ketamine Infusion Dose/Dosage
Researchers are working to find the perfect ketamine dose for depression patients. The risk of overdosing on this drug is high for the recreational user because there is only a slight difference between a dosage that leads to desirable effects and one that can cause a lethal overdose. The goal for researchers is to find an exact dosage that’s high enough to get rid of symptoms of depression but low enough to prevent patients from experiencing hearing and sight disturbances as well as the other negative effects from the drug . Ketamine produces only temporary effects on severe depression. Patients must continue to return to the clinic for infusions every few weeks to keep their depression symptoms in check .
Ketamine therapy cost? Is ketamine therapy covered by insurance?
Ketamine therapy is rarely covered by insurance and it’s pricey. Patients typically pay between $400 and $800 per infusion in many centers.
Ketamine Infusion Side-Effects
Ketamine use can cause a variety of side effects including:
Extreme fatigue or exhaustion
Nervousness or restlessness
Puffy or swollen eyelids, lips, or tongue
Hives, itching, or rash
Difficulty thinking or learning
Loss of appetite
Fast heartbeat, slow heartbeat, irregular heartbeat
Chest pain or discomfort
Inability to control eye movement
Difficulty urinating, frequent urination, cloudy or bloody urine
Paleness, bluish lips, skin, or fingernails
Increased pressure in the brain and the eyes 
Off-label ketamine infusion therapy is an unregulated business that has gotten the attention of both clinicians and medical organizations. There are currently ketamine clinics in a number of cities throughout the United States .
s ketamine therapy addictive?
Patients who use ketamine long-term may develop a tolerance and addiction to the drug over time. In medical settings, ketamine is safe to use because the dosage is carefully calibrated and monitored, but there is a high potential for abuse when patients use ketamine recreationally as a street drug. If patients don’t follow their doctor’s prescription for ketamine it can have extremely negative mental and physical effects particularly on the brain and bladder .
Ketamine-Based Drugs in Late Stage Trials
Both Rapastinel and Esketamine are ketamine-based drugs that have been ‘fast-tracked’ by the FDA because the FDA has identified them as “breakthrough drugs” .
Allergan developed Rapastinel, a ketamine drug that can be administered in 30 seconds intravenously. It works on the same receptors as ketamine, but it doesn’t produce hallucinations. An oral version of Rapastinel is also in development. The FDA considers Rapastinel to be a “breakthrough drug” which means that Allergan can speed through the lengthy drug approval process and get the drug to market by 2019 .
The FDA has designated Esketamine a “breakthrough therapy”, which means that the drug developers, a subsidiary of Johnson & Johnson, can speed through the lengthy drug approval process to get the drug on the market more quickly. Esketamine can be administered like a nasal decongestant, which would make it more convenient than intravenous therapy for depression patients. Experts feel that Esketemine would be most appropriately used as an adjunct therapy in combination with other anti-depressant medications, not as a standalone treatment for depression .
According to one recent study, when administered in combination with other oral antidepressants, Esketamine reduced patients’ depression symptoms more than oral anti-depressants alone. The anti-depressant effects of using a conventional anti-depressant in conjunction with Esketamine occurred within only about 1 week. When used alone, Esketamine effects seem to last 1 to 7 days in most patients. Esketamine is in Phase 3 testing with the FDA for use as a drug for ‘Treatment Resistant Depression’ and Major Depression with risk of suicide. Johnson & Johnson will file for FDA approval for this drug as a depression treatment in 2018 .
Risks of Ketamine Abuse
Ketamine abuse is a serious problem. It is possible to become addicted to ketamine. Patients may begin to need higher doses of the drug in order to experience the positive effects. An overdose of ketamine can be deadly. The effects of using ketamine chronically over a long period of time have not been established, but recreational drug users who have used ketamine long-term have developed ulcerative cystitis as well as cognitive issues .
The Ketamine Controversy
While ketamine can literally save lives by relieving the symptoms of major, Treatment Resistant Depression, including the risk of suicide, research still has not established the safety of ketamine for long-term use. The lethal dose of ketamine is only slightly higher than the therapeutic dose and its addictive properties mean that it could cause depressed patients more problems than it solves. Ketamine clinics have popped up all over the country to cash in on the high demand for a depression treatment that really works, but the research hasn’t demonstrated that this drug is safe for chronic use. So this is an instance where the buyer needs to beware. The FDA has fast-tracked these drugs because it’s constituents see market potential, but important research still needs to be done on this drug to demonstrate it’s safety and long-term efficacy.
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New Drug Combo Shows Promise for Treatment of Depression and Addiction
The combination of naltrexone and ketamine can help treat both symptoms of addiction and depression, a preliminary study by Yale University researchers suggests.
Substance abuse and depression are common in many patients, and efforts to treat both conditions simultaneously have had limited success. One recent study suggested that the antidepressant effects of ketamine might blunted by administration of naltrexone, used to limit cravings of those addicted to opioid drugs and alcohol.
A preliminary study of five patients suffering from both depression and substance abuse disorders suggest that isn’t the case. The study was published Jan. 9 in the journal JAMA Psychiatry.
The results “raise the possibility that for people who have depression complicated by substance abuse disorders, the combination of ketamine and naltrexone may be a strategy to explore in the effort to optimally treat both conditions,” said senior author John Krystal, Yale’s Robert L. McNeil Jr. Professor of Translational Research; professor of psychiatry, neuroscience, and psychology; and chair of the Department of Psychiatry.
Krystal and lead author Gihyun Yoon, assistant professor of psychiatry, treated the five patients suffering from depression and alcohol use disorder with a long-lasting form of naltrexone and then administered ketamine. Four of the five responded to the first ketamine dose and all five found relief from depression after multiple doses.
The study also challenges the idea that ketamine might produce antidepressant effects by stimulating opiate receptors.
Krystal cautioned that larger studies are needed to confirm beneficial effects of the combination treatment.
Krystal and Yoon have provisional patents on the use of ketamine and naltrexone to treat comorbid depression and substance abuse.
The study was primarily funded by the U.S. Department of Veterans Affairs.
Publication: Gihyun Yoon, et al., “Association of Combined Naltrexone and Ketamine With Depressive Symptoms in a Case series of Patients With Depression and Alcohol Use Disorder,” JAMA Psychiatry, 2019; doi:10.1001/jamapsychiatry.2018.3990
At NOVA Health Recovery, we do use Ketamine and other combinations to treat Alcoholism and Opioid and Pain pill addiction using Ketamine Treatment. Dr. Sendi is Board Certified in Addiction Medicine. Call 703-844-0184 Today. Fairfax, Va 22304.
A one-off dose of the drug could help alcohol addicts reduce their intake by ‘erasing’ drink-related memories, say psychologists testing treatment. There is a growing body of research to support the idea that ketamine, a horse tranquiliser, can be used to disrupt harmful patterns of behaviour
Scientists believe that a radical treatment involving the tranquilliser ketamine could help overcome alcohol addiction by “erasing” drink-related memories.
Psychologists based at University College London are testing whether a one-off dose of the drug could help hazardous drinkers who are trying to reduce their alcohol intake. Alcohol addiction is notoriously difficult to treat, and there are few effective therapies available.
Using a recreational drug to treat addiction may sound counterintuitive, but the researchers say there is a growing body of research suggesting that ketamine can be used to disrupt harmful patterns of behaviour.
Ravi Das, one of the lead researchers, said: “There is evidence that it could be useful as a treatment for alcoholism.”
Crucially, ketamine can disrupt the formation of memories, and scientists believe that this property could be harnessed to over-write the memories that drive addiction and harmful patterns of behaviour.
“Memories that you form can be hijacked by drugs in some people,” said Das. “If you were an alcoholic you might have a strong memory of being in a certain place and wanting to drink. Those memories get continuously triggered by things in the environment that you can’t avoid.”Advertisement
For instance, seeing a glass of beer, hearing the clinking of glasses or even arriving home from work may trigger memories of the rewarding sensation of taking a drink – and might prompt a person to follow this urge.
“The main problem is the really high relapse rate after treatment,” said Das. “People can successfully quit using over the short term while they’re being monitored in the hospital … but when they return home they’re exposed to those environmental triggers again.”
There is increasing evidence, however, that memories are less stable than once assumed and may be open to manipulation.
Each time our brain accesses a memory, the neural connections that encode it are temporarily destabilised, meaning that our recollection can be slightly altered before it goes back into storage. This is one reason why, in everyday life, people can recall wildly different versions of the same events.
In the clinic, scientists believe this short period of instability, represents a window of opportunity. Ketamine blocks a brain receptor called NMDA, which is required for the formation of memories. So the logic is that giving someone the drug just as a memory has been destabilised could help weaken the memory, or even erase it.
A similar approach with a different drug was shown to eradicate people’s phobia of spiders. And research in rats that were made to be addicted to cocaine showed that the memories underpinning their addiction could be completely wiped out using a similar strategy (although this involved injecting a chemical into the brain).
In the UCL trial, the scientists will intentionally trigger alcohol-related memories by placing a glass of beer in front of the participants, who are all heavy drinkers. They will then disrupt the memory, by surprising the participant (the team is not disclosing the exact details as this could bias the results).
Participants will then be given either a ketamine infusion, with a concentration equivalent to a high recreational dose, or a placebo. The team will follow up the people for a year and monitor whether their drinking has changed and by how much.
In total the scientists are aiming to include 90 people in the trial and more than 50 have already taken part. It involves people who drink harmful quantities of alcohol, but excludes anyone who meets the clinical criteria for alcoholism. The participants were drinking at least 40 units a week for men (equivalent to four bottles of strong wine) and 28 units for women, and drinking on at least four days. The UK needs common sense about ketamine
Nikki, 31, who works as a consultant in London said she decided to take part in the study when she had some time off between jobs and realised she was drinking more than she wanted to. “It’s just in the culture, that’s what all my friends are like. Everyone drinks to excess,” she said.
She described the experience of being given the ketamine as “overwhelming and intense”, but not unpleasant. “My body felt like it was melting away,” she said. “It was quite psychedelic, I felt untethered from my body.”
In the week after the session, she said, she felt in an “incredibly positive mood” and that since taking part she has been more conscious about deciding whether to have a drink, although said this could also be linked to starting a new job and taking up meditation. “In the past, there were occasions where I would be drinking and I’d be on autopilot ‘Let’s get another drink’,” she said.
If the trial yields promising results, the team hope that the approach could form the basis for therapy sessions targeted at alcoholics and people who are drinking unhealthily. However, they acknowledge that there may be resistance to the use of a recreational drug to treat people with addiction.
“There’s just the general social attitude that everything that’s illegal is terrible. There will obviously be that kind of narrow-sighted pushback,” said Das. “But if it’s safe and effective enough it should be recommended.”
Andrew Misell, a spokesman for Alcohol Concern, said: “The researchers have quite rightly highlighted what a lot of people in recovery from alcohol problems know from experience, namely that cues or triggers like the smell of beer can cause a relapse even after long periods of abstinence. Any work looking at how people can overcome these pitfalls is going to be useful.”
However, he added, no drug-based therapy is risk-free “and that certainly includes ketamine”.
Professor Michael Saladin, of the Medical University of South Carolina, is looking at similar approaches to help people quit smoking. “There is a vast animal research literature that suggests memories can be manipulated following reactivation,” he said. “I am convinced that there is sufficient evidence to believe that memory reconsolidation can be harnessed for clinical purposes.”
January 2018 has come to an end and with it the month that people increasingly use to abstain from alcohol. It is still unknown whether Dry January has a lasting effect on drinking behaviours, and people with an alcohol dependency problem should always seek support from their GP before going through detox. Nonetheless, Dry January undoubtedly drives a critical conversation about alcohol use and provides an opportunity for us to reconsider our relationship with alcohol (one of the main goals of the charity Alcohol Concern, who support the challenge).
While overall alcohol consumption in the UK is falling, alcohol abuse still represents the fifth biggest risk factor for illness, death and disability across all ages. With current treatments often failing to prevent relapse in the long term, researchers are investigating the possibility of using ketamine combined with psychological therapy to help people stay dry, and not just for January. Despite its often cited use as a recreational drug and “horse-tranquilizer” ketamine is also the most widely used anaesthetic in humans. Administered appropriately in a controlled and safe medical environment, ketamine may also have benefits in the treatment of drug problems.
Evidence for this originally came from a research group in Russia in the 1980s. In this study, patients who had alcohol problems were given three weekly ketamine treatments in conjunction with psychological therapy. After one year, 66% of patients who underwent this treatment regime were abstinent, in comparison to 24% of patients who received treatment as usual, without any ketamine. This abstinence rate is much greater than those documented with any other relapse prevention method.
Inspired by the promising results seen in Russia, we are now conducting the KARE trial (Ketamine for reduction of Alcoholic Relapse) at the University of Exeter and University College London. In this trial participants who have made the decision to abstain are administered ketamine once a week for three weeks. Participants also receive seven sessions of cognitive behavioural therapy to aid their quit attempt and are followed up for six months. Unlike the earlier study, this trial is placebo controlled, thus participants have an equal chance of receiving either ketamine or a matched placebo as well as either cognitive behavioural therapy or alcohol education as a placebo for therapy. It is also double-blind, meaning neither the participant nor the researcher know whether the active treatment or a placebo treatment are administered. This controls for placebo effects and bias due to expectancies of the researcher – putting the original findings to the test with a more rigorous research design.
Why might ketamine help people stay sober? Recent studies have demonstrated that ketamine has rapid and powerful anti-depressant properties, while people with alcohol problems often also experience symptoms of depression. The direction of the relationship between alcohol problems and depression is not clear, but depressive symptoms are thought to be a common trigger for relapse. Treating people who have alcohol problems with ketamine, therefore, could help them to remain abstinent for longer by lifting their mood.
Furthermore, laboratory research has demonstrated that ketamine promotes the growth of new neurons and connections in the brain. These processes are essential to learning and memory, and are suggested to be impaired in both depression and problematic alcohol use. Thus ketamine might make people more receptive to new information and able to plan effectively for the future, which in turn may enhance the effect of psychological therapy.
We do not yet know how effective the ketamine treatment will be. However, well-designed research studies, such as the KARE trial, could be critical in helping people achieve their abstinence goals.