A very good friend sent me a landmark study surrounding Ketamine a little while ago.  In drug research, big effects and powerful findings are usually accompanied by tiny sample sizes and weird statistics magic to rig the findings. So when I read the meta-analysis and systematic review published in The American Journal of Psychiatry, I was heartened. This is serious science and serious stats, with 167 patients evaluated across multiple studies. Also, the reporting scales (MADRS, HAM-D, QIDS-SR & the BDI) are well understood, robust and respected in the field. All of this adds up to this results abstract being very, VERY important:

Ketamine rapidly (within 1 day) reduced suicidal ideation significantly on both the clinician-administered and self-report outcome measures. Effect sizes were moderate to large (Cohen’s d=0.48–0.85) at all time points after dosing. A sensitivity analysis demonstrated that compared with control treatments, ketamine had significant benefits on the individual suicide items of the MADRS, the HAM-D, and the QIDS-SR but not the BDI. Ketamine’s effect on suicidal ideation remained significant after adjusting for concurrent changes in severity of depressive symptoms.
~The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review & Individual Participant Data Meta-Analysis (Wilkinson et al)

That’s a dense couple of sentences, so let me explain why it’s so earth shattering. Suicidal thoughts, (known as suicidal ideation in clinical psychology) and depressed feelings are very difficult to get rid of, especially for depressed people. Treatment-resistant depression is a term associated with someone who has attempted multiple types of treatment for their Axis I disorder, but it hasn’t gotten better. After trying multiple types of interventions with no success, people slide quickly into hopelessness and thoughts of self harm. Up until now, depression treatments like SSRI drugs and Cognitive Behavioral therapy take time to work, sometimes more than a month. If you’re not in a good place right now, these things can’t help you. Ketamine infusions help immediately, and the change is apparent both to the patient and to the interviewing physician afterwards. This bit is huge, as most drug research relies heavily on self-report, which leads to bias and distorted findings. But, people are already talking to the press swearing by it, and it’s getting quite a lot of press, so here’s what they’re talking about.

When they say “intravenous Ketamine,” they mean an IV clinical grade ketamine, administered in a doctor’s office, by a licensed medical professional.  This is not doing key bumps all night at BassCenter. A lot of writing about Ketamine on music blogs or surrounding party culture doesn’t make the distinction between celebratory & restorative/medicinal drug use. There’s a big difference between snorting powders of questionable purity while doing 2-3 other drugs, staying out all night, eating shit for 3 days and not having any Serotonin on Tuesday, and receiving an infusion in a controlled environment with vital signs being monitored and post-experience work with licensed professionals. But I wanted to know more, so I dunked my head under the putrescent waters of knowledge to find out what other research has been done with K and what it means for people, depressed and wook alike.

Ketamine was originally seen as a “psychomemetic” or a substance that stimulates or mimics psychotic symptoms. 6 patients in 1994 were shown to have spikes in ratings on the Brief Psychiatric Rating Scale, including a bunch of symptoms seen in schizophrenia. Also in 1994, Yale released the first study categorizing the effects of Ketamine on non-psychotic, healthy humans. Now, many who have taken ketamine recreationally think that the hallucinations, delusions, thought disorders and disassociation aren’t bugs but features. At the time, it was seen as potentially amplifying psychotic or schizophrenic syndromes in patients. In 2000, the same group evaluated the effects of K on both healthy & schizophrenic volunteers, in an effort to determine whether the effects of the drug were consistent between mentally ill & non-mentally ill people. Interestingly, while the schizophrenic patients saw the expected amplification of their symptoms, the healthy controls saw both those “psychotic” symptoms, but also the expected symptoms of withdrawal, motor function retardation and blunted affect that we’ve all seen people in K-holes exhibit.

The similarity between ketamine-induced symptoms in SVs and their own positive symptoms suggests that ketamine provides a unique model of psychosis in human volunteers. The data suggest that the phencyclidine (PCP) model of schizophrenia maybe a more valid human psychosis/schizophrenia drug model than the amphetamine model, with a broader range of psychotic symptoms.
~Effects of Ketamine in Normal and Schizophrenic Volunteers (Lahti et al)

One of the first studies to show the non-psychotic potential of Ketamine came out of Yale & the West Haven VA Hospital. Only 7 people participated, but the effect size was huge. That HAM-D survey from before? Patients saw a 14 point drop on a scale that only has 25 items. In 2007 scientists pumped the brake a bit, with some clinicians worrying about the long-term safety profile of Ketamine as a therapeutic drug. After reviewing studies with 450 subjects, receiving a total of 833 real doses of ketamine administered in an experimental environment (not clinical), the Yale Ketamine Study Group only found ten (10) adverse mental status events. An adverse mental status event includes dizziness, confusion, disorientation or, you know, most of the stuff that happens when you take K. Ten, documented in nine patients, with all of the effects ending by the end of the experimental session except for one. That’s 2% of patients. Only one adverse experience lasted for longer than 4 days. Does anyone want to compare that to Vioxx or Tramadol or Seroquel? Cause that’s a shockingly low adverse event rate, especially for a drug associated with comatose farm animals.

To be clear, Ketamine has also been shown to be exceptionally effective at alleviating treatment resistant depression symptoms, albeit temporarily. The NIMH cites a landmark study from 2006, published in the Archives of General Psychiatry which showed patients seeing relief from depression symptoms in as little as 2 hours. This June, a study published in Nature documented the “super sticky SSRI” effect that a number of other reporters and researchers showed in smaller sized trials. This is due to the effects of (2R,6R)-hydroxynorketamine (HNK), a ketamine metabolite. Because K’s metabolites are active, the anti-depressant effects are much more durable, especially over the mid-term, like the following week.

In their new laboratory research, Monteggia and her colleagues studied what happens when a metabolite of ketamine is applied to a certain part of the brain called the NMDA receptor, which plays a role in many brain functions. Past research has indicated that ketamine blocks this receptor, which seems to trigger psychedelic and antidepressant effects. They found that it does block the receptor, which sets off a cascade of effects, including antidepressant ones. But the newest and most exciting finding is that ketamine appears to block the NMDA receptor by sitting on a very particular region of it.
~There’s More Proof That Ketamine Works for Depression, TIME 6/21/17

Ketamine was also evaluated as a potential treatment for PTSD in 2014 at the Icahn School of Medicine of the Mount Sinai Hospital system here in NYC. The study, published in JAMA Psychiatry, showed that single infusion not only rapidly reduced PTSD symptoms, but also kept them down for up to 2 weeks for some patients. The study only had 41 patients, so the findings aren’t quite as seminal, but definitely cause for further research. Ketamine & MDMA could end up being the pivotal medicines needed to heal the thousands of wounded veterans returning home from our wars in the Middle East.

After finding that Ketamine works on treatment-resistant depression, PTSD, and even obsessive compulsive disorder, researchers wondered just how many things K would work on. So, some researchers in New Zealand dosed 12 patients on Ketamine, at 3 levels (0.25, 0.5 & 1mg/kg, delivered under the skin, but not IV). The patients saw their anxiety drop in under an hour, with this effect persisting for up to a week. After seeing K work for all of these things, the researchers from down under could hardly contain their excitement:

Ketamine may be a potential therapeutic alternative for patients with refractory generalized anxiety disorder/social anxiety disorder. Along with its demonstrated effectiveness in patients with treatment-resistant depression, obsessive compulsive disorder and post-traumatic stress disorder, these data raise the intriguing possibility that ketamine may have broad efficacy in disorders characterized by negative emotional states, and that these disorders may share a common precipitating neurobiology.
~Ketamine’s dose-related effects on anxiety symptoms in patients with treatment refractory anxiety disorders (Glue et al)

It’s even been found to help reduce symptoms of bipolar depression, or manic depressive disorder, as it’s more commonly known. A very small (n=12) study out of Columbia University’s Department of Psychiatry showed it could work in tandem with another FDA approved drug, D-cycloserine. When K was administered, followed up by D-cycloserine, 4 met remission criteria by 8 weeks out. This is a study so small it could almost be seen as anecdotal, but we need to start thinking of how Ketamine can work in tandem with other drugs. Ketamine is a potent and drug, that interacts with our brain in tremendously complex ways.

While most of these studies have evaluated Ketamine as an IV-delivered substance, a study published in the Journal of Palliative Medicine in 2014 showed that it could still provide a startlingly effective antidepressant and anxiolytic (anxiety reducing) effect, with anxiety reduction being seen in patients on day 3. However, please don’t take this to mean that K can be self-dispensed or that you can snort your way to happiness. One 2012 review of recreational Ketamine use published in Addiction found ulcerative cystitis as a “major physical harm”, while a study out of the Clinical Psychopharmacology Unit of the University College in London back in 2010 detailed the breadth and depth of cognitive functioning problems associated with recreational ketamine use over the long term. Consequences include:

In frequent users, increasing Ketamine use over the year was correlated with decreasing performance on spatial working memory and pattern recognition memory tasks. Assessments of psychological wellbeing showed greater dissociative symptoms in frequent users and a dose–response effect on delusional symptoms, with frequent users scoring higher than infrequent, abstinent users and non-users, respectively.
~Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study (Morgan et al)

So what is it about ketamine infusions that make them so effective, compared to your random friend who loves classic Raja Ram and redefined couch lock in the 2000’s? Signs point to Ketamine’s action at the NMDA receptor site, one of the glutamate receptors. By affecting glutamate receptors, a wide range of changes associated with learning and memory are thought to be effected. But, recent research confirms Ketamine’s NMDA receptor activity. Make sure not to miss the next installment, where I explain how Ketamine and its metabolites have become the linchpin in a new understanding of the neurobiology of depression, PTSD and mental illness.