What Does It All Ketamine?

By Neuroskeptic | April 3, 2018 2:41 pm

Regular readers will know of my interest in the theory that ketamine is a rapid-acting antidepressant. I’ve blogged about developments in ketamine-depression research for several years now, my interest being spurred partly by my own struggles with depression.


As I’ve said previously, the research on ketamine as an antidepressant is promising, but I do not think it is possible to say yet how ketamine works in depression. I think it is possible that ketamine’s apparently powerful effects are a kind of psychological response, related to (but not limited to) the placebo effect, and driven by the striking subjective ‘dissociative’ effects of the drug.

In this post I’ll look at two new papers that relate to this theory. First off, we have Niciu et al. in the Journal of Affective Disorders. Niciu and colleagues report that acute experiences of ‘depersonalization’ in response to a dose of ketamine predicts the subsequent improvement in depression symptoms (HAMD17 score) after 7 days.

Depersonalization is one of the effects of ketamine and it refers to a feeling of “detachment from the self”. Other aspects of ketamine’s effects, ‘derealization’ and ‘amnesia’, did not consistently predict the antidepressant outcome.


Niciu et al. propose a neurobiological explanation for this correlation – essentially, that the dissociative and the antidepressant effects of ketamine have the same molecular basis.

We hypothesize a potential causal link between Depersonalization and antidepressant response, initiated by glutamate receptor modulation

But, like me, they also acknowledge the possibility of dissociation-induced unblinding, driving placebo effects (although I think there may be even more going on):

Due to its psychoactive and sympathomimetic effects even at low doses, many patients can distinguish ketamine from an inert (saline) placebo… In this regard, both subject and staff unblinding may overestimate antidepressant response to ketamine in placebo-controlled studies, especially in subjects who exhibit more dissociative side effects.

Overall, this study is consistent with a ‘psychological’ interpretation of ketamine’s effects – but it’s also fully consistent with a purely neurobiological interpretation. In short, it doesn’t distinguish between them. It is hard to see how any purely correlational study could settle this issue, which is why I think we need more creative study designs comparing ketamine to other drugs with profound mind-altering effects, like, say, mescaline.


Now, we come to the second paper. This one isn’t actually a ketamine study, but it was inspired by the ketamine-depression model, and it comes from the same NIMH lab as did Niciu et al. Writing in the Journal of Clinical Psychopharmacology, Kadriu et al. describe a failed clinical trial of a drug called diazoxide for the treatment of depression.

The diazoxide trial was halted soon after it began because of ‘severe adverse effects’ caused by the drug, including headache, low blood pressure, pain, nausea, and more. Of the six volunteers who took diazoxide, five quit early because of the side effects, so the study was abandoned.

What went wrong? Well, diazoxide’s medical use is to lower blood pressure and raise blood sugar (by suppressing insulin). In physically healthy people, like the volunteers in this study, both of these effects are undesirable and probably account for the side-effects.

Now, what does this have to do with ketamine? Well, Kadriu et al. report that they tried diazoxide because it is believed to increase glutamate reuptake (and thus decrease available glutamate) in the brain, making it a little bit like ketamine, which blocks glutamate receptors. So, although they are very different, the two drugs broadly share ‘anti-glutamate’ effects, leading Kadriu et al. to wonder if they share antidepressant effects too.

So why am I blogging about this paper? Because to me, it illustrates why the debate over ketamine’s mode of action matters. It matters because it determines the kind of research that is carried out.

If the antidepressant effects of ketamine are a neurobiological consequence of glutamate receptor blockade, then studies like the diazoxide study make sense. If it’s all about glutamate, then studying other glutamatergic drugs might reveal an even better antidepressant than ketamine.

But if a psychological reaction to the dissociative effects is what makes ketamine work in depression, then everything changes. In this case, research on glutamatergic drugs would not be advisable unless they were dissociative (and diazoxide isn’t.) On the other hand, non-glutamatergic drugs with powerful subjective effects might be worth a look. The psychology of the therapeutic experience (mindset, expectations, and interpretations) would also be of interest.

This is why I disagree with the idea that ‘who cares how it works? If it works, it works.’ When we consider the big picture, including the research priorities, I think it really does matter how ketamine works.

CATEGORIZED UNDER: drugs, ketamine, papers, placebo, select, Top Posts
  • Acrophonous

    I thought the beneficial effects of Ketamine were from causing new neural connections? Depression often manifests itself by getting “stuck” on thinking only about certain bad things over and over again. Ketamine alleviates this by cause new connections to form and thereby breaking up the old routine ways of thinking… or so many popular science articles have said. Is this completely wrong?

  • Bernard Carroll

    If ketamine ‘works’ in depression we can infer that it does so by reducing overactivity in a mood circuit through blocking a glutamate step. Ketamine has a similar action in overactive motor circuits in Parkinson’s disease – a fact exploited by anesthetists to assist with difficult intubations. So far so good. But the plasma half-life of ketamine is short at <15 minutes, while the biological half-life is just around 3 hours. It is hard to see how the primary pharmacological action of ketamine explains clinical improvement of depression 7 days later. For a comparison, when the mood circuit overactivity in mania is subdued by increasing brain acetylcholine levels with physostigmine, the patients quickly return within hours to their original intensity of manic symptoms.
    I agree with your final paragraph. The developing ketamine-depression narrative elides too many issues.

    • seanfw

      One possible explanation could come from dynamical systems point of view. The could be attracted towards a depression
      baseline state under normal conditions (e.g. a recurring pattern of brain activity, or in dynamical systems speak a stable fixed point or limit cycle) . However, it is possible that ketamine could cause such a big shift of the system as to push the system closer to another attractor (e.g. stable pattern of brain activity), and could even make the depression state disappear (through a bifurcation). Just a speculative thought, but perhaps that’s what blog comment sections are for. :-)

    • Evan Cary

      It could be that the antidepressant effects come not from the drug´s initial effects, but from the body´s reaction to those effects, I.E. tolerance to the ketamine. That would explain the peak of the effects being several days after peak levels of the drug have been reached. Ketamine slows down glutamate signalling, and the body reacts by increasing it across the board, which causes the antidepressant effects. This peaks after a few days, and then drops off. NMDA antagonists are well known to induce mania if taken over time. The mania peaks not during the drug effects, but days afterward in my experience. I think this works through the same mechanism. NMDA antagonist tolerance is what is producing the effect.

  • Danai Riga

    I just wanted to mention last year’s paper from Donegan et al.,
    which shows glutamate-independent effects of ketamine contributing to it’s behavioral (antidepressant-like) effects. And this is just an example…Just focusing on glutamate and downstream targets is rather simplistic. Network effects and changes in E/I balance should be accounted for.

    • TLongmire


  • TLongmire

    Imagine the multiverse, now imagine divergence within it. Take a unique disassociatitve and break from the gravitational pull of suffering within it.

  • CL

    I think it (also) acts through anti-inflammatory pathways. In many aspects, depression can be viewed as a form of sickness behavior. Social withdrawal, action avoidance and excessive, but light sleeping all makes sense if you are a hurt animal.

  • jrkrideau

    involved in a Ketamine trial for depression, anxiety and mood stabilising.

    Who is hosting this trial? Is it home-based in an academic setting or possibly by a drug company? Does it have approval from what looks to be a reputable ethics committee (IRB in the US?).

    Do you or your siblings have your copies of the consent to participate forms that you signed?

  • Time

    If you struggle with anxiety, depression, etc, read the book Nutrient Power by William Walsh, PhD. He talks about how these conditions are created biochemically, such as being caused by under-methylation, which can be corrected with nutrients. There is a simple test to determine this. He also notes that there are only 6 or 7 nutrients which dominate processes in the brain, so it is relatively easy to figure it out and correct this. My mother struggled with depression for 50 years. I wish that I had this knowledge while she was alive to help her.

    • Bharati_shahida

      Exercise, some strenuous, for an hour daily, natural B vitamins, eating yogurt (with bacteria) from time to time, no white sugar or alcohol and plenty of hilarious movies/books may help. Some exercises/Yoga postures are especially good. If not too sceptical, do use Reiki: one hour daily. Counting one’s blessings daily with gratitude too may help emotionally.

  • http://juancmirre.com/ juan carlos mirre

    Tons of Bullshit!
    It’s well known that ketamine increses BDNF >> brins down depressio

  • Maryanna Starr

    That’s very interesting news about the effects of Ketamine in antidepressant therapy. I wholeheartedly agree, It is imperative to know exactly how the drug works in depression before it is set up to use as a therapy. Being a part of the medical community for 30+ years, I have one concern. This drug has been actively used as a “Recreational drug” since it’s invention. It has been highly sort after by addicts for it’s relaxation & hallucinatory effects and, from what I hear, has quite an accessible black market supply. The addiction rate is rapidly increasing, (as in all additions). This is evident in the previous post about the girl who was released from her study for continually asking for increases in her drug doses. Ketamine has great addiction potential when not used in the clinical hospital setting and has the same classification as Class I Narcotics. Do the benefits outweigh the addiction potentials? Maybe, I do not know and can not say. I have just experienced Ketamine when used as an intravenous anesthesia agent. What I can say is that it would have to be very closely monitored by a physician who has experience with prescribing its specific use in depression. Now that would be a cross between an Anesthesiologist and a Psychiatrist. The drug was originally developed as an anesthesia agent for children. It was said to cause a “twilight sleep”, greatly reducing pre-operative anxiety in children. Also, early in the drug’s history, it was used for women suffering intense anxiety during child labor. As med students we were always instructed about Ketamine’s great potential for abuse, not only by the public, but in the medical profession as well. So this drug has a great addiction potential, in a world that already has so many addiction choices. Therefore I conclude, Yes, it is essential to know what the drug actually does, and how it works to achieve its effects, BEFORE it is considered as a viable depression therapy. Lord knows we already have so many drug recalls & related lawsuits as it is.

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  • DZ-015, M.D.

    Another way to test the glutamate theory is through ketosis, either with fasting or exogenous ketones. BHB over glucose favors GABA to glutamate.

  • My Own Life

    Here’s a rodent study that compares an alternative with ketamine:
    “S 47445 is a positive modulator of glutamate AMPA-type receptors, possessing neurotrophic and enhancing synaptic plasticity effects as well as pro-cognitive and anti-stress properties.
    S 47445 by inducing a direct activation of AMPARs displayed an antidepressant activity without the adverse effect of ketamine. Indeed, contrary to ketamine, S 47445 presented no psychotomimetic effects and induced no occurrence of spontaneous epileptic seizures.
    Ketamine, however, causes severe cognitive impairment and psychotomimetic effects that are direct consequences of the prolonged inhibition of NMDA receptors in cortical and hippocampal interneurons, and seriously limit the chronic administration of the drug in the clinical setting.”

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  • B Waldrop

    I am desperate for help with my 20 year long battle with treatment resistant MDD and am thinking of trying ketamine infusions. The cost is very prohibitive, however, and it is well-known that they do not work for everyone. I have read that there are genetic tests that can help predict if ketamine will have an effect on you or not. Have you heard or read anything about this? I need to know before I go into debt with my money and involve my body. One thing I’ve read mentions something to do with methylation, one says the COMT gene and another suggests checking out my expression for CYP2D6 SNP. This is all over my head, but it might be right up your alley. I’d love to hear your thoughts.

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About Neuroskeptic

Neuroskeptic is a British neuroscientist who takes a skeptical look at his own field, and beyond. His blog offers a look at the latest developments in neuroscience, psychiatry and psychology through a critical lens.


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