Brain Health,

#135: Treating Depression with Ketamine

July 01, 2016

Falling down the K-HoleTaking “Special K.”   Ketamine has quite the reputation as a recreational club drug.  But research is showing its promising potential as a treatment for severe cases of depression.

Jesse talks to Dr. Panos Zanos, Postdoctoral Researcher at the University of Maryland School of Medicine, (who has possibly the best name of any Smart Drug Smarts guest to date) about his research on ketamine and depression.

Medical and Recreational Uses

Ketamine was originally synthesized in a lab as a safe anesthetic and continues to be approved in many countries (including the US) for anesthesia and sedative use.  In the US, it’s classified as a Schedule III drug, meaning it has currently accepted medical uses, but carries a danger of abuse.

It’s the dissociative effects — feeling detached from the environment and users’ own selves, as well as experiencing sensory distortion — of ketamine that’s made it popular as a recreational club drug.  Users report feeling numb and serene, like they’re in another world or walking on clouds.  Important note:  while there’s no current evidence of any addiction potential, there’s certainly abuse potential.

A New Use For Ketamine:  Treating Depression

For sheer speed of efficacy, ketamine blows conventional antidepressant therapies out of the water.  Patients feel relief within two hours after a single ketamine injection, while traditional medicine can take up to three months to work.  It’s no surprise, then, that ketamine is often used as an emergency treatment in crisis situations to disperse suicidal thoughts.

But ketamine has potential as a long-term treatment as well.  The antidepressive benefits from one injection last up to two weeks. Multiple studies have confirmed these antidepressive effects.  Unfortunately, you’ll have to contend with all the side effects as well.  The dissociative effects of ketamine may become more pronounced and enduring with repeated treatment.  This is something that needs to be researched further — no one knows the long-term effects of persistent ketamine treatment.

How Does Ketamine Work?

There’s a lot we don’t know about ketamine yet, and it contains a shit ton (that’s the technical term) of substances, each with its own effect.  Here’s what we do know:

Once ketamine enters the body, the liver quickly breaks it down, creating metabolites (a chemical byproduct of the breakdown process), which stay in the body for up to a week.

Metabolites are responsible for the mood-boosting effects of ketamine, without all the side effects (anesthesia, dissociation).  Dr. Zanos’s recent research shows that a metabolite called (2R, 6R)-hydroxynorketamine is at least partially responsible for ketamine’s antidepressant benefits.

This is good news for depression sufferers, since if the active metabolites can be isolated, they can be used to treat depression without the ketamine high.

As for how ketamine metabolites lift depression, the jury’s still out, but a few likely theories have emerged.  Ketamine may work by…

  1. Increasing levels of glutamate, an excitatory neurotransmitter that may be linked to depression.
  2. Inhibiting NMDA receptors, a type of glutamate receptor.  NMDA receptors are a component of the glutamate pathway, involved in memory and cognition.  However, human trials of non-metabolite NMDA-receptor blockers were unable to replicate ketamine’s powerful antidepressant effects.
  3. Promoting the release of brain-derived neurotrophic factor (BDNF).  Depression damages neurons and synapses, while BDNF promotes neurogenesis and strengthens existing synapses.

Perhaps the most promising theory so far:  activation of AMPA receptors (another type of glutamate receptor).  Dr. Zanos’s recent research shows that, at least in mice, antidepressant effects depend on activating AMPA receptors.

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Read Full Transcript
Show Notes
  • 00:00:22

    Ketamine and depression

  • 00:01:40

    This Week in Neuroscience: Why We Sleep Badly on Our First Night in a New Place

  • 00:04:24

    The audience interaction section

  • 00:06:26

    Dr. Panos Zanos and his work with Ketamine

  • 00:08:35

    Ketamine as an anaesthetic

  • 00:09:45

    Recreational versus medical use

  • 00:10:31

    Are there downsides with repeated use?

  • 00:11:10

    Acute effects of ketamine

  • 00:11:52

    Therapeutic uses

  • 00:14:44

    The legality of ketamine in different parts of the world

  • 00:16:38

    Which metabolites are pharmaceutically active?

  • 00:17:44

    How was ketamine discovered?

  • 00:18:16

    How ketamine treats depression

  • 00:20:31

    Memory impairment

  • 00:22:07

    Are there any contraindications?

  • 00:23:37

    How long have scientists been researching ketamine as an antidepressant?

  • 00:26:03

    Ketamine as an off-label therapeutic treatment

  • 00:28:07

    Scheduling of ketamine in the U.S.

  • 00:30:00

    Ketamine’s additive effects

  • 00:32:40

    A first-hand account of ketamine treatment for depression

  • 00:34:45

    Ruthless Listener-Retention Gimmick: Doctor’s Plan for Full-Body Transplants Raises Doubts Even in Daring China


  1. Ela says:

    This was a fascinating interview–I love these dicussions when we’re pretty much at the “sandbox” stage of research.

    Something that jumped out at me to comment on here was that ketamine’s method of action as characterized also contraindicates it for certain situations. Anyone who needs to _reduce_ glutamate as part of their mood-disorder amelioration program will need to try something different.
    I have Bipolar 1 disorder, and the best treatment for it hands down (gotten me off of meds) has been a classic 4:1 ketogenic diet, part of whose method of action is glutamate reduction. For bipolar depression, I would therefore say no to ketamine, just as SSRIs should not be used for bipolar depression because they can cause breakthrough mania. Unfortunate that “ketamine” sounds a liitle like “keto”!!

    My n=1 may be complicated because I have celiac and a lot of gut damage too, but I’m a “paradoxical responder” to a lot of nervine herbs and supps that work on the GABA pathway (ashwagandha, skullcap, California poppy) and have had weird responses to other neurostimulant compounds too. I suspect I was making GABA into glutamate in these cases too. I’m not unique in this–“paradoxical/backward responder” is a thing herbalists are aware of. I don’t yet understand the whole of how/why this happens, but I like being able to see some common patterns.

    Unsolicited comment: the new(ish) tagline “where smart people talk about smart drugs” is nowhere near as fun as the old one “so smart we have smart in our title — twice!” I used to enjoy that old tagline every time, whereas this new one sounds tautological and gratuitous and makes me roll my eyes.

    Thank you so much for this treasure of a podcast!
    Ela (pronounced eela)

    1. Jesse Lawler says:

      Thanks Ela! Yeah, it sounds like right now ketamine “best practices” are a little more like “fondest hopes” and the specific how-to’s and caveats will still take a while to work out. Thanks for your additional notes on glutamate/ketosis/bipolar.

      As for the taglines — we just must not be shuffling them as much as we used to. We’ve had the same grab-bag almost ever since the show started and aren’t trying to play favorites. 🙂


  2. Jen says:

    “Jesse: Are there particular contraindications, people that should never be given ketamine for one reason or another because of what it’s doing physiologically? ”

    If you check, you will see that mixing ketamine with alcohol will cause vomiting.

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