AMA on Wed 5/13/20: renowned ketamine psychiatrist and geneticist

Huge subject! Let me say that we now know that there are no major genes (meaning genes with big effect sizes) for psychiatric disorders with the exception of certain genes that contribute to autism spectrum disorders. Rather, many genes each of small effect contribute to psychiatric disorders. This means that we are unlikely to have a situation like in the movie GATTACA where one could predict who will have a psychiatric disorder from birth. Many genes and many environmental factors interact to produce mental illness. In terms of precision medicine, It is more likely that we will find genes that contribute to aspects of mental illness, like certain types of symptoms or response to certain treatments. There are a number of companies that currently offer genetic tests to help evaluate potential responses to various medicines. These tests largely predict the speed at which an individual can metabolize various drugs.

There is actually quite a bit of research on ketamine for PTSD, though less so on anxiety. Those of us who have a lot of experience with ketamine see great success with PTSD, and less so with generalized anxiety for example. Anxiety is tough to treat, it’s a core evolutionary strategy to protect and motivate us and tough to extinguish. I think of it as a U-shaped curve- the up slope is the good kind of anxiety that leads you to get your projects in on time but then too much anxiety leads to mental paralysis. What I have seen with PTSD is that sufferers are able to anchor the past in the past, they can recall the event(s) in a state of physiologic calm and experience a sense of forgiveness for self and others. Some of the effects are mystical in nature and continue to amaze me.

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I would say the former is very popular its just more underground. The vast majority of academic centers study IV. Yale has also looked at IV with CBT done in a separate session. KAP is usually done while the person is under the influence of ketamine. I have extensive experience with both methods and I think it really just depends on the individual which approach is best.

You have it in the UK though I am pretty sure it’s mostly oral. You can look up Dr. Rupert McShane who can probably give you lots of info. Germany, Australia, France, Canada, Brazil. These are just off the top of my head. I’m sure it’s wide spread. Ketamine is one of WHO’s essential medicines and it is available everywhere.

Hello, can you talk about the4 potential of ketamine and/or other psychedelics in helping people break addictions to alcohol, benzodiazepines or opiates? I recall reading about old studies from the 60’s on this, but nothing recent. Thank you.

Ketamine and traditional ADs both promote the secretion of Brain Derived Neurotrophic Factor (BDNF) which is a growth factor for neurons. Ketamine does this much more rapidly AND it releases mTORC1- which is another growth factor that, in concert with BDNF, cause the rapid formation of new neuronal synapses (connections) which is the cellular basis for learning. Hence it is a powerful procognitive therapy (and this is one of the reasons why it enhances talk therapy so much). Ketamine also causes neurons in certain regions of the brain to start firing in synchrony. Please see the April 2019 issues of Science for a thorough scientific discussion (geek alert!). It has anti-inflammatory effects AND it changes the ratio of certain tryptophan breakdown products in the brain to one that enhances NMDA-R antagonism (the opposite ratio of products has been shown to be elevated in patients who suicide). All the mechanisms I just mentioned happen after the ketamine leaves the body (and we know they happen because of work in mice). The transformational experiences ‘in the chair’ are also a very important part of its mechanism of action and are more mysterious.

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In rare cases, total alleviation of depression. Much more commonly I see an initial profound improvement but then a long recovery period with ups and downs as the person adjusts to going back to work, trying to restore relationships, trying to cope with the demands of wellness and changing the expectations of others.

Group Dosing! Giving oral ketamine in a group format was the most fun I have ever had as a physician.
Oral ketamine is the most affordable. It is about 70$ a month from most compounding pharmacies. Then you are just paying for the physician’s time. IV is expensive because you need a medical provider and a nurse who can put in an IV-the ketamine is itself just pennies. Intranasal esketamine is newly patented and ridiculously expensive, even if its covered by insurance you still have to pay upwards of 250 per session for the medical supervision (2.5 hours) and every session must be supervised.

Theoretically you should also try an SNRI (duloxetine, venlafaxine) because they can work when SSRIs don’t. While ketamine is fantastic in many ways because of its rapid action, it’s also expensive to get and it can kind of tie you down if you want to travel abroad for a while.

I don’t have enough experience with persons overusing ketamine to comment. Actually it amazes me that in the 6 years I have been working with K I have only very rarely observed anyone trying to game the system and use more than they should.

Dissociation results from antagonism of the NMDA receptor (a type of glutamate receptor) which is believed to be critical to the mechanism of action of ketamine therapy for depression and pain. Many people, but not everyone, also enjoy the sensation of dissociation which can be defined as distortion of any of the 5 senses but is commonly experienced as a floaty feeling.

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Yes to both

Jimmy is helping me out during this AMA :slight_smile:


Possibly, IV ketamine is 100% bioavailable. IN ketamine is quite close to that but its bioavailability can be variable depending on your nasal mucosa. Lozenges have low bioavailability (17-23%) and you could also be a rapid metabolizer. Very important to do therapy in conjunction with ketamine (either in the treatment session or same week) if you can. This greatly enhances response.

Oh this is super interesting Dr. McInnes! Could you briefly describe a typical group session? I’ve never been part of one. I assume a handful of clients in each session? Would this group meet together multiple times, or are there different people in each group over time? As a doctor how do you coordinate this?
Thanks so much

All the different psychedelic medicines (including ketamine for our purposes) will be useful. Depression has many etiologies and we need many approaches. Benzodiazepines for sure diminish the effectiveness of ketamine treatments. There is a paper on this which you can look up or take it from me. Alcohol and benzodiazepines both work via the same inhibitory neurotransmitter system (gaba) and both are to be avoided while having K treatments.

Not that I know of.

Ketamine has been used extensively to treat alcoholism since the 1970s, an effort led by Eugene Krupitsky in Russia among others. Elias Dakwar at Columbia University is now doing fantastic work using a single ketamine infusion and therapy for cocaine addiction. There is also renewed interest in using ketamine for alcohol use disorder in this country. AND it is used to treat pain in patients who have become tolerant to opioids so that is another area to be explored.

It is actually really straightforward though an additional person (therapist, RN) is helpful. Folks come in and will sit in regular chairs in a circle. They do their mood surveys, we have a brief check in then the SL ketamine is given (dosing between 50-200- you can do an individual dose finding session first for each member or do dose finding together). Then there is a mindfulness activity for about 20 minutes or so and then patients and the providers use a side-effect rating sheet to assess the degree of mood elevation, dissociation and other side-effects that are present. The target dose is the one in which the patient exhibits mild-mod mood elevation and dissociation with all other side-effects being low. Then the group leader(s) facilitates a discussion and patients can go on their way. The whole process takes about 90 min at most. I’m sure I left something out but you can ask me more about it later.
About 4-6 clients max and yes, meeting for once weekly for two months works really well.

Hi Dr. McInnes,

Thank you for being here to chat with us! Do you have any recommendations for how psychiatry residents, or medical students interested in psychaitry, could get experience with treating patients with ketamine-assisted psychotherapy?