podcast Peter Attia 2022-08-29 topics

#220 ‒ Ketamine: Benefits, risks, and promising therapeutic potential | Celia Morgan, Ph.D.

Audio

Show notes

Celia Morgan is a Professor of Psychopharmacology at the University of Exeter who has authored numerous publications on the potential therapeutic uses of ketamine in mental healthcare. In this episode, Celia dives deep into the neurobiology of ketamine, how it affects users, and how it differs from other, more classical psychedelics (LSD, MDMA, PCP, and psilocybin). She explains the potential promise of ketamine as a treatment for recalcitrant depression and addiction, and she details the results from her clinical trials in these areas. She discusses the importance of using ketamine in combination with psychotherapy to maximize its benefits, the potential risks associated with ketamine use, and advice for those interested in the therapeutic use of ketamine.

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We discuss:

Celia’s training and interest in ketamine [2:15];
The history of ketamine, medical uses, and use as a party drug [3:30];
Neurobiology and pharmacology of ketamine [8:15];
Ketamine regulation and abuse, and how it compares with psychedelics and other molecules [18:15];
Ketamine as a therapeutic for depression [30:45];
The brain under the influence of ketamine and theoretical mechanisms for its anti-depressive effects [48:00];
Risks and concerns with overusing ketamine, and what an intermittent or maintenance dose might look for a patient [57:15];
Treating addiction with ketamine: Celia’s studies of alcohol dependance [1:04:00];
Advice for people considering the therapeutic use of ketamine [1:19:45]; and
More.

Show Notes

*Notes from intro :

Celia Morgan is a Professor of Psychopharmacology at the University of Exeter in the United Kingdom
Celia’s research focuses on the benefits and side effects of recreational drugs and alcohol on cognition, behavior, and neurobiology
She has authored numerous publications on the potential uses of ketamine and other drugs as therapies in mental health
She completed her undergraduate degree and PhD at University College London, followed by a scholarship program at Yale University
Celia conducted research at the University of Melbourne prior to returning to University College London
She eventually moved on to the University of Exeter, where she became the Chair of Psychopharmacology in 2015
In this episode, we dig deep into ketamine We talk about the neurobiology and the chemistry of ketamine How it affects individuals How it affects specific parts of the brains How it differs from other things that we might think of as psychedelics Although Peter doesn’t really consider ketamine to be a psychedelic We contrast it with things like psilocybin and LSD
We then talk about the potential promise of ketamine for treating drug-resistant (or recalcitrant) depression and alcoholism
We talk about the importance of therapy being offered concurrently with ketamine treatment, as many people listening to this might wonder if ketamine therapy is indeed for them
We talk about the neurobiology and the chemistry of ketamine
How it affects individuals
How it affects specific parts of the brains
How it differs from other things that we might think of as psychedelics Although Peter doesn’t really consider ketamine to be a psychedelic We contrast it with things like psilocybin and LSD
Although Peter doesn’t really consider ketamine to be a psychedelic
We contrast it with things like psilocybin and LSD

Celia’s training and interest in ketamine [2:15]

Celia’s training

Celia did her undergraduate in psychology with pharmacology and astrophysics
She did a PhD program at University College London As part of that, she spent time at Yale on a scholarship to do some research in the US
Her PhD was largely focused on the effects of ketamine She looked at the acute effects of ketamine as a model of psychosis At the time people were using ketamine with the idea that would help us understand the neuro-biological underpinnings of psychosis, because actually, from the outside, ketamine looks a little bit similar to people who are psychotic They were using that to map the kind of cognitive processes altered by ketamine Simultaneously, she was also looking at people who take ketamine recreationally At the time that was quite a big problem in the UK
When she went to the US, it was to work on neuro-imaging studies looking at ketamine as a model for psychosis This was before it really became established as an antidepressant
As part of that, she spent time at Yale on a scholarship to do some research in the US
She looked at the acute effects of ketamine as a model of psychosis At the time people were using ketamine with the idea that would help us understand the neuro-biological underpinnings of psychosis, because actually, from the outside, ketamine looks a little bit similar to people who are psychotic They were using that to map the kind of cognitive processes altered by ketamine
Simultaneously, she was also looking at people who take ketamine recreationally At the time that was quite a big problem in the UK
At the time people were using ketamine with the idea that would help us understand the neuro-biological underpinnings of psychosis, because actually, from the outside, ketamine looks a little bit similar to people who are psychotic
They were using that to map the kind of cognitive processes altered by ketamine
At the time that was quite a big problem in the UK
This was before it really became established as an antidepressant

The history of ketamine, medical uses, and use as a party drug [3:30]

Figure 1. The chemical structure of ketamine. Image credit: c&en 2020

Ketamine was synthesized in the ‘60s as an anesthetic to replace PCP (phencyclidine)
People know PCP as angel dust There is a kind of folklore around it, of people running at the police and being shot down yet kept running. The problems with PCP is it had this protracted psychosis-like effects that lasted for a really long time following anesthesia It was still a good analgesic anesthetic
Ketamine was synthesized as a similar molecule, so it still worked on the same receptor in the brain, the NMDA receptor , but it was 10 times less potent
The drug company that synthesized it was initially really impressed by its analgesic and anesthetic effects, but then with increasing clinical experience, it was noticed that people were coming around from ketamine anesthesia reporting a variety of weird effects Things like hallucinations and out-of-body experiences And that’s what’s really limited its routine clinical use
But it’s still one of the most widely used anesthetics in the world today
It’s on the World Health Organization list of essential medicines
One of the things Peter remembers from his clinical training is ketamine doesn’t produce respiratory depression This was a perk Most things used as anesthetic agents have this problem where if you overshoot them you can cause respiratory depression This is not an issue if you’re doing general anesthesia because you have an endotracheal tube in the main stem bronchus, so you’re breathing for the patient Otherwise though, respiratory depression is a frightening consequence that must be managed closely You don’t have to do this with ketamine
There is a kind of folklore around it, of people running at the police and being shot down yet kept running.
The problems with PCP is it had this protracted psychosis-like effects that lasted for a really long time following anesthesia
It was still a good analgesic anesthetic
Things like hallucinations and out-of-body experiences
And that’s what’s really limited its routine clinical use
This was a perk
Most things used as anesthetic agents have this problem where if you overshoot them you can cause respiratory depression This is not an issue if you’re doing general anesthesia because you have an endotracheal tube in the main stem bronchus, so you’re breathing for the patient Otherwise though, respiratory depression is a frightening consequence that must be managed closely You don’t have to do this with ketamine
This is not an issue if you’re doing general anesthesia because you have an endotracheal tube in the main stem bronchus, so you’re breathing for the patient
Otherwise though, respiratory depression is a frightening consequence that must be managed closely
You don’t have to do this with ketamine

Is it true that kids are less susceptible to the hallucinogenic effects of ketamine?

It is used more with children
Celia tried to do a study on this, but it never really came off
She doesn’t know if people have asked kids on ketamine if they have hallucinations
Ketamine is widely used in pediatrics, geriatrics, and battlefield medicine It was the most widely used anesthetic in the Vietnam War
It’s a really good question about kids
Some people are trialing ketamine for antidepressant use in adolescents
It was the most widely used anesthetic in the Vietnam War

The benefits of ketamine as an anesthetic

It’s really safe, physiologically as an anesthetic, because it doesn’t slow your breathing or your heart rate So when you’ve lost a lot of blood, it’s good as well because it actually even vaguely increases your blood pressures That’s why it’s a widely used aesthetic
Peter can understand why it became a turning point in the field medicine of Vietnam It’s the perfect anesthetic in trauma and shock where patients are hypovolemic, their blood pressure is going down Ketamine is an agent that acts slightly like a vasopressor, it raises blood pressure without the respiratory depression Celia adds, “ The acute experience must be really unusual when you’re in that setting ”
The benefit of not having to intubate people made it really popular in developing countries where there is limited ability to intubate patients
Ketamine is a really important medicine in anesthesia still, and Celia thinks that’s something people forget with all the new uses of ketamine
It’s ridiculous to think that anesthesia is something we’ve only had vor about 140 years
The concept of losing consciousness and how you measure it is fascinating
We can measure on an EEG how your consciousness drops, but Celia doesn’t think we really know what turns it on and off
So when you’ve lost a lot of blood, it’s good as well because it actually even vaguely increases your blood pressures
That’s why it’s a widely used aesthetic
It’s the perfect anesthetic in trauma and shock where patients are hypovolemic, their blood pressure is going down
Ketamine is an agent that acts slightly like a vasopressor, it raises blood pressure without the respiratory depression
Celia adds, “ The acute experience must be really unusual when you’re in that setting ”

Is ketamine an analog of PCP?

They’re all under the class of arylcyclohexylamines
Edward Domino coined the term, dissociative anesthetics to describe PCP and ketamine People include nitrous oxide in that category This is based on the fact that they kind of disassociate you from your body and are characterized by these out-of-body experiences This can be quite helpful in anesthetic use They are related compounds; their main action is on the NMDA receptor
People include nitrous oxide in that category
This is based on the fact that they kind of disassociate you from your body and are characterized by these out-of-body experiences This can be quite helpful in anesthetic use
They are related compounds; their main action is on the NMDA receptor
This can be quite helpful in anesthetic use

Neurobiology and pharmacology of ketamine [8:15]

A primer on how neurotransmitters work, how neurons can amplify or attenuate the response to them, and the action of ketamine on the NMDA receptor

Glutamate is the major excitatory neurotransmitter in the brain and it’s prevalent all across the brain
One of the receptors that glutamate works on is the NMDA receptor (N-methyl-D-aspartate receptor)
The NMDA receptor is really important in a lot of our higher cognitive functions
It plays a fundamental role in learning and memory Particularly in a process in learning called long term potentiation This is where brain cells that activate at the same time‒ if they both activate, then they’re more likely to activate in future This is characterized by this saying, “ Neurons that fire together, wire together ” Glutamate is really important in that and other excitatory functions in the brain
GABA is an inhibitory neurotransmitter It shuts down the flow of electrical impulses across the brain
Particularly in a process in learning called long term potentiation
This is where brain cells that activate at the same time‒ if they both activate, then they’re more likely to activate in future
This is characterized by this saying, “ Neurons that fire together, wire together ”
Glutamate is really important in that and other excitatory functions in the brain
It shuts down the flow of electrical impulses across the brain

Peter’s summary: glutamate is excitatory and GABA is inhibitory

We will talk about GABA analogs that mimic alcohol later on

Are there examples of drugs that work to amplify glutamate?

Lamotrigine is a drug used in seizures tend to reduce the flow of glutamate in the brain, particularly in the prefrontal context
Celia can’t think of examples that amplify glutamate

What are GABA analogs doing? Why do people feel relaxed when they drink?

Things like benzodiazepines are working on GABA

Drugs like alcohol and benzos, they all increase GABA activation

These slow down, kind of dampens down the brain
They reduce things like anxiety
They slow your motor function
They generally work by inhibiting the flow of electrical impulses across your brain This is part of the reason why we get symptoms you get, when you stop drinking Your brain is a bit like a seesaw‒ the alcohol’s being pushing down on that side and keeping it dampened down, and then you release that and you go into a more excitatory state
Celia works a lot with alcoholics.
From alcohol withdrawal , you can get seizures and the shakes, and that’s all due to this increase in excitation
This is part of the reason why we get symptoms you get, when you stop drinking
Your brain is a bit like a seesaw‒ the alcohol’s being pushing down on that side and keeping it dampened down, and then you release that and you go into a more excitatory state

That’s why withdrawal from strong GABA promoters like benzos and ethanol can be fatal if not managed correctly

People intuitively know that you can stop opioids immediately, and it might be the most painful thing in the world, but it won’t be fatal
Whereas if you take a person who’s on a high dose of benzodiazepines or a person who drinks a lot of alcohol and you stop that abruptly, it actually can be fatal
Withdrawal can be lethal when you stop taking certain drugs Because of this huge increase in excitation
With repeated alcohol use, your brain gets used to having all this GABA on board and then you get adaptation and your brain kind of up-regulates to counteract that And then when you remove it… you can die from withdrawal
Celia works with severe alcoholics, it’s unsafe for them to stop straight away They have to cut down and use things like benzodiazepines in withdrawal
People do think about opiate withdrawal as a really difficult thing, but you wouldn’t die from that
It’s only from withdrawal from these inhibitory substances like alcohol and benzodiazepines
Because of this huge increase in excitation
And then when you remove it… you can die from withdrawal
They have to cut down and use things like benzodiazepines in withdrawal

Theory of how ketamine works

It’s not 100% clear how ketamine works
The theory is that ketamine blocks directly the NMDA receptors on inhibitory (GABAergic) neurons, triggering a downstream cascade involving increased excitatory (glutamatergic) signaling The blue cells in the figure below is a glutamatergic neuron (excitatory neuron) The green cell in the figure below is an GABAergic interneuron (inhibitory neuron) containing NMDA receptors that can be blocked by ketamine Inhibitory neurons release neurotransmitters that limit release of glutamate Glutamate is an excitatory neurotransmitter Ketamine is thought to block NMDA receptors which reduces neurotransmitter release from inhibitory neurons, shown as an X in the figure below This results in increased release of glutamate
The blue cells in the figure below is a glutamatergic neuron (excitatory neuron)
The green cell in the figure below is an GABAergic interneuron (inhibitory neuron) containing NMDA receptors that can be blocked by ketamine
Inhibitory neurons release neurotransmitters that limit release of glutamate Glutamate is an excitatory neurotransmitter
Ketamine is thought to block NMDA receptors which reduces neurotransmitter release from inhibitory neurons, shown as an X in the figure below This results in increased release of glutamate
Glutamate is an excitatory neurotransmitter
This results in increased release of glutamate

Figure 2. Proposed mechanism of ketamine’s action on NMDA receptors in the neocortex. Image credit: c&en 2020

And maybe it’s a combination of the two, that the ketamine blocks NMDA receptors on GABAergic neurons So GABA neurons synapse to your glutamate neurons The blue cell in the figure above is a presynaptic glutamatergic neuron The red cell is a postsynaptic neuron Ketamine blocks release from the GABA neuron thereby affecting glutamate neurons GABA neurons put the brakes on excitation
So GABA neurons synapse to your glutamate neurons The blue cell in the figure above is a presynaptic glutamatergic neuron The red cell is a postsynaptic neuron Ketamine blocks release from the GABA neuron thereby affecting glutamate neurons
GABA neurons put the brakes on excitation
The blue cell in the figure above is a presynaptic glutamatergic neuron
The red cell is a postsynaptic neuron
Ketamine blocks release from the GABA neuron thereby affecting glutamate neurons

If you block an NMDA receptor on a GABAergic neuron, then you’re going to have a net effect of increasing glutamate flow in presynaptic cells

People have become interested in the downstream mechanisms for potential therapeutic uses of ketamine

Does ketamine have different effects on a person based on the dose they receive?

Peter notes, “ Ketamine is one of these drugs where the dose makes the poison. I mean, I think that’s true of most drugs .”
Yes, it can cause anything from mild hypnosis to some dissociation, to complete anesthesia
Celia works a lot with people who take ketamine non-medically or recreationally At lower doses they get stimulant properties As the dose increases, they get perceptual distortions and illusions… people talk about floating Higher doses produce a more profound effect; maybe not hallucinations, but changes in perception of reality At the highest dose, people experience catatonic effects and really, really profound hallucinations It’s these really high doses that are very dangerous A couple of people have died from taking ketamine and then having a bath because they’re completely disassociated from reality and they drowned
At lower doses they get stimulant properties
As the dose increases, they get perceptual distortions and illusions… people talk about floating
Higher doses produce a more profound effect; maybe not hallucinations, but changes in perception of reality
At the highest dose, people experience catatonic effects and really, really profound hallucinations It’s these really high doses that are very dangerous A couple of people have died from taking ketamine and then having a bath because they’re completely disassociated from reality and they drowned
It’s these really high doses that are very dangerous
A couple of people have died from taking ketamine and then having a bath because they’re completely disassociated from reality and they drowned

“ Ketamine users are very vulnerable to accidents at these higher doses because you are completely dissociated from reality ”‒ Celia Morgan

Peter compares this to LSD in the sense where it really has no LD 50 , meaning there’s no amount of LSD that is going to create a lethal physiologic process But this is not to say that LSD is completely safe because it can alter your behavior and perception of reality such that you put yourself in harms way Tylenol (acetaminophen) would poison your liver at a certain dose
There’s no LD 50 for ketamine from a purely pharmacological standpoint because it doesn’t cause respiratory depression and other things that we worry about
Celia doesn’t know of anyone getting a large enough dose of ketamine to be toxic
But this is not to say that LSD is completely safe because it can alter your behavior and perception of reality such that you put yourself in harms way
Tylenol (acetaminophen) would poison your liver at a certain dose

There are physiological problems with repeatedly taking high doses of ketamine

Ketamine has direct toxicity on the epithelial cells It can damage the lining of your bladder This is something that only emerges with people who use really high doses
With LSD, more of your top down higher cognitive functions are preserved as compared to ketamine
People taking high doses of ketamine will become completely catatonic and are much more vulnerable to accidents The example of drowning in a bathtub seems tragic It’s hard to imagine how dissociated you would have to be to go into a bathtub, inhale water, and not respond You are completely dissociated Various accidents can happen
It can damage the lining of your bladder This is something that only emerges with people who use really high doses
This is something that only emerges with people who use really high doses
The example of drowning in a bathtub seems tragic
It’s hard to imagine how dissociated you would have to be to go into a bathtub, inhale water, and not respond
You are completely dissociated
Various accidents can happen

How ketamine can be administered

Most studies of ketamine used as an anesthesia or to treat depression give it intravenously This is the most characterized route of administration It provides the best bioavailability
There are other ways to administer it Intramuscular injection provides good availability in the blood People are starting to use sublingual administration‒ putting it under the tongue Drug users first re-popularized intranasal administration Now intranasal administration is patented by the pharmaceutical company for treating depression Oral dosing in another option, but the bioavailability is not as good
This is the most characterized route of administration
It provides the best bioavailability
Intramuscular injection provides good availability in the blood
People are starting to use sublingual administration‒ putting it under the tongue
Drug users first re-popularized intranasal administration
Now intranasal administration is patented by the pharmaceutical company for treating depression
Oral dosing in another option, but the bioavailability is not as good

With oral administration, what happens in the liver with the first-pass effect? Is there any liver toxicity?

Celia assumes people are currently doing toxicity studies
Pharmaceutical companies are looking at overall dosing as a potential
The bulk of the research has been done on intravenous, intramuscular, and more recently, intranasal administration

Ketamine regulation and abuse, and how it compares with psychedelics and other molecules [18:15]

Ketamine is currently a schedule III drug

In the 1970s it was used liberally as an anesthetic and was unscheduled
Now it’s a much more regulated compound
In the late 90s it was classified as a schedule III drug The figure below summarizes drug scheduling
The figure below summarizes drug scheduling

Figure 3. Scheduling of controlled substances. Image credit: Congressional Research Service 2021

Putin banned ketamine in Russia, it’s an interesting story The very attractive French actress Brigitte Bardot petitioned Putin to use ketamine in animals Its widely used in veterinary anesthesia So he removed the ban for animals but kept the ban in place for humans This is horrendous considering what an amazing anesthetic it is
In the UK in 2006 it became a Class B drug scheduled under the Misuse of Drugs Scheduling Act It still has medical use
In the United States, the other psychedelics, LSD, psilocybin, and even MDMA (which is not a psychedelic) are schedule I, which means they have no medical use at all See the previous figure
Celia finds this drug policy interesting because of all these compounds, ketamine is the most likely to be abused
Ketamine is still legal for medical use; it has an amazing number of medical uses
The very attractive French actress Brigitte Bardot petitioned Putin to use ketamine in animals Its widely used in veterinary anesthesia
So he removed the ban for animals but kept the ban in place for humans This is horrendous considering what an amazing anesthetic it is
Its widely used in veterinary anesthesia
This is horrendous considering what an amazing anesthetic it is
It still has medical use
See the previous figure

Do you consider MDMA a psychedelic?

Peter is not an expert but he does not personally consider MDMA a psychedelic
He would put it in the category of an empathogen because it doesn’t really cause any dissociation It’s not altering perception in the way that LSD or psilocybin would
It’s not altering perception in the way that LSD or psilocybin would

Schedule I drugs

Schedule I implies no medical use and a high potential for addiction
There is certainly medical use for psilocybin and MDMA They have a low potential for abuse
Interestingly, ketamine clearly has a high medical use
They have a low potential for abuse

What is the potential for abuse of ketamine?

How addictive is ketamine as compared to benzodiazepines and opioids?

Celia doesn’t have good data on this but in terms of physical withdrawal symptoms…. It depends on how you assess addictive properties People become addicted to things that are also multifunctional tools, such as coffee
Celia did a study of people that use ketamine People who use ketamine non-medically are probably at a higher potential for abuse About 9% of them had symptoms of some sort of dependence or craving It’s hard to benchmark ketamine against opioids and benzos
Peter’s memory is that about 20% of users of prescription opioid painkillers become addicted This is staggering, 1 in 5 people who get an opioid prescription could go on to abuse them later It seems absurdly high This doesn’t include heroin, where the number may be higher Heroin users would be a different subgroup of the population so it’s not really an apples-to-apples comparison
Celia notes that so far the data seem to suggest that a very low number of people prescribed ketamine (for recalcitrant depression or something else) experience dependency
This depends on how you define addiction Is it physical withdrawal? Is it impacting everyday functioning? Is it seeking drug beyond your prescription (dose escalation)?
People become addicted to things that are also multifunctional tools, such as coffee
People who use ketamine non-medically are probably at a higher potential for abuse
About 9% of them had symptoms of some sort of dependence or craving
It’s hard to benchmark ketamine against opioids and benzos
This is staggering, 1 in 5 people who get an opioid prescription could go on to abuse them later It seems absurdly high
This doesn’t include heroin, where the number may be higher
Heroin users would be a different subgroup of the population so it’s not really an apples-to-apples comparison
It seems absurdly high
Is it physical withdrawal?
Is it impacting everyday functioning?
Is it seeking drug beyond your prescription (dose escalation)?

Celia has worked with people who take ketamine and a small proportion do become addicted

Ketamine can have serious physical consequences, bladder toxicity

Celia has worked with 16-year old girls who abuse ketamine that had their bladder removed (cystectomy) Now they have to wear a colostomy bag This is a really dire consequence but it’s quite rare These are girls who were not using ketamine for any medical indication but became addicted to it recreationally
There was a ketamine epidemic in the UK in the early 90s-2000s Celia was researching it then People didn’t really know anything about ketamine
Peter was in medical school in the 90s and learned about it as Special K
In the UK some people called it kiddie smack They compared it to heroin for kids
Recreational users were taking grams and grams of it every day This can produce the serious side effects discussed Tachyphylaxis occurs; this is like a rapidly developing tolerance
Now they have to wear a colostomy bag
This is a really dire consequence but it’s quite rare
These are girls who were not using ketamine for any medical indication but became addicted to it recreationally
Celia was researching it then
People didn’t really know anything about ketamine
They compared it to heroin for kids
This can produce the serious side effects discussed
Tachyphylaxis occurs; this is like a rapidly developing tolerance

If you do administer ketamine repeatedly in a short time window, you do need to give higher and higher doses

These people would take doses that would floor an elephant, but they would still be walking around and functioning They weren’t passing out in their apartments for hours
They weren’t passing out in their apartments for hours

What is the drive for people to abuse ketamine?

Celia spoke to about 120 ketamine users about this Some of them said very pragmatic things, “ It’s cheap. It gets me really off my head ”
Escapism is one reason people take it
There are some slight opioid actions of ketamine
Psychonauts were almost addicted to chasing the consciousness and the insights they felt they were getting They would take more and more to try and get more insights A high-profile example is John Lilly , a neuroscientist in California; the film Altered States is about him He did a lot of unusual research He gave LSD to dolphins He writes in his book, The Scientist , that he invented flotation tanks His book is a great account of ketamine addiction He became completely addicted to ketamine to the extent that he had an intravenous drip of ketamine pretty much 24 hours a day He became a psychotic where he had these revelations and went to tell the president of the USA, about the world being taken over by computers Celia can’t remember the end of the book, how he managed to get off ketamine
Another book is Journeys to the Brighty World by Marcia Moore Her husband was an anesthetist and she experimented with ketamine She had a very different subjective experience John Lilly had hallucinations related to being in a computer in a machine state Her hallucinations were very soft and round and going back to the earth Sadly, she took some ketamine outside and froze to death Again, this is the thing where you completely dissociate from your body
When people take really high intravenous doses of ketamine they rapidly develop tolerance
Some of them said very pragmatic things, “ It’s cheap. It gets me really off my head ”
They would take more and more to try and get more insights
A high-profile example is John Lilly , a neuroscientist in California; the film Altered States is about him He did a lot of unusual research He gave LSD to dolphins He writes in his book, The Scientist , that he invented flotation tanks His book is a great account of ketamine addiction He became completely addicted to ketamine to the extent that he had an intravenous drip of ketamine pretty much 24 hours a day He became a psychotic where he had these revelations and went to tell the president of the USA, about the world being taken over by computers Celia can’t remember the end of the book, how he managed to get off ketamine
He did a lot of unusual research
He gave LSD to dolphins
He writes in his book, The Scientist , that he invented flotation tanks
His book is a great account of ketamine addiction
He became completely addicted to ketamine to the extent that he had an intravenous drip of ketamine pretty much 24 hours a day
He became a psychotic where he had these revelations and went to tell the president of the USA, about the world being taken over by computers
Celia can’t remember the end of the book, how he managed to get off ketamine
Her husband was an anesthetist and she experimented with ketamine
She had a very different subjective experience
John Lilly had hallucinations related to being in a computer in a machine state
Her hallucinations were very soft and round and going back to the earth
Sadly, she took some ketamine outside and froze to death Again, this is the thing where you completely dissociate from your body
Again, this is the thing where you completely dissociate from your body

How does ketamine compare to PCP?

Peter hasn’t taken care of any patients strung out on PCP
He remembers the lore of the drug, it was a much more aggressive drug People on PCP seemed almost bulletproof They’d punch their hand through a glass window, be unfazed by the fact that they just broke every bone in their hand
Celia thinks PCP produces a protracted psychotic state
She thinks police were given nets to catch people on PCP There was a lot of police brutality associated with people taking PCP
She has looked in the literature for examples of this kind of bulletproof phenomena and can’t find any
There are definitely examples of people having protracted psychotic-like symptoms with hallucinations and needing to be hospitalized when on PCP
She find the violent aspect of people on PCP running at police hard to imagine
PCP was never really a street drug in the UK She’s not aware of many reports in the US either
People on PCP seemed almost bulletproof
They’d punch their hand through a glass window, be unfazed by the fact that they just broke every bone in their hand
There was a lot of police brutality associated with people taking PCP
She’s not aware of many reports in the US either

“ Nobody’s really thinking about using PCP, but maybe that would be something to investigate ”‒ Celia Morgan

Contrast ketamine with psilocybin and LSD

Psilocybin and LSD are much more similar to each other
Psilocybin and LSD have a completely different action, they work on the 5-HT2A receptor
Ketamine works on these kind of glutamatergic receptors
There are some similarities in the acute experience People talk about EO dissolution and ketamine causes that quite profoundly‒ so you lose your sense of self You can think more clearly on LSD and psilocybin Ketamine impairs some of your higher cognitive functions and causes that kind of analgesia , which is associated with ketamine’s anxiolytic effect Even at higher doses, people don’t report anxiety , whereas some patients describe things that sound scary, but they don’t feel the kind of physiological anxiety In contrast, people on drugs like LSD and psilocybin report being absolutely terrified by the experience Maybe that’s the dissociation that happens more on drugs like ketamine where you have the sense of being separate and everything’s kind of emotionally numb
Peter comments that perhaps ketamine has a greater inhibitory effect It has less of a negative feedback loop Anybody who’s tried other psychedelics will say, “ Look, if you go back to the well too many times, you can get stung .”
Celia adds that ketamine is unpredictable in that sense
If you’re looking for escapism, you don’t want to escape into absolute terror
People talk about EO dissolution and ketamine causes that quite profoundly‒ so you lose your sense of self
You can think more clearly on LSD and psilocybin
Ketamine impairs some of your higher cognitive functions and causes that kind of analgesia , which is associated with ketamine’s anxiolytic effect Even at higher doses, people don’t report anxiety , whereas some patients describe things that sound scary, but they don’t feel the kind of physiological anxiety
In contrast, people on drugs like LSD and psilocybin report being absolutely terrified by the experience
Maybe that’s the dissociation that happens more on drugs like ketamine where you have the sense of being separate and everything’s kind of emotionally numb
Even at higher doses, people don’t report anxiety , whereas some patients describe things that sound scary, but they don’t feel the kind of physiological anxiety
It has less of a negative feedback loop
Anybody who’s tried other psychedelics will say, “ Look, if you go back to the well too many times, you can get stung .”

Ketamine as a therapeutic for depression [30:45]

Early research on using ketamine to treat depression

7-9 years ago a physician friend of Peter’s told him about prescribing intranasal ketamine for patients with depression They used it once a week
At the time Peter couldn’t find a lot of literature on it, only some interesting case reports
One study in India was interesting but he forgot about it until recently with the advent of ketamine clinics, which have become almost as ubiquitous as Starbucks
Celia mentions an early study in Iran, it may even date back to dodgy work by Salvador Roquet He was a psychotherapist He was working for the Mexican government interrogating people He was giving ketamine with other psychedelics to try to produce changes in people’s brain state This is probably the first documented cases of people using ketamine as a psychiatric therapy, in the 60s A summary of his work using psychedelic psychotherapy was published in 1977
In the 70s a study came out of Iran that caused an explosion in ketamine depression research
Robert Berman’s group at Yale did an early study in 2000 giving a single ketamine infusion to patients with treatment-resistant depression They showed groundbreaking results , you could get rapid reduction in depressive symptoms Traditional SSRIs ( Prozac and traditional antidepressant drugs) have a delayed onset of action It was accepted that they would take 2 weeks to work Why ketamine works immediately in people with treatment-resistant depression was unknown
They used it once a week
He was a psychotherapist
He was working for the Mexican government interrogating people
He was giving ketamine with other psychedelics to try to produce changes in people’s brain state This is probably the first documented cases of people using ketamine as a psychiatric therapy, in the 60s A summary of his work using psychedelic psychotherapy was published in 1977
This is probably the first documented cases of people using ketamine as a psychiatric therapy, in the 60s
A summary of his work using psychedelic psychotherapy was published in 1977
They showed groundbreaking results , you could get rapid reduction in depressive symptoms
Traditional SSRIs ( Prozac and traditional antidepressant drugs) have a delayed onset of action It was accepted that they would take 2 weeks to work
Why ketamine works immediately in people with treatment-resistant depression was unknown
It was accepted that they would take 2 weeks to work

What dose of ketamine is used?

Early studies administered ketamine intravenously using 0.5 mg/kg So an 80 kg person would get 40 mg intravenously over 40 minutes
A recreational user whos not habituated but simply bought ketamine from a drug dealer would take 100-200 mg They would typically take in intranasally which has slightly less bioavailability But it’s still a good way to administer it
So an 80 kg person would get 40 mg intravenously over 40 minutes
They would typically take in intranasally which has slightly less bioavailability But it’s still a good way to administer it
But it’s still a good way to administer it

What is the experience of the patient getting 40 mg of ketamine?

It’s highly variable
Celia must have given hundreds of people ketamine in research studies and the response is really variable and not necessarily predictable They weight-adjust all of their doses
At 0.5 mg/kg patients might feel slightly drunk and disoriented, slightly dissociated
At the other end of the spectrum (at higher doses) Celia remarks, “ People have gone down a canoe in their mother’s eardrum… doing really weird stuff, having frank hallucinations ”
Peter is curious‒ for any agent he has ever ingested, from alcohol to acetaminophen to a psychedelic agent, he needs 3x what anybody else needs to feel it He’s always been curious why that is
In her research, Celia has found that people with a family history of alcohol problems, their acute response to ketamine is less
A higher BMI is predictive of a higher acute effect Maybe this has something to do with the ratio of lean muscle to fat
Therapeutically with depression, they have found that the more suicide attempts people have made, the better their response
They weight-adjust all of their doses
He’s always been curious why that is
Maybe this has something to do with the ratio of lean muscle to fat

More severe patients are more likely to have a response

Is the acute response predictive of abatement of depression?

The acute response is what happens in the 2-3 hours the person is under the influence of the drug It’s a 40 minute infusion and presumably they are under the influence of the drug for another couple hours
This is a good question and the field is divided
Acute effects have typically been measured with a scale called the Clinician-Administered Dissociative States Scale It was designed to look at dissociation from people having flashbacks from traumatic experiences They ask some questions relevant for ketamine, but some that are not For example, “ Are things moving in slow motion? Have colors changed? Do you have a sense of forgetting chunks of what has happened? ”
In studies of dissociative effect, about 25% find this predicts the therapeutic effects
Celia has done a systematic review of this
In general psychiatry, there’s a feeling that these acute effects are a nuisance and there’s a whole research effort devoted to finding drugs that don’t have these acute effects, with limited success
When you look at the data and people who use a more nuanced way of looking at the acute effects, mystical experiences do seem to predict the success of ketamine treatment
It’s a 40 minute infusion and presumably they are under the influence of the drug for another couple hours
It was designed to look at dissociation from people having flashbacks from traumatic experiences
They ask some questions relevant for ketamine, but some that are not
For example, “ Are things moving in slow motion? Have colors changed? Do you have a sense of forgetting chunks of what has happened? ”

Peter’s summary: it’s not clear if the person who’s feeling slightly drunk is going to have a lesser outcome or a greater outcome than the person who’s on the canoe in their mom’s eustachian tube

Is it a fair assessment to say we don’t know what questions to ask patients during the acute phase window or we’re not doing analysis on a fine enough gradient of symptoms?

Yes, we need more nuanced understanding of the effects
Celia is studying this now, recording what people say and getting them to describe it, then using artificial intelligence/ machine learning algorithms to find patterns in that To see if something from the acute experience can predict the therapeutic benefits of ketamine for treating depression
It seems like a no-brainer, but they have quite a long way to go with it, using natural language to predict outcomes
To see if something from the acute experience can predict the therapeutic benefits of ketamine for treating depression

Does ketamine produce amnesia?

Yes, some people get amnesia but other can remember the experience
You might forget aspects of what’s happened, it only impairs episodic memory

When the patient returns to their baseline state 3 hours later, do they immediately feel alleviation of depression?

People can feel considerably better
Celia’s colleague, Rupert McShane set up the first NHS treatment-resistant depression clinic in the UK
He likened it to the film Awakenings (which is actually about Parkinson’s)
These patients are severely depressed, often they can’t get off the bed, and suddenly after treatment the come alive
Not everyone responds to it, but that is pretty rapid
People say they feel a sense of clarity, ab it more interest in the world Like they are able to detect novelty that they couldn’t before It’s a great thing to see
The response is variable, 50-60% of people don’t respond at all Peter had no clue this was so high
Early studies , Carlos Zarate study showed 75% of patients responded, but as more studies came out, the response rate went down This is typical for any new treatment as additional studies are performed
The duration of these effects last 2 days to a week, longer for some people
This is where Celia’s research comes in, she’s been looking at how the response might be extended
Like they are able to detect novelty that they couldn’t before
It’s a great thing to see
Peter had no clue this was so high
This is typical for any new treatment as additional studies are performed

If you give it alongside psychological therapy of some kind, you can really extend the response to ketamine and the antidepressant effects

Celia ran a trial looking at using ketamine in the treatment of alcoholics They found reductions in drinking 6 months after just 3 infusions These infusions were spaced apart 1-2 weeks and given along with 7 sessions of psychological therapy This is really a limited treatment program
They found reductions in drinking 6 months after just 3 infusions
These infusions were spaced apart 1-2 weeks and given along with 7 sessions of psychological therapy This is really a limited treatment program
This is really a limited treatment program

How does ketamine help people with treatment-resistant depression? [43:30]

Define treatment-resistant depression

This is tricky because different trials define it differently
Often people define it as not responding to conventional antidepressants in the current depressive episode or having had multiple different treatments
Some people take a more conservative definition‒ 3 failed responses

Is depression classified as at least 2 weeks of the set of symptoms typically associated with depression?

Would it be classified as depression if there is an obvious externality such as loss of a child?

If your child dies and a month later you can’t get out of bed, is that depression?

No, that’s natural sadness
If this continued for a really prolonged period of time it may be classified as depression but even then it would be contentious

There is a clear boundary between what we would anticipate from grief and natural sadness compared to depression

Peter asks about this scenario‒ a person is depressed for months

There is not something clearly associated to trigger it, such as grief
They have gone through one SSRI at a therapeutic dose with no benefit
They moved to a different SSRI or different class of drug and similarly received no benefit

Do we assess how much psychotherapy they have been doing at the same time?

Celia reflects on clinical trials or reasons they give for prescribing off-label ketamine in the UK Typically, it’s because the patient is not responding to antidepressants It could be due to a failed response to CBT (cognitive behavioral therapy) A lot of trials use non-responders to CBT, especially for psilocybin studies
Peter recalls their earlier discussion, “ We’ve just said 50% of those people are not going to respond. That’s pretty sad. So what are we saying to those 50% of people? ”
There is some evidence that depression might not respond to 3 ketamine doses, but the 4th dose or having extra doses beyond 3 may increase the response
On-label ketamine is indicated for repeated dosing This is Spravato , the Janssen version of ketamine, given intranasally Doses begin twice weekly for a month then move to weekly Long term studies are finding that people stay on the dose There was an idea that people might progress off the drug or drop down in the dosing They may have dropped down to fortnightly (2 weeks), but patients are staying on it for a number of years now as a maintenance
Typically, it’s because the patient is not responding to antidepressants
It could be due to a failed response to CBT (cognitive behavioral therapy)
A lot of trials use non-responders to CBT, especially for psilocybin studies
This is Spravato , the Janssen version of ketamine, given intranasally
Doses begin twice weekly for a month then move to weekly
Long term studies are finding that people stay on the dose There was an idea that people might progress off the drug or drop down in the dosing They may have dropped down to fortnightly (2 weeks), but patients are staying on it for a number of years now as a maintenance
There was an idea that people might progress off the drug or drop down in the dosing
They may have dropped down to fortnightly (2 weeks), but patients are staying on it for a number of years now as a maintenance

Is there a plan to wean off ketamine?

Hypothetical patient

The patient has profound depression for which none of the treatments have worked
They feel remarkably better after their first ketamine infusion
This lasts 4 days then all of the sudden the depression sets back in
Peter asks, “ Is the thinking that we’re going to repeat this treatment and get longer and longer periods of benefit during which time we can work more on psychotherapy to try to wean off the need for ketamine? ”
Yes, and some people think targeting therapy during that time is really important if you don’t want to keep someone on ketamine as a maintenance dose

Do patients need to stop their traditional antidepressants when they come to a ketamine trial?

In Celia’s trial in the UK, yes Their funding body didn’t want them to include people on an SSRI
Their funding body didn’t want them to include people on an SSRI

But in most of the depressions studies, people are still on them and there are no interactions

The brain under the influence of ketamine and theoretical mechanisms for its anti-depressive effects [48:00]

Why does ketamine help with depression? What is the proposed mechanism of action? [48:00]

People have talked about ketamine and the other psychedelics/ psychoplastogens , as provoking a kind of cascade
There is a study showing they increase synaptic plasticity in the prefrontal cortex Ketamine certainly does
Ketamine certainly does

This increases the growth of new synapses and dendrites and basically the ability of the brain to form new connections

This is correlated with the antidepressant effect
Celia is doing some work at the moment to chart the time cause of that in humans, by looking at EEG This looks at electrical signals from the brain She’s trying to target the window of this synaptic plasticity We know from animal studies, this might start 4 hours following the ketamine dose and peak at about 24 hours So they are tracking the antidepressant effects, which is quite interesting
Celia’s view as a psychologist is, this is the time your brain is most plastic, most able to learn new things, and could be the best time for psychological therapy
This looks at electrical signals from the brain
She’s trying to target the window of this synaptic plasticity
We know from animal studies, this might start 4 hours following the ketamine dose and peak at about 24 hours
So they are tracking the antidepressant effects, which is quite interesting

Plasticity is impaired across a whole range of psychiatric disorders

Not just for depression but also in alcohol, and addiction, and trauma

So being able to stimulate the brain to learn new things while it’s really plastic and giving psychological therapy that uses that process is thought to be a key part of successful treatment

During psychological therapy we are asking people to think about things differently To learn new ways of thinking about old problems
This seems like an intuitively appealing mechanism
Some may argue, “ Is this specific enough as a process? Are the drugs producing neuroplasticity that we wouldn’t say were necessarily potential treatments for mental health problems in psychiatry disorders? ”
There are some problems with this mechanism in that neuroplasticity happens from all sorts of things Such as cocaine People say the neuroplasticity produced from cocaine is why it becomes addictive An acute dose of cocaine stimulates that
This is something we need to find out more about
Maybe it’s down to something really specific and neurological This is a question for the preclinical researchers
Peter asks, “ When you about things like MDMA and psilocybin, a lot of the therapy takes place while under the influence of the drug, whether it be for PTSD or depression, is that happening also with ketamine when that patient is in the aftermath of the infusion or are they basically just left alone during that period of time and the psychotherapy takes place immediately following the next day and the next day and the next day trying to take advantage of them being less dysthymic? ”
Celia doesn’t try to do any therapy under the influence of ketamine People are too dissociated, the memory is impaired
Some ketamine therapists do use a psycholytic approach They use mild doses to be able to do some therapeutic process
There is an interesting study from a guy in Texas looking at complex PTSD and really severe multiple traumas He’s treating complex regional pain syndrome on top of that These are really traumatized people who have got really severe pain He was giving drug continuously at quite a low dose, over 96 hours And he was doing very basic psychological therapy during that time He found massive reductions in CAPS score, which is a measure of PTSD symptoms It was a really small study, but Celia thought that was an interesting approach
To learn new ways of thinking about old problems
Such as cocaine
People say the neuroplasticity produced from cocaine is why it becomes addictive
An acute dose of cocaine stimulates that
This is a question for the preclinical researchers
People are too dissociated, the memory is impaired
They use mild doses to be able to do some therapeutic process
He’s treating complex regional pain syndrome on top of that
These are really traumatized people who have got really severe pain
He was giving drug continuously at quite a low dose, over 96 hours
And he was doing very basic psychological therapy during that time
He found massive reductions in CAPS score, which is a measure of PTSD symptoms
It was a really small study, but Celia thought that was an interesting approach

Celia does therapy outside of the acute ketamine experience; this is true for most people and true for work with psilocybin

They simply support patients during the acute experience
There is very little research on what the integration is or even then key fundamentals of integration

What do we know about the brain under the influence of ketamine?

Have people done fMRI or FDG-PET and looked at either the metabolic state of the brain or the activity of the brain?

There’s a lot of interesting work on the default mode network This is what happens in your brain when you’re not doing anything active Subjects are in a scanner, they’re not doing anything‒ this is a resting state
The brain is imaged in a resting state to see how networks connect People say it’s the background activity of the brain and have likened it to things like rumination Rumination is important in depression, repetitive thoughts about something You can have positive rumination as well Repetitive thinking about something bad or mind wondering occurs in depression
This is what happens in your brain when you’re not doing anything active
Subjects are in a scanner, they’re not doing anything‒ this is a resting state
People say it’s the background activity of the brain and have likened it to things like rumination
Rumination is important in depression, repetitive thoughts about something
You can have positive rumination as well
Repetitive thinking about something bad or mind wondering occurs in depression

The default mode network has been shown to be disrupted following psychedelics

This background, normal chatter of the brain
Similar things have been shown with mindfulness
There are some interesting studies looking at prediction error signalings The idea that your brain is making predictions all the time about the world and that’s how we understand everything perceptually For example, if she puts her laptop screen down she expects to see the world behind it But if she put her laptop screen down and found a gap in reality, she’s have a massive shock of surprise because that would be a signal to her brain to learn something new So every time a prediction you make based on our learning is violated, there is a subsequent increase in learning and attention and activity in your brain Ketamine disrupts this
The idea that your brain is making predictions all the time about the world and that’s how we understand everything perceptually
For example, if she puts her laptop screen down she expects to see the world behind it But if she put her laptop screen down and found a gap in reality, she’s have a massive shock of surprise because that would be a signal to her brain to learn something new
So every time a prediction you make based on our learning is violated, there is a subsequent increase in learning and attention and activity in your brain Ketamine disrupts this
But if she put her laptop screen down and found a gap in reality, she’s have a massive shock of surprise because that would be a signal to her brain to learn something new
Ketamine disrupts this

The lateral prefrontal cortex is associated with this prediction error processing and that is disrupted with ketamine

“ So things that aren’t surprising become surprising (the things that shouldn’t be surprising and are completely predictable), and things that aren’t predictable are no longer surprising ”‒ Celia Morgan

An interesting way to think about the subjective experience is maybe a lot of these drugs turn off some of that forward prediction from the brain and make a noisier signal

Is the brain hyper metabolic under the influence of ketamine?

The idea is the brain is hypo in some ways
There is an increase in prefrontal glutamate
Neuroimaging as it’s been done in the past is not Celia’s area of expertise

How many patients do you think when relieved of their depression during these ketamine trips will need to stay on ketamine as a long term treatment?

Celia comments that one of the frustrating things about all of the ketamine clinics that have sprung up across the US is the lack of data There is better data in the UK because they have a state healthcare system, the NHS In the UK, most patients receiving ketamine for depression get it through the NHS There are a couple of private clinics now giving ketamine Celia is involved with one There are 5 centers prescribing on the NHS, but this is all off-label because the state healthcare regulator has not recommended Spravato yet (intranasal ketamine) It’s all prescribed for treatment-resistant depression
In the UK there’s a lot of data out there they could be looking at, but they don’t have a good registry of all the patients
There is better data in the UK because they have a state healthcare system, the NHS
In the UK, most patients receiving ketamine for depression get it through the NHS There are a couple of private clinics now giving ketamine Celia is involved with one There are 5 centers prescribing on the NHS, but this is all off-label because the state healthcare regulator has not recommended Spravato yet (intranasal ketamine) It’s all prescribed for treatment-resistant depression
There are a couple of private clinics now giving ketamine
Celia is involved with one
There are 5 centers prescribing on the NHS, but this is all off-label because the state healthcare regulator has not recommended Spravato yet (intranasal ketamine)
It’s all prescribed for treatment-resistant depression

As to the question, a lot of people probably respond to treatment in these clinics, but Celia’s sense is that not everyone has treatment-resistant depression

Particularly in the US, ketamine is given for a wide range of indications
Celia thinks it would be amazing if we could have an international registry of data on patients using ketamine This would provide information about how long people are on ketamine It would potentially add a level of safety for the patients and clinicians
This would provide information about how long people are on ketamine
It would potentially add a level of safety for the patients and clinicians

Risks and concerns with overusing ketamine, and what an intermittent or maintenance dose might look for a patient [57:15]

Concerns about use of prescription ketamine

Celia has seen some slightly worrying trends recently
She helped organize a ketamine conference This included colleagues from the US and some pharmaceutical companies
They are developing ketamine for daily dosing‒ this is worrying
She has worked with ketamine users for 10 years and even if you are using a very low dose, daily dosing will lead to an escalation of the dose
This included colleagues from the US and some pharmaceutical companies

“ So where’s the end point? If you aren’t giving it in a supportive therapy is the idea that people are just on ketamine all the time… To me, it seems a bit worrying .” ‒ Celia Morgan

Peter takes the skeptics point of view‒ it’s a land grab for a greater profit motive without enormous consideration for the downside
Peter doesn’t know what it is about ketamine that makes him cautious
Maybe it’s the anecdotes and that’s a bad frame
He asks, “ Have you ever seen people with these sort of ketamine eyes ‒ sunken, distant? This person has taken too much ketamine in their life and their brain doesn’t work as well anymore. I’m sure there are lots of different drugs that can produce that phenotype .” Somebody who’s taken far too much cocaine can experience something He would think this is more commonly seen with ketamine than LSD or psilocybin because the frequency of use with those other drugs is much harder It’s less likely that a person is going to take heroic doses of LSD or psilocybin over and over again Whereas you can get down that path with ketamine
There are areas of concern with ketamine beyond its toxicity to the bladder Cystitis is a very obvious and tangible objective side effect that can be devastating
There can be more subtle changes in a person’s brain that are not for the better
Peter asks, “ Am I just sort of making this up and it’s possible I am and that I’m just over extrapolating from something else, but you’ve been around this more than almost anyone. Do you have a concern around that? ”
Celia has done a lot of studies on this
She hasn’t studied the sunken eyes, but she has looked at the brain Peter has not noticed physically sunken eyes, like you would for hypothyroidism, it’s more of a vacancy Celia adds, “ A kind of dullness ”
Like any addiction, one thing she has noticed anecdotally with addiction is people lose their sense of humor
Somebody who’s taken far too much cocaine can experience something
He would think this is more commonly seen with ketamine than LSD or psilocybin because the frequency of use with those other drugs is much harder
It’s less likely that a person is going to take heroic doses of LSD or psilocybin over and over again
Whereas you can get down that path with ketamine
Cystitis is a very obvious and tangible objective side effect that can be devastating
Peter has not noticed physically sunken eyes, like you would for hypothyroidism, it’s more of a vacancy
Celia adds, “ A kind of dullness ”

“ The spark has gone out of life ”‒ Celia Morgan

This is an odd vibe considering ketamine is given to treat depression, to put the spark back
But then it makes sense, you do it too much and maybe that spark is gone
She has found cognitive changes cognitive impairments and with planning Actual reductions in the hippocampus, which is involved in processing novelty and encoding memories That function is reduced in some of their brain imaging studies with people who take daily heavy doses of ketamine
She’s not saying your non-medical recreational user would show this kind of symptoms, people who take it occasionally
But she thinks it’s possible for people who take really, really heavy doses
cognitive impairments and with planning
Actual reductions in the hippocampus, which is involved in processing novelty and encoding memories
That function is reduced in some of their brain imaging studies with people who take daily heavy doses of ketamine

Ketamine prescribing practices for treating depression

Ketamine is administered in clinics as a rapid acting antidepressant
The promise of it was it’s not a maintenance medication It would be empowering for patients to not be on a daily medication
This is why Celia feels a little sad that there’s not more research effort aimed at understanding the potential of ketamine to enhance therapy for depression Do we have to give people hundreds of doses? Maybe just some people need that
Maybe that’s a cost-benefit analysis made when prescribing any drug to patients who are heavily suicidal This depression is life threatening, right?
It would be empowering for patients to not be on a daily medication
Do we have to give people hundreds of doses?
Maybe just some people need that
This depression is life threatening, right?

Has anyone done a quality-adjusted life year analysis of patients with the most treatment-resistant depression? Have differences in suicide rate been reported?

People have worked with suicidal patients and you get reduced mortality with ketamine These are tough studies
These are tough studies

What does your intuition say is probably the sweet spot for what the intermittent/ transient but fixed use of ketamine is, as a bridge to go from completely treatment resistant depression to treatable depression?

Celia’s clinical trial on alcohol dependence used 3 doses of ketamine and 7 sessions of psychotherapy 0.8 mg/kg ketamine was given over 40 minutes This is a slightly higher dose than used for depression because you get a sort of cross-tolerance with alcohol Because alcohol works on the same receptor as ketamine at higher doses When people get really intoxicated and feel like they’re spinning out, that’s the alcohol working on their NMDA receptors Doses were separated by 7 days to 2 weeks
People with alcohol problems tend to have depression as well and it can be quite severely treatment-resistant
Her study found a reduction in rumination‒ repetitive, negative thinking
Reduction in anhedonia which is a hallmark of depression and many disorders That’s the inability to experience pleasure in the world She saw reductions in anhedonia at 3 months but they were back to baseline at 6 months
Subjects were still showing reduced drinking at 6 months
0.8 mg/kg ketamine was given over 40 minutes
This is a slightly higher dose than used for depression because you get a sort of cross-tolerance with alcohol Because alcohol works on the same receptor as ketamine at higher doses When people get really intoxicated and feel like they’re spinning out, that’s the alcohol working on their NMDA receptors
Doses were separated by 7 days to 2 weeks
Because alcohol works on the same receptor as ketamine at higher doses
When people get really intoxicated and feel like they’re spinning out, that’s the alcohol working on their NMDA receptors
That’s the inability to experience pleasure in the world
She saw reductions in anhedonia at 3 months but they were back to baseline at 6 months

This might suggest in depression that weekly or fortnightly (bi-weekly) dosing might be needed

Pros and cons of different maintenance doses of ketamine

Peter thinks this model of treating once a quarter (every 3 months) makes more sense
What worries him is he is seeing people taking ketamine twice weekly for life He worries about the toxicity of the drug It would need to show enormous efficacy to justify this dosing schedule
When he looks at short-term studies comparing ketamine to Versed , ketamine is not that much better Versed is a good option Using Versed as a control shows there is a pretty big placebo effect
Celia agrees
He worries about the toxicity of the drug
It would need to show enormous efficacy to justify this dosing schedule
Versed is a good option
Using Versed as a control shows there is a pretty big placebo effect

Treating addiction with ketamine: Celia’s studies of alcohol dependance [1:04:00]

Why is ketamine working to treat addiction?

Celia is studying alcohol dependence but wants to look at opioid addiction as well
There is work in the US looking at opioid addiction
This dates back to the Russian Psychiatrist Jenny Kopitski She worked with heroin addicts and found a similar dosing regime of 3 infusions combined with psychological therapy They used higher doses of ketamine (1-2 mg/kg) administered intramuscularly This produced significant reduction in heroin use at 12 months
She worked with heroin addicts and found a similar dosing regime of 3 infusions combined with psychological therapy They used higher doses of ketamine (1-2 mg/kg) administered intramuscularly
This produced significant reduction in heroin use at 12 months
They used higher doses of ketamine (1-2 mg/kg) administered intramuscularly

How much of a reduction is seen?

For alcohol there was a 40% reduction in relapse rate at 12 months
These studies were done in the 80s in Russia They were on inpatient alcoholics in locked wards, they couldn’t drop out It wasn’t the normal consent and ethics processes we have now, but still a really important study Both groups had a hundred people in them but it wasn’t a randomized control trial They simply asked people if they wanted to be in the group receiving ketamine and psychotherapy or in the group with standard therapy Celia comments, “ This is dodgy ” They don’t have any access to alcohol They detok, get ketamine treatment, and are then discharged Follow-up occurs 12 months later
They were on inpatient alcoholics in locked wards, they couldn’t drop out
It wasn’t the normal consent and ethics processes we have now, but still a really important study
Both groups had a hundred people in them but it wasn’t a randomized control trial They simply asked people if they wanted to be in the group receiving ketamine and psychotherapy or in the group with standard therapy Celia comments, “ This is dodgy ”
They don’t have any access to alcohol
They detok, get ketamine treatment, and are then discharged Follow-up occurs 12 months later
They simply asked people if they wanted to be in the group receiving ketamine and psychotherapy or in the group with standard therapy
Celia comments, “ This is dodgy ”
Follow-up occurs 12 months later

Has a head-to-head study of ketamine + behavioral therapy versus pharmacologic + behavioral therapy for alcohol been done?

Celia’s latest clinical trial was a 4-arm trial

1 – Ketamine + psychological therapy
2 – Saline placebo + psychological therapy
3 – Ketamine + alcohol education
4 – Saline placebo + alcohol education

“ It was great because that’s what we hypothesized (and that’s quite rare), but I wasn’t expecting to get what we hoped for ”‒ Celia Morgan

They saw the greatest reductions in drinking and greatest abstinence in group #1 (ketamine + therapy) where at 6 months the abstinent rate was 86%

The figure below shows the most recent published data from this randomized clinical trial

Figure 4. Percentage of days of alcohol abstinence across the four treatment conditions. Image credit: The American Journal of Psychiatry 2022

The second best effect was in group #3 (ketamine + education control, shown in green in the figure above) They wanted to look at the effects of ketamine without therapy, but there are really nonspecific effects of spending hours with a therapist who’s quite nice
Peter notes, “ That’s a very elegant trial design because you get away from what’s called the performance bias of the therapy , the therapy itself. You have to make sure you’re controlling for just the fact that an hour, three times a week, they have to go talk to somebody .”
They wanted to look at the effects of ketamine without therapy, but there are really nonspecific effects of spending hours with a therapist who’s quite nice

What was done in the education arm of the trial?

People learned how alcohol affects the body
They did some relaxation, just as a bare minimum of what they wanted to do with people going into a ketamine session Maybe the relaxation helped with the blinding
The placebo was just saline There were no dissociative effects, which is a bit of a shame in retrospect Celia notes, “ We should have used something like midazolam ” (brand name Versed)
The response in the other groups was good as well
There were 96 patients 24 patients per arm They weren’t powered for the full interaction
They are moving forward now with a phase II trial of 280 patients funded by the UK state This is run in a NHS setting Celia hopes to see ketamine as a medicine in those contexts
Celia comments, “ I don’t know what you think of the psychedelics world and I think some of the therapies are amazing, but for our state healthcare system, those things are not ever going to happen. You’re never going to have 2 therapists for 40 hours .”
She wanted to come up with a therapy that was deliverable in her state healthcare system
They have a lot of slightly lower-level trained therapists in the NHS
So they designed their therapy to be quite manualized so they could deliver it in a short amount of time
Maybe the relaxation helped with the blinding
There were no dissociative effects, which is a bit of a shame in retrospect
Celia notes, “ We should have used something like midazolam ” (brand name Versed)
24 patients per arm
They weren’t powered for the full interaction
This is run in a NHS setting
Celia hopes to see ketamine as a medicine in those contexts

How much therapy were they getting in the active therapy group?

A total of about 11 hours in 6 months
So they have a therapy session immediately before their infusion
If they’re in a therapy group they would be doing a mindfulness practice
In the education group: there’s some relaxation, then they have the ketamine session, then they recover as you would from an anesthetic, and then they go home
They come back the next day and have another longer therapy session of 1.5 hours This where we think the peak of the synaptic plasticity effects occur
This where we think the peak of the synaptic plasticity effects occur

So it’s a ketamine infusion sandwich between 2 therapy sessions, and they repeat that three times

What is the therapist talking about?

Some of it’s very pragmatic things What are your most risky situations for drinking, trying to preempt situations where they might relapse But some of it’s more about how you want to live your life and the values you want to embody Trying to think about your life without alcohol, how would you structure that Things about thinking about your thinking around drinking, which is more cognitive behavioral therapy based What are your thinking biases? Let’s identify those And then planning
So they have quite a lot of activities to do in the week or weeks in between the sessions, like standard homework Planning their days, journaling, keeping track of those things
They teach mindfulness techniques to enable people to deal with cravings To get a bit more of a space between them and their addictive impulses
There’s a whole range of stuff really
What are your most risky situations for drinking, trying to preempt situations where they might relapse
But some of it’s more about how you want to live your life and the values you want to embody
Trying to think about your life without alcohol, how would you structure that
Things about thinking about your thinking around drinking, which is more cognitive behavioral therapy based What are your thinking biases? Let’s identify those And then planning
What are your thinking biases? Let’s identify those
And then planning
Planning their days, journaling, keeping track of those things
To get a bit more of a space between them and their addictive impulses

“ We threw the book of the evidence-based therapies at them ”‒ Celia Morgan

Explain the inclusion criteria

Subjects go through a number of screenings to get into the clinical trial
One problem with clinical trials is they end up with quite pure populations
They needed people to be abstinent when they started A lot of people who are drinking can’t stop straight away They needed to go through a medical detox and most of those are in the community now
They worked with people’s healthcare providers to support them as they went through detox And they kept checking in with them until they were ready to start, maybe 2 weeks after they’ve done a full detox
They didn’t include people with Psychosis Psychosis in a first degree relative Uncontrolled blood pressure because ketamine is associated with increased blood pressure A variety of other things excluded people from the study
They had access to the medical notes for subjects of the study
It’s quite a process, but the main bit is getting people abstinent
A lot of people who are drinking can’t stop straight away
They needed to go through a medical detox and most of those are in the community now
And they kept checking in with them until they were ready to start, maybe 2 weeks after they’ve done a full detox
Psychosis
Psychosis in a first degree relative
Uncontrolled blood pressure because ketamine is associated with increased blood pressure
A variety of other things excluded people from the study

The therapy is all around supporting people with their new life and using the ketamine experience really to get that perspective

This is a perspective they might not have had for a while A new perspective to think about their life in a new way and try and focus on how they want to go forward
It’s really using the ketamine as a catalyst for their therapy rather than purely focusing on the pharmacological properties of it
A new perspective to think about their life in a new way and try and focus on how they want to go forward

How much does blood pressure go up when administering 0.8 mg/kg ketamine?

It varies
On the order of 10
Celia is a psychologist, they had an anesthesiologist there for the whole thing
They had to stop the infusion for 1 patient because it went over 180

What the response rate was in the double negative group (#4)?

It was still high, about 68%

What does she attribute this to? There’s a 20% difference between the 2 extremes (groups #1 and #4)

She thinks it was pretty extraordinary for any clinical trial
You often see people do better in clinical trials They’ve going through this whole process with a really strong intention to stop They’ve been through quite a lot of hurdles The trial was pretty demanding if you stuck with it
Some things she didn’t mention, subjects wore a SACM (sweat alcohol content monitor) ‒ a tag that you put around your ankle that measures your alcohol transdermally Because you’re excrete about 1% of alcohol in sweat This measurement may have actually acted as an intervention on its own Now they use a much more discreet wearable, but then it was a clunky thing
Many of these people don’t have a lot of social connections Some of them did But the fact of having people looking after them, checking in on them all the time, people just showing you general human kindness, can have a really positive effect in a group that might be quite isolated
They’ve going through this whole process with a really strong intention to stop
They’ve been through quite a lot of hurdles
The trial was pretty demanding if you stuck with it
Because you’re excrete about 1% of alcohol in sweat
This measurement may have actually acted as an intervention on its own
Now they use a much more discreet wearable, but then it was a clunky thing
Some of them did
But the fact of having people looking after them, checking in on them all the time, people just showing you general human kindness, can have a really positive effect in a group that might be quite isolated

What can we learn from this about the big picture?

Alcohol services here in the UK are just so dysfunctional at the moment
By the time people get any sort of treatment they have multiple complex health problems Or they’ve been through multiple treatments that haven’t worked It’s really hard toa access therapists
Or they’ve been through multiple treatments that haven’t worked
It’s really hard toa access therapists

“ It’s really sad. It doesn’t actually take that much to shift something that’s pretty entrenched ”‒ Celia Morgan

Peter wonders about the response rate of less motivated cohorts down the line Some individuals are less interested in not drinking Someone who maybe hasn’t fully hit rock bottom but acknowledges they drink too much may say “ I’m going to keep drinking… I haven’t destroyed my life yet ”
Peter comments, “ I just sort of wonder if you have these places for earlier intervention, as someone is on the path towards really destructive alcoholism ”
Some individuals are less interested in not drinking
Someone who maybe hasn’t fully hit rock bottom but acknowledges they drink too much may say “ I’m going to keep drinking… I haven’t destroyed my life yet ”

Further study of ketamine [1:17:30]

Celia’s phase III trial (in progress)

It’s funded by the NHS Department for Health
They are taking the 2 most extreme arms In an ideal world of infinite resources she would have continued to study the 4 arms because she really likes that design She also thinks that is something that is missing from the psychedelics world, teasing apart the impact of the therapy and the drug
They have a patient advocacy group involved at the start that provides some of the risks of ketamine They wouldn’t want to give it without a therapeutic container
Having found these promising effects for the efficacy study (which was more of a definitive study), they decided to just take the most extreme arms
They are looking just with the therapy and then the various other more discrete variables compared to our placebo that we’re using They’re using the same education protocol The high dose will be 0.8 mg/kg The low dose will be 0.05 mg/kg, they’re still working out the dose with pilot trials
Studies with morphine and childhood trauma, looking at how childhood trauma seems to synthesize the brain to respond to opiates found that using a very low dose of morphine was a better control than another drug
In an ideal world of infinite resources she would have continued to study the 4 arms because she really likes that design
She also thinks that is something that is missing from the psychedelics world, teasing apart the impact of the therapy and the drug
They wouldn’t want to give it without a therapeutic container
They’re using the same education protocol
The high dose will be 0.8 mg/kg
The low dose will be 0.05 mg/kg, they’re still working out the dose with pilot trials

Celia thinks a very low dose is helpful in expectancy, you get to tell people they will receive the drug no matter what

Patients will receive either the high or low dose of ketamine

Advice for people considering the therapeutic use of ketamine [1:19:45]

What cautions would Celia tell people here in the US where ketamine clinics are ubiquitous?

Peter thinks anyone can get treatment, they don’t need a referral
He suspects there’s a really good conduit of therapists sending patients appropriately to good ketamine clinics

Hypothetically, let’s say anybody can walk into a ketamine clinic, explain their issue, and get treatment

Peter asks, “ How would you caution people around ketamine use, liberally in that context? ”

The evidence Celia has gathered suggests trying ketamine embedded within therapy

Sam Wilkinson at Yale has also looked at therapy + ketamine in a small RCT
She doesn’t think you need all those doses
People should think about what they are trying to get out of the experience
It’s great to hear therapists are referring people to ketamine clinics
Using ketamine in combination with therapy is a much more appealing model
She doesn’t think people want to be stuck on a drug Even if you’re not addicted, but you’re going in twice a week or even once a week That’s so disempowering for patients
Celia’s patients say one of the things about her treatment approach that is great is not being on daily meds They feel liberated and they know they’re doing the healing themselves Which Celia thinks is an important part of the process
Even if you’re not addicted, but you’re going in twice a week or even once a week
That’s so disempowering for patients
They feel liberated and they know they’re doing the healing themselves Which Celia thinks is an important part of the process
Which Celia thinks is an important part of the process

“ Get a therapist to think about using a really minimal number of doses ”‒ Celia Morgan

Celia recommends caution

One worrying practice she has heard about is mail order ketamine clinics She’s not worried from the abuse side It’s just so expensive
She’s not worried from the abuse side
It’s just so expensive

It’s unsafe to take ketamine at home unsupervised

The drug makes you completely dissociated from your environment
If something happens (a fire), you can’t take it unsupervised
The lack of clinical care and supervision in some of these models is really worrying

Advice for people using ketamine recreationally

Start with really small doses
Take it in a safe place with someone who’s not under the influence of any substances
Be careful of getting ketamine cut with other things Such as ketamine analogs The drug methoxetamine is a research chemical that has come out of labs in China and Israel It’s an analog of ketamine but much more toxic to the bladder It may have a higher abuse potential
Such as ketamine analogs
The drug methoxetamine is a research chemical that has come out of labs in China and Israel It’s an analog of ketamine but much more toxic to the bladder It may have a higher abuse potential
It’s an analog of ketamine but much more toxic to the bladder
It may have a higher abuse potential

Celia doesn’t think ketamine is normally cut with things, but it’s something to be mindful of and why it’s really important to take a small dose

This discussion has been really useful for Peter since ketamine has been a bit of a black box, yet he’s seen the most people use it because it’s legal

Selected Links / Related Material

Addiction to ketamine and other phenomenology : Journey through the K-hole: phenomenological aspects of ketamine use | Drug and Alcohol Dependance (L Muetzelfeldt et al. 2008) | [20:45]

Autobiography of John Lilly, a great account of ketamine addiction : The Scientist: A Metaphysical Autobiography by John Lilly (1978) | [25:45]

Another account of experiences using ketamine : Journeys to the Brighty World by Marcia Moore and Howard Alltounian (1978) | [26:30]

Celia’s systematic review of the predictive value of acute psychoactive effects of ketamine for treating depression : Ketamine as a mental health treatment: Are acute psychoactive effects associated with outcomes? A systematic review | Behavioral Brain Research (M Grabski et al. 2020) | [39:00]

Celia’s clinical trials combining ketamine with psychotherapy to treat alcohol dependance :

A proof-of-concept investigation into ketamine as a pharmacological treatment for alcohol dependence: study protocol for a randomised controlled trial | Trials (A McAndrew et al. 2017) | [43:15, 1:02:00]
Adjunctive Ketamine With Relapse Prevention-Based Psychological Therapy in the Treatment of Alcohol Use Disorder | The American Journal of Psychiatry (M Grabski et al. 2022) | [43:15, 1:02:00]

Small study treating pain plus PTSD with Ketamine : Continuous Ketamine Infusion for Pain as an Opportunity for Psychotherapy for PTSD: A Case Series of Ketamine-Enhanced Psychotherapy for PTSD and Pain (KEP-P2) | Psychotherapy and Psychosomatics (BM Keizer et al. 2020) | [51:15]

Sam Wilkinson’s study study of the effects ketamine plus therapy for patients with treatment-resistant depression : Cognitive Behavioral Therapy to Sustain the Antidepressant Effects of Ketamine in Treatment-Resistant Depression: A Randomized Clinical Trial | Psychotherapy and Psychosomatics (ST Wilkinson 2021) | [1:20:45]

Celia’s review of the mechanism of action of ketamine : Ketamine for the treatment of addiction: Evidence and potential mechanisms | Neuropharmacology (I Ezquerra-Romano et al. 2018)

Antidepressant mechanism of action by ketamine : Mechanisms of Ketamine Action as an Antidepressant | Molecular Psychiatry (P Zanos and TD Gould 2018)

Cognitive and psychological characterization of frequent ketamine use : Ketamine use, cognition and psychological wellbeing: a comparison of frequent, infrequent and ex-users with polydrug and non-using controls | Addiction (CJ Morgan et al. 2009)

People Mentioned

Edward Domino (Neuropharmacologist who coined the term dissociative anesthesia) [7:45]
Vladimir Putin (President of Russia) [18:30]
Brigitte Bardot (French actress, singer, and model) [18:30]
John Lilly (Neuroscientist and psychonaut who inspired the film Altered States ) [25:30]
Marcia Moore (experimented with ketamine, author of Journeys to the Brighty World ) [26:30]
Salvador Roquet (Mexican pioneer in psychedelic psychotherapy) [32:15]
Robert Berman (former Professor of Psychiatry at Yale University, now working in biotech) [33;15]
Rupert McShane (Professor of Psychiatry and Neuroscience at the University of Oxford) [41:30]
Carlos Zarate (Section Chief of Neurobiology and Treatment of Mood Disorders and Chief of Experimental Therapeutics and Pathophysiology Branch (ETPB) at NIMH, and Clinical Professor of Psychiatry and Behavioral Sciences, at The George Washington University) [42:30]
Jenny Kopitski (Russian Psychiatrist worked with heroin addicts) [1:04:30]
Samuel (Sam) Wilkinson (Assistant Professor of Psychiatry and Associate Director, Yale Depression Research Program) [1:20:45]

Celia Morgan completed her undergraduate degree and Ph.D at the University College London (UCL). She then spent time at Yale University on a scholarship program before returning to UCL for postdoctoral research. Following this she worked at University of Melbourne as a visiting research fellow; then she returned to UCL for a fellowship and then Lectureship. She joined University of Exeter as a Senior Lecturer in May 2013 and was given a Chair in Psychopharmacology in 2015. She co-directs the Beckley/Exeter Cannabis Centre at the University of Exeter. She is also the Head of Ketamine Assisted Psychotherapy for Addiction at Awakn Life Sciences Corp . Additionally, she currently holds an Honorary Readership at UCL.

Dr. Morgan is interested in the effects of drugs and alcohol on the brain and behavior. Her research examines both the benefits and side effects of recreational drugs on cognition, mental health, and neurobiology. Through behavioral, neuroimaging studies, and clinical trials, she has investigated potential therapeutic uses of controlled substances. She uses a range of techniques from experience sampling and qualitative interviews to cognitive testing and functional and structural neuroimaging of the DTI and VBM. In particular, she has investigated treatment of addiction with a combination of psychological therapy and drugs such as ketamine and MDMA. [ University of Exeter ]

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