#220 ‒ Ketamine: Benefits, risks, and promising therapeutic potential | Celia Morgan, Ph.D.
Celia Morgan, Professor of Psychopharmacology at the University of Exeter, delves into ketamine's neurobiology, its therapeutic promise for recalcitrant depression and alcohol addiction, and how it differs from other psychedelics. She emphasizes the critical role of psychotherapy in maximizing ketamine's benefits and discusses potential risks and safe usage.
Deep Dive Analysis
14 Topic Outline
Celia Morgan's Background and Early Ketamine Research
History of Ketamine: Anesthetic Use and PCP Comparison
Neurobiology of Ketamine: Glutamate, GABA, and NMDA Receptors
Ketamine's Dose-Dependent Effects and Recreational Use Risks
Ketamine Regulation and Abuse Potential Compared to Other Drugs
Distinguishing Ketamine from Classical Psychedelics (LSD, Psilocybin)
Ketamine's Emergence as a Treatment for Depression
Acute Effects of Ketamine Infusion and Response Variability
Duration of Ketamine's Antidepressant Effects and Neuroplasticity
Concerns with Long-Term or Daily Ketamine Dosing
Ketamine as a Treatment for Alcohol Addiction: Historical Context
Celia Morgan's Clinical Trial on Ketamine and Therapy for Alcoholism
Insights from the Alcohol Addiction Trial's Control Groups
Advice for Navigating Ketamine Clinics and Safe Use
8 Key Concepts
NMDA Receptor
A crucial receptor in the brain where glutamate, the major excitatory neurotransmitter, acts. It's fundamental for higher cognitive functions like learning and memory, and ketamine primarily exerts its effects by blocking this receptor.
Glutamate
The brain's primary excitatory neurotransmitter, found throughout the brain, essential for processes like long-term potentiation, which is the basis of learning and memory. Ketamine's action on NMDA receptors influences glutamate flow.
GABA
An inhibitory neurotransmitter in the brain that works to slow down or shut off electrical impulses. Drugs like alcohol and benzodiazepines increase GABA activation, leading to relaxing or sedating effects.
Dissociative Anesthetics
A class of drugs including ketamine, PCP, and nitrous oxide, named for their ability to dissociate individuals from their body and induce out-of-body experiences. This property is what limited ketamine's routine clinical use initially.
Tachyphylaxis
A rapid decrease in response to a drug after repeated administration, requiring increasingly higher doses to achieve the same effect. This phenomenon is observed with ketamine, especially in recreational users taking high doses frequently.
Treatment-Resistant Depression
A classification for depression where a patient has not responded to at least two conventional antidepressant treatments during their current depressive episode. Ketamine has shown promise in providing rapid relief for this severe form of depression.
Synaptic Plasticity
The brain's capacity to change and adapt by forming new connections between neurons, including the growth of new synapses and dendrites. Ketamine is thought to increase this plasticity, which correlates with its antidepressant effects and the brain's ability to learn new things.
Default Mode Network (DMN)
A network of brain regions active during resting states or when the mind is not focused on a specific task, often associated with self-referential thought, rumination, and mind-wandering. Psychedelics like ketamine are shown to disrupt this network.
11 Questions Answered
Ketamine was synthesized in the 1960s as an anesthetic, intended as a safer replacement for PCP, and is still widely used in medicine today due to its physiological safety profile, especially in trauma settings.
Ketamine primarily works by blocking NMDA receptors on glutamatergic neurons and GABAergic interneurons, leading to a net effect of increasing glutamate flow and triggering a downstream cascade that enhances synaptic plasticity.
At low doses, ketamine can have stimulant properties; at increasing doses, it causes perceptual distortions, floating sensations, profound hallucinations, and at the highest doses, a catatonic, anesthetized state where individuals are completely dissociated from reality.
While 9% of recreational ketamine users in one study showed signs of dependence, it's difficult to benchmark against opioids or benzodiazepines directly; however, repeated high doses can lead to severe physiological consequences like bladder toxicity.
Ketamine works on glutamatergic NMDA receptors, unlike LSD and psilocybin which act on 5-HT2A receptors; ketamine causes profound ego dissolution and anxiolytic effects, often without the intense anxiety that can accompany classical psychedelics.
Ketamine can produce a rapid reduction in depressive symptoms, often immediately after infusion, with effects typically lasting from two days to a week, though some individuals experience longer relief.
Early studies showed response rates as high as 75%, but with more data, the response rate for ketamine in treatment-resistant depression is estimated to be around 50-60%.
Combining ketamine with psychological therapy, especially when the brain is most plastic after ketamine administration, appears to significantly extend the antidepressant response and enhance outcomes in conditions like alcohol addiction.
Chronic, high-dose recreational ketamine use can lead to severe physiological problems like direct toxicity to the bladder lining (requiring cystectomy in extreme cases) and cognitive impairments, including reductions in planning ability and hippocampal function.
A clinical trial found that ketamine combined with psychotherapy resulted in 86% abstinence rates at six months for individuals with alcohol problems, significantly outperforming control groups.
It is advisable to seek ketamine treatment embedded within a therapeutic framework, as evidence suggests therapy enhances and extends the benefits; patients should also be wary of unsupervised use or models that promote continuous, high-frequency dosing.
14 Actionable Insights
1. Avoid Unsupervised Ketamine Use
Never take ketamine at home unsupervised, especially at high doses, due to the risk of complete dissociation from your environment, making you vulnerable to accidents like drowning or inability to respond to emergencies.
2. Combine Ketamine with Therapy
To maximize and extend the antidepressant effects of ketamine, ensure it is administered alongside psychological therapy, as this approach has shown to significantly prolong the positive response.
3. Target Therapy to Neuroplasticity Window
Schedule psychological therapy sessions approximately 24 hours after ketamine administration, as this period is when the brain is most plastic and able to form new connections, optimizing the learning of new thought patterns.
4. Avoid Daily Heavy Ketamine Dosing
Refrain from daily heavy doses of ketamine, even if low, as this can lead to dose escalation, cognitive impairments, reduced hippocampal function, and a general ‘dullness’ or loss of life’s ‘spark’.
5. Be Aware of Bladder Toxicity
Understand that repeated high-dose ketamine use can cause direct toxicity to the bladder lining, potentially leading to severe physiological problems like the need for a cystectomy.
6. Ketamine for Alcohol Addiction Protocol
For alcohol use disorder, consider a protocol involving three ketamine infusions (0.8 mg/kg, 7-14 days apart) combined with 11 hours of manualized psychological therapy, as this demonstrated significant abstinence rates at six months.
7. Alcohol Addiction Therapy Focus
In therapy for alcohol addiction, focus on identifying risky situations, preempting relapse, envisioning a life without alcohol, challenging thinking biases, planning, journaling, and using mindfulness techniques to manage cravings.
8. Question Frequent Ketamine Dosing
If considering ketamine treatment, question the necessity of frequent, long-term dosing (e.g., twice-weekly for life), as this model can be disempowering for patients and may not be necessary for sustained benefit.
9. Recreational Ketamine Harm Reduction
If using ketamine recreationally, always start with a very small dose, use it in a safe place, and ensure a sober person is supervising, as the drug can be cut with other substances and cause complete dissociation.
10. Recognize Non-Pharmacological Addiction Factors
Understand that strong intention, overcoming treatment hurdles, consistent monitoring (e.g., ankle tags), and social support/human kindness can significantly contribute to abstinence in alcohol addiction, even without active drug or intensive therapy.
11. Avoid Psychotherapy During Ketamine Influence
Do not engage in intensive psychotherapy during the acute influence of ketamine, as patients are too dissociated and their memory is impaired; focus on support during this phase and therapy afterwards.
12. Consider Additional Ketamine Doses
If initial ketamine infusions (e.g., three doses) for depression do not yield a response, consider additional doses, as some evidence suggests a fourth dose might increase the response.
13. Understand Ketamine Dose Effects
Be aware that ketamine’s effects vary significantly by dose, ranging from mild stimulant properties at low doses to profound dissociation and hallucinations at higher doses.
14. Explore Podcast Membership Benefits
If you want to deepen your knowledge of health and wellness, consider subscribing to the podcast’s membership program for more in-depth, exclusive content.
6 Key Quotes
If you're looking for kind of escapism, you don't want to escape into absolute terror.
Peter Attia
neurons that fire together, wire together.
Celia Morgan
You are completely dissociated. And it's really sad. It was someone that I was working with, and it's not the only example I know of people who that's happened to, various different accidents. It's really tragic.
Celia Morgan
The film Awakenings, which is actually about Parkinson's. These people are really severely depressed. They often can't get out of bed and that they suddenly come alive.
Celia Morgan
I think the idea, you know, for me as a psychologist is that you could time your psychological therapy when your brain is most plastic and most able to learn new things.
Celia Morgan
I don't think people want to be kind of 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 Morgan
1 Protocols
Ketamine-Assisted Therapy for Alcohol Addiction (Celia Morgan's Trial)
Celia Morgan- Achieve abstinence from alcohol, often requiring medical detox, before starting treatment.
- Undergo a pre-screening process to check for medical and psychiatric contraindications, such as psychosis or uncontrolled blood pressure.
- Receive a therapy session (e.g., mindfulness practice) immediately before the ketamine infusion.
- Receive a ketamine infusion (0.8 mg/kg intramuscularly).
- Recover from the acute effects of the infusion.
- Attend a longer (90-minute) therapy session the following day, timed to coincide with peak synaptic plasticity.
- Repeat steps 3-6 for a total of three ketamine infusions, typically spaced one to two weeks apart, for a total of seven therapy sessions.