Ketamine: Benefits, risks, and promising therapeutic potential | Celia Morgan, Ph.D. | The Drive with Peter Attia (#220)

Key Takeaways

  • Ketamine was synthesized as an anesthetic in the 60s
    • Today it’s one of the most widely used anesthetics in the world
    • Ketamine is considered safe to use in pediatrics 
  • How does ketamine work?
    • One theory says it blocks the NMDA receptors and glutamatergic neurons directly: this then triggers a downstream cascade
    • When used in non-medical doses, ketamine can cause perceptual distortions, illusions, changes in perception of reality, and sometimes hallucinations
    • Ketamine addiction can have direct physical consequences, e.g. bladder toxicity
  • Ketamine is a Schedule III drug in the USA
    • Putin banned it for human use in Russia 
  • Reasons why people use ketamine recreationally: escapism, cheapness, chasing “consciousness” 
  • Combined with psychotherapy, ketamine infusions can lengthen the positive response duration
  • Ketamine increases the growth of new synapses and dendrites in the brain 
  • Ketamine use in patients with suicidal ideation can decrease the mortality rate
  • The ketamine + therapy group had the greatest reduction in drinking: 86% abstinence rates at 6 months

Introduction

  • Celia Morgan (@profceliamorgan) is a Professor of Psychopharmacology at the University of Exeter in the UK. Her research focuses on the benefits and side effects of recreational drugs and alcohol on cognition, behavioral, and neurobiology. Celia authored numerous publications on the potential uses of ketamine and other drugs as therapies in mental health
  • In this episode, Peter and Celia dig deep into ketamine; talking about neurobiology and the chemistry of ketamine, its effects on individuals and specific parts of the brain, and potential risks associated with its usage 
  • Host: Dr. Peter Attia (@PeterAttiaMD)

Ketamine: History, Medical Uses, Parties

  • Ketamine was synthesized as an anesthetic in the 60s
    • The drug company that synthesized it was initially impressed by its analgesic and anesthetic effect
    • Today it’s one of the most widely used anesthetics in the world
    • Perks: patients don’t experience respiratory depression, and it doesn’t lower blood pressure
    • Ketamine is considered safe to use in pediatrics 

Neurobiology & Pharmacology

  • Ketamine is an analog of phencyclidine (both are considered dissociative anaesthetics)  
    • They dissociate you from your body and are characterized by out-of-body experiences
    • Their main action is on the NDMA receptor
  • Glutamate is the major excitatory neurotransmitter in the brain
    • NDMA (N-methyl-D-aspartate) is one of the receptors it works with – it’s important for higher cognitive functions, learning, and memory  
  • GABA (Gamma-Aminobutyric Acid) is an inhibitory neurotransmitter – it shuts down the flow of electro impulses across the brain 
    • GABA potentiation makes people feel relaxed, reduces anxiety, and slows motor function (e.g. alcohol)
  • How does ketamine work?
    • One theory says it blocks the NMDA receptors and glutamatergic neurons directly: this then triggers a downstream cascade
    • It has different effects on an individual based on dosage, ranging from mild hypnosis and some dissociation to complete anesthesia 
    • When used in non-medical doses, ketamine can cause perceptual distortions, illusions, changes in perception of reality, and sometimes hallucinations
    • Users are very vulnerable to accidents at higher doses
    • Ketamine addiction can have direct physical consequences, e.g. bladder toxicity
    • There is no lethal dose when it comes to ketamine 
  •  Routes of ketamine administration
    • Intravenous (for medical purposes)
    • Intramuscular 
    • Sublingual 
    • Intranasal 
    • Oral dosing (easy to use, but not as great in terms of bioavailability)
  • Few predictions based on various research
    • People with a family history of alcohol problems have a greater response to the therapeutic effects of ketamine
    • People with higher BMI are expected to have a higher acute effect 

Ketamine Regulation and Abuse

  • Ketamine is a Schedule III drug in the USA
    • Putin banned it for human use in Russia 
    • In the UK, ketamine is a Class B drug
    • Ketamine clinics are available both in the USA and the UK
  • Out of people who use ketamine recreationally, about 9% had symptoms of light dependence or craving 
  • When administering ketamine repeatedly in a short time window, higher and higher doses are needed as people increase their tolerance
  • Cognitive impairments and reduction in hippocampus functioning have been found in people who take daily heavy doses of ketamine 
  • Reasons why people use ketamine recreationally: escapism, cheapness, chasing “consciousness” 
  • John Lilly, a neuroscientist, developed the isolation tank and did quite a lot of unusual research
    • In his book “The scientist” he documents becoming completely addicted to ketamine
    • Movie inspired by his life: “Altered states”

Ketamine and Depression – Usage and Brain Influence

  • An early study in 2020 done by a group at Yale and Robert Berman sparked interest in researching the use of ketamine in patients with treatment-resistant depression
    • A single ketamine infusion rapidly reduced depressive symptoms
    • Dosage: 0.5 mg per kilogram
  • People can feel considerably better after a 40-minute infusion of a therapeutic dose of ketamine
    • They get a sense of clarity and a bit more interest in the world
    • A positive response usually lasts from 2 days to a week
    • About 50% of people do not respond to the treatment and don’t experience any benefits 
  • Combined with psychotherapy, ketamine infusions can lengthen the positive response duration
    • Targeting therapy during response time is important to avoid keeping someone on ketamine as a maintenance dose
    • There is no interaction with SSRIs 
  • Ketamine increases the growth of new synapses and dendrites in the brain 
    • It’s also associated with the disruption of prediction error processing: things that aren’t surprising become surprising
  • Ketamine use in patients with suicidal ideation can decrease the mortality rate

Celia’s Studies on Treating Addiction with Ketamine

  • Evgeny Krupitsky found a dosing regime that produced a reduction in heroin use at 12 months 
    • 3 infusions of ketamine combined with psychological therapy  
  • Celia did a full clinical trial on ketamine + therapy, compared to ketamine with therapy control, compared to placebo + education 
    • Psychotherapy encompasses various things: identifying the most risky situations for the patient, trying to pre-empt situations where they might relapse, defining values and life goals, mindfulness techniques
    • The ketamine + therapy group had the greatest reduction in drinking: 86% abstinence rates at 6 months
    • The placebo + education only group had a 68% abstinence rate at 6 months

Advice for People Considering the Therapeutic use of Ketamine

  • Start with small doses
  • If people are to use ketamine recreationally, there should be somebody around watching them, due to dissociation and accident risk 
  • Avoid using ketamine analogs at the same time
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