Molecules: Ketamine
Ketamine
Ketamine is a medication primarily used for anesthesia and pain relief, but also has some psychedelic properties. Here are some key facts about ketamine:
- Chemically, it is classified as a dissociative anesthetic and is part of the arylcyclohexylamine drug class.
- Ketamine was first synthesized in 1962 and approved for medical use in 1970. It is commonly used in veterinary medicine as well.
- It can induce analgesia, sedation, and anesthesia by disrupting communication between neurons in the brain and spinal cord.
- In lower doses, it can cause hallucinations, sensory distortions, and dissociation - a sense of detachment from oneself.
- Recently, ketamine has shown promising results as a rapid-acting antidepressant for major depression and suicidal thinking when administered in low doses.
- It appears to work by temporarily restoring connections between brain cells in areas that regulate mood, emotion and cognition.
In summary, ketamine is a dissociative anesthetic agent that in sub-anesthetic doses demonstrates unique antidepressant and psychedelic mental effects.
Arylcyclohexylamines are a chemical class of hallucinogenic drugs that includes ketamine. Some key facts about arylcyclohexylamines:
- They contain a cyclohexane ring bonded to an aromatic ring along with an amino group.
- Ketamine, methoxetamine, tiletamine, and PCP are examples of pharmaceutical arylcyclohexylamines.
- They act primarily as NMDA receptor antagonists, blocking glutamate activity in the brain and spinal cord.
- This NMDA receptor blockade produces analgesia, anesthesia, dissociation, hallucinations and other psychedelic effects.
- Arylcyclohexylamines are thought to cause their dissociative, dream-like mental state by disrupting communication between cortical and subcortical brain circuits.
- Ketamine and some other arylcyclohexylamines are being studied for psychiatric treatment.
The bioavailability of ketamine refers to the amount and rate that ketamine is absorbed into the bloodstream and reaches the sites of action after administration. Here are some details on ketamine's bioavailability:
- When taken intravenously, ketamine has a bioavailability of around 93-100%. This means almost all of the dose injected intravenously reaches systemic circulation. Onset of effects is within seconds.
- Intramuscular injection of ketamine has a bioavailability around 90-93%. It takes 5-15 minutes to exert its effects this way.
- Insufflation (snorting) ketamine has a lower bioavailability of around 45-50%. Effects come on within 5-15 minutes.
- Oral ketamine has very low bioavailability, around 16-24%, due to extensive first-pass metabolism in the liver. Effects take 45-75 minutes when swallowed.
- Sublingual (under the tongue) administration has slightly higher bioavailability at around 30% because some absorption occurs via oral mucosa.
- Transdermal and rectal administration methods are also being explored to avoid first-pass metabolism.
- Dose must be adjusted based on the route of administration to account for differences in bioavailability.
In summary, IV ketamine has almost complete bioavailability, while IM, insufflation and oral routes result in progressively less ketamine reaching circulation and sites of action in the central nervous system.
Ketamine-assisted therapy refers to the use of low, sub-anesthetic doses of ketamine in a therapeutic setting to treat mental health conditions like depression and PTSD. Some key points:
- It is typically administered as a single IV infusion or a series of 6-8 low dose infusions over several weeks.
- Patients are monitored by mental health professionals before, during, and after the ketamine infusion.
- The dissociative effects from ketamine last about 1-2 hours, during which patients often experience a detached, dreamlike state.
- Ketamine is thought to help "reset" neural circuits and rapidly relieve depressive symptoms when other treatments have failed. Effects can last weeks to months.
- Therapy sessions focus on processing emotions, trauma, or thought patterns while under the influence to make lasting gains.
- Potential side effects include anxiety, dizziness, nausea and increased blood pressure during the infusion.
- Treatment protocols and eligibility criteria vary across clinics. Ketamine is not a first-line antidepressant.
- Researchers are also exploring other routes of administration such as intranasal spray to maintain efficacy while improving convenience.
In summary, ketamine-assisted therapy combines the rapid antidepressant properties of ketamine with psychotherapy techniques to durably treat mood disorders.
R-ketamine and S-ketamine refer to the two different enantiomers (mirror image isomers) of ketamine:
- Ketamine contains one chiral carbon atom, meaning it exists as two stereoisomers - S-ketamine and R-ketamine.
- S-ketamine is the more common form used clinically as an anesthetic and recreationally, while R-ketamine was thought to be less potent.
- Research shows that R-ketamine has around 4 times greater affinity for NMDA receptors than S-ketamine.
- However, R-ketamine is metabolized faster, so S-ketamine remains more clinically active over time.
- For antidepressant effects, several studies indicate R-ketamine is more potent and longer-lasting than S-ketamine.
- R-ketamine appears to promote greater synapse formation and function in prefrontal cortex regions involved in mood regulation.
- The esketamine nasal spray for treatment-resistant depression contains the S-enantiomer only.
- R-ketamine may induce fewer negative psychotomimetic side effects than S-ketamine, but more research is needed.
- While R-ketamine shows promise, S-ketamine is better for anesthesia since R-ketamine is shorter acting.
In summary, R-ketamine displays greater potency specifically for rapid antidepressant effects, while S-ketamine remains valued for its anesthetic properties. Understanding chiral differences could optimize therapeutic applications.
There are several types of medications and drugs that are contraindicated or interact adversely with ketamine:
- CNS depressants - Opioids, benzodiazepines, alcohol can enhance ketamine's sedative effects and dangerously suppress breathing and cognition.
- Stimulants - Cocaine, amphetamines may counteract ketamine's ability to sedate and anesthetize.
- Psychotomimetics - Psychedelics like LSD could potentially exacerbate ketamine's dissociative, hallucinatory effects.
- MAOIs - Concomitant use with MAO inhibitor drugs puts one at risk of serotonin toxicity due to excessive serotonin activity.
- Cholinergics - Donepezil and other cholinergic drugs could worsen ketamine's side effects.
- Cardiac medications - Beta blockers, antiarrhythmics may increase the risk of blood pressure/heart complications.
- Sympathomimetics - Using ketamine alongside stimulants like epinephrine can dangerously raise blood pressure.
- Lithium and haloperidol - These antipsychotic drugs may prolong and intensify ketamine anesthesia and recovery.
- Grapefruit - Grapefruit inhibits CYP3A4 metabolism of ketamine, increasing its effects.
Ketamine's complex effects on multiple neurotransmitter systems underlie many of its potentially hazardous drug interactions. Close monitoring and dosage adjustments are required.
The main routes of administering ketamine include:
- Intravenous (IV) - This is the most common way to administer ketamine clinically. It has high bioavailability and rapid onset of action. Effects are felt within seconds.
- Intramuscular (IM) - Injecting ketamine into a muscle, often the deltoid or thigh. Has good bioavailability (~90%) but slower onset than IV. Takes 5-15 minutes to work.
- Oral - Swallowing ketamine capsules or liquid. Oral ketamine undergoes extensive first-pass metabolism resulting in low bioavailability (around 20%). Effects take 45-75 minutes.
- Insufflation - Snorting or inhaling crushed ketamine powder into the nostrils. This has moderate bioavailability (45-50%) and rapid absorption via the nasal mucosa. Effects begin in 5-15 minutes.
- Sublingual - Taking liquid ketamine drops absorbed under the tongue. Avoids first-pass metabolism for faster onset than oral use. Bioavailability around 30%.
- Rectal - Inserting ketamine via the rectum, either as a suppository or gel. Bypasses digestion for higher bioavailability than oral use.
- Transdermal - Ketamine creams, patches or gels absorbed through the skin into the bloodstream. Helps prolong effects compared to other routes.
- Subcutaneous - Injected into the fatty tissue under the skin. Slower than IV but faster than intramuscular injections.
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