Ketamine Information for Patients

  • Ketamine is a dissociative anesthetic. In lower doses it has good data to support its use as an antdepressant.

  • Ketamines mechanism of action is thought to be related to its effects on the following brain receptors:

    • Opioid receptor agonist (activator)

    • NDMA (N-methyl-D-aspartate) receptor antagonist (blocker)

    • AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor agonist (activator)

  • It’s important to remember that ketamine is not a cure for depression. However, ketamine can offer very fast relief for some patients. The effect can wear off within days to weeks for some patents. It’s important to think about ketamine as one part of your overall treatment plan. Regular maintenance treatments may be required to help sustain any mood improvements.

  • During an infusion, the patient is usually resting in a comfortable reclining chair. It is common to be connected to telemetry like a pulse oximeter (measures heart rate and blood oxygenation), blood pressure cuff, and even an EKG (measures electrical activity of heart)

    As noted in other sections, Ketamine is a dissociative anesthetic. Because of this patients can have an out of body experience while under the influence of Ketamine. Some patients report feeling very heavy in their body while others feel like they are floating or flying. Some can feel euphoric, some can feel scared and even hallucinate, while others can feel nothing at all. Sometimes strange thoughts or feelengs may come into your awareness. This could be scary, exciting, sad, intriguing or painful. Again, It is important to remember that the Ketamine experience can be a very different experience for each individual patient.

    This speaks to the importance of having good communication with your ketamine provider, asking good questions, being open about your fears/concerns and discussing possible strategies should difficult psychological content come up.

  • It is important to remember that results vary from patient to patient. Most treatment protocols for Ketamine infusions involve 6 treatments over a 2 to 3 week period followed by several tapering infusions.

  • Common side effects of Ketamine:

    • Feeling intoxicated

    • Dissociation (out of body experience)

    • Evlevated blood pressure

    • Elevated heart rate

    • Anxiety

    • Blurred vision

    • Dizziness

    • Headache

    • Nausea

    Less common long term side effects:

    • Abuse and addiction

    • Neurotoxicity

    • Bladder toxicity

    • Liver toxicity.

  • It’s important to have a psychiatric and medical evaluation prior to taking Ketamine.

    Medical reasons to not take ketamine may include:

    • Uncontrolled blood pressure

    • Aneurism

    • Heart issues

    • Pregnancy

    Psychiatric reasons to not take Ketamine may include:

    • Active substance use

    • Psychosis

    • Schizophrenia

    • Schizoaffective disorder

    • Mania

    • IV Ketamine

    • Spravato (nasal spray)

    • Oral Ketamine:

    • IM (Intramuscular) ketamine

  • It’s very important to follow the instructions for your Ketamine provider. Usually patients will be NPO (that means nothing to eat or drink) 8 hours prior to an infusion. For some patients it’s ok to drink clear liquids up to 3 hours before the infusion. Be sure to discuss this with your doctor.

    There are several medications that can interfere with Ketamine. Benzodiazepines, Lamictal and Naltrexone are known to interfere with the efficacy of Ketamine. This means if you take them your Ketamine may be less likely to work. Please consult with your doctor about what to do with these medications if you are taking them and planning to undergo Ketamine treatments.

    As I am a certified Psychdelic-Assisted Therapy Provider, I think it is imperative to prepare for taking Ketamine much like a person should prepare for any psychdelic journey. This includes the ideas of SET (mindset) and SETTING (physical sourundings). Setting includes the room, the lighting, the chair, the clothing you are wearing, the people you are with etc. The SET is more about the expectations, intentions, self-awareness and attitude that you bring to the experience. For instance, how good are you at recognizing your own feelings vs. thoughts? When you get uncomfortable how do you interface with that discomfort? How do you self sooth? How do you feel when you are altered or not in control? If difficult content comes up during the ketamine session how will you work through it?

    (Personal Opinion Alert!!!)

    While there is no definitive data that the psychological experience of the drug (the trip) is necessary for symptoms improvement, I believe it can be a useful tool for some to bring unresolved content into conciseness awareness that can ultimate help with symptoms improvement and healing.

  • ECT appears the most effective treatment for MDD but there is some evidence that ketamine can work just as quickly.

    It is important to have a careful discussion with your doctor about the risks and benefits of all treatment options before making the best decision for you.

  • There are several medications that can reduce the effectiveness of ketamine. They include;

    • Benzodiazapines (valium, klnopin, ativan etc.)

    • Lamotrigine (lamictal)

    • Naltrexone

    You should discuss any medication changes with your physician.

More Detailed Information for Clinicians

What is Ketamine?

Ketamine is a dissociative anesthetic. It was first synthesized in 1962 by Calvin L. Stevens. It is very similar in chemical structure to Phencyclidine (PCP.) The main difference is the addition of a ketone group and an amine group. Hence the name KET + AMINE.

Ketamine has been used as an anesthetic since 1970. In subanesthetic doses ketamine has demonstrated consitent data to support its use as a reasonable and safe treatment for Major Depressive Disorder, Bipolar Depression, suicidal thoughts and PTSD.

Ketamine is available in Oral (PO), IV (Intravenous), IM (Intramuscular) or Nasal spray form.

As of 2019 only the s-enantiomer of ketamine (Spravato) is FDA approved for the treatment of treatment resistant Major Depressive Disorder or Major Depressive Disorder with suicidal thoughts or behaviors.

Ketamine is generally considered a safe and well tolerated medication in medical settings under the supervision of a physician. Because Ketamine is a dissociative anesthetic, patients can have an out of body experience like they are intoxicated while they take the medication. Some patients report feeling very heavy in their body while others feel like they are floating or flying. Some can feel euphoric, some can feel scared and even hallucinate, while others can feel nothing at all. The ketamine experience can be very different for each individual patient.

What are the different routes of Ketamine?

  • IV Ketamine:

    • IV ketamine is usually a racemic mixture of R-ketamine and S-ketamine. It is generic and readily available in most compounding pharmacies.

  • IV Ketamine is administered via a needle in the vein, typically at a dose of 0.5-1.0 mg per kg of body mass. It is 100 percent bioavailable. It is typically administered over 40-60 minutes. Because it is a dissociative anesthetic, it is administered under the supervision of a physician like a psychiatrist, anesthesiologist or emergency medicine physician.

Pros of IV Ketamine:

  • Racemic mixture (no one really knows which enantiomer is the more effective one as there has been no study comparing the two)

  • 100 % Bioavailability. Because the medication is going directly into your blood there is more getting to your brain where it needs to go. With a nasal spray, who knows how much you are truly absorbing.

  • Weight based dosing (we are all different sizes and may be over/under dosed with the standard dosing of 56mg or 84 mg of Spravato.

  • Can be shut off in the event of adverse side effects like panic attacks or hallucinations

Cons of IV ketamine:

  • Cost. It is not usually covered by insurance

  • Difficulty of use as compared to nasal spray

  • Pain from needle, risk of infection etc.

  • Spravato:

  • Spravato is the S-Enantiomer of ketamine. It is sometimes called “S-ketamine.” It is technically the only formulation that is FDA approved for the treatment of MDD. It is administered via nasal spray. It is avaiable in 56 mg and 84 mg dose containers. It has 35-50 percent bioavailability.

  • For treatment resistant depression the starting dose is 56 mg which may be increased (after first dose) based on response and tolerability to 84 mg twice weekly for 4 weeks. After 4 weeks, the patient is evaluated for therapeutic benefit to determine need for continued treatment. At week 5, using the previously established dose (56 or 84 mg) the frequency is decreased to once weekly for 4 weeks. At week 9 the patient may continue effective dose (56 or 84 mg) once weekly or decrease to every 2 weeks.

  • For Major Depressive Disorder with suicidality the Initial dose is 84 mg twice weekly for 4 weeks. This may be reduced to 56 mg twice weekly based on tolerability. After 4 weeks the patient is evaluated for evidence of therapeutic benefit to determine need for continued treatment. The use beyond 4 weeks has not been evaluated.

Pros of Spravato:

  • Usually covered by insurance

  • Easy to administer

  • FDA approved

Cons of Spravato:

  • Fixed dosing (56 or 84 mg)

  • Unpredictable absorption via nasal mucosa

  • Has to be monitored in clinic after administration

  • Unclear it works better or worse than IV

  • PO Ketamine:

    • Ketamine can also be formulated in PO (Oral) form. This is the easiest and cheapest route to administer as it can be done in a patients home. It is 20-30 percent bioavailable. This obviously creates more potential problems with dosing. PO Ketamine also creates more potential for abuse or complications if done outside the supervision of a physician. While there is some data to support its use, the data is not as robust as the IV or nasal routes of administration.

Pros of PO Ketamine:

  • Easily available

  • Cheap

  • Can be used at home

  • Data to support that it can help with depression

Cons of PO Ketamine:

  • More difficult to control absorption

  • More potential for abuse

  • Unclear if its as helpful as IV ketamine

  • IM (Intramuscular) Ketamine:

    • While there is limited data on this route of administration there is some Chilukuri et al. 2014. IM administration of ketamine is not common in clinical settings but may be a reasonable option. The IM formulation is 93 percent bioavailable.

How long does ketamine last?

While ketamine can work incredibly fast for some patients in alleviating their symptoms (within hours for some), the effect tends to wear off. According to Murrough et al. 2013 the median time to relapse after a patients last infusion was 18 days.

Continuing ketamine at a greater interval (tapering) after an acute series (usually 6 treatments over 2-3 weeks) can help sustain clinical improvement. For instance, getting an infusion once weekly after completing a course of 6 treatments may help people more than stopping the infusions abruptly after the 6 treatments. Philips et al. 2019

Two papers worth noting are Philips et al. 2023 and Wilkinson et al. 2021 which indicate that incorporating CBT or Behavioral activation may help sustain the antidepressant effects of ketamine.

A review paper by McMullen et al 20211 concluded that continuing ketamine infusions seems to be one of the most effective strategies for sustaining improvement but “psychotherapeutic strategies may possibly prolong the anti depressant efficacy of ketamine.”

I think these studies reenforce the importance of thinking about ALL aspects of a treatment plan. For example, ketamine in addition to exercise, psychotherapy, eating a healthy diet, psychiatric medications, treating underlying medical conditions, staying socially engaged and leaning into the things that give the patient satisfaction, can all help with depression.

Ketamine Evidence:

  • Berman et al. 2000 was a randomized, placebo controlled, double blinded study that compared a single infusion dose of ketamine (0.5mg/kg) with normal saline. This study showed that a single dose of ketamine reduced HAMD rating scales by 14 points in the ketamine group compared to 0 in the control group.

  • Zarate et al. 2006 was a randomized, placebo-controlled, double-blind crossover study comparing a single infusion dose of ketamine (0.5mg/kg) with placebo. Out of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week.

  • Murrough et al. 2013 was a randomized, placebo controlled, double blinded study comparing a single infusion dose of ketamine (0.5mg/kg) with an active placebo of midazolam. Response rate 24 hours after infusion was 64% in the ketamine group and 28% as measured by the MADRS.

  • Lapidus et al. 2014 was a randomized, double-blind, crossover study comparing 50 gm of nasal ketamine with saline. 24 hours after dosing 44 % of the ketamine group met criteria for response as measured by the MADRS as compared to 6% in the placebo group.

  • Singh et al. 2016 was a multicenter, randomized, placebo-controlled trial comparing single dose esketamine 0.20 mg/kg with 0.40 mg/kg and placebo over 40 minutes and measuring MADRS 24 hours after infusion. The 0.2mg/kg group showed a reduction of 16.8 in their MADRS scores while the 0.40mg/kg group showed a reduction of 16.9 while the placebo group showed a reduction of 3.8.

  • Price et al. 2009 showed reduction of explicit and implicit measures of suicidality after administration of ketamine.

  • McGirr et al 2015 was a meta analysis of randomized, double-blind, placebo controlled trials of Ketamine in the rapid response of a major depressive episode. The authors concluded a ”Our meta-analysis suggests that single administrations ketamine are efficacious in the rapid treatment of unipolar and bipolar depression.”

  • Nikon et al. 2023 was a meta analysis looking at randomized control trials for ketamine in treating depression. This paper concluded “Our findings suggested that effect sizes for depression severity, as well as response and remission rates, were numerically greater for racemic ketamine than esketamine. Higher doses were more effective than low doses. Differences were evident in initial effects, ongoing treatment, and lasting effects after the final dose.”

Ketamine compared to other treatments:

  • Anand et al. 2023 was an open label, randomized, non-inferiority trial of patients who either received ketamine infusions (n = 195) or ECT (n = 170). The primary outcome was measured in change in QIDS-SR-16 score between baseline and 3 weeks following initiation of treatment. The trial showed at primary end point (3 weeks) 55.4% in the ketamine group met response criteria vs. 41.2% in the ECT group. The study concluded “Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis.”

  • Rhee et al. 2022 was a systematic review and meta-analysis of 6 clinical trials (5 of which were randomized clinical trials), composed of 340 patients, who either received ECT (n = 162) or ketamine (n = 178). The SMD per this paper was -0.69 (95% CI, -0.89 to -0.48; Cochran Q, P = 0.15; I^2 = 39%). This study concluded “ECT may be superior to ketamine for improving symptom severity in the acute phase, but treatment options should be individualized and patient-centered.”

  • Ekstrand et al. 2021 was a randomized, open label, non-inferiority trial composed of 186 patients who either received ECT or ketamine infusions. 63 % of those receiving ECT remitted compared to 46% of those who received ketamine. This paper concluded, “Remission and cumulative symptom reduction following multiple racemic ketamine infusions in severely ill patients (age 18-85 years) in an authentic clinical setting suggest that ketamine, despite being inferior to ECT, can be a safe and valuable tool in treating unipolar depression.”

Mechanism of Action:

Ketamine is an opioid receptor agonist (activator), NDMA (N-methyl-D-aspartate) receptor antagonist (blocker) and an AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor agonist (activator). Ketamines action on these receptors appears to have a downstream effect of increasing activity in the prefrontal cortex which could increase neural plasticity and thus help with depression symptoms. This of course is an overly simplified explanation. There are a lot of steps that occur between the binding of ketamine to the above mentioned receptors and the phenomenon of clinical improvement.

NMDA Receptor Background:

  • NMDAR’s are glutamanergic, ligand gated, ion-channel receptors. The NDMAR (N-methyl-D-aspartate receptor) has 7 known subunits. GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A and GluN3B. NMDAR usually contains two GluN1 subunits and either two GluN2 subunits or a mixture of GluN2 and GluN3 subunits. Zanos et al. 2018

Typically, L-glutamate binds to the GluN2 subunit in addition to glycine or D-Serine binding to the GluN1 subunit. This leads to a conformational change in the protein. But wait! That is typically not enough to cause the NMDA channel to open. NMDA and AMPA are usually found in close proximity. When glutamate binds to AMPA that causes the post synaptic neuron to become slightly depolarized. (This is due to the influx of sodium ions into the cell body through the AMPA channel.) This slight depolarization of the cell, plus the conformational change on the NMDAR due to the above mentioned binding of glutamate causes the release of the magnesium ion (mg2+) that was stuck in the channel. This then allows the channel to fully open which leads to an influx of more sodium and calcium. It is the calcium in particular that acts as an intracellular messenger. For more information on receptor functioning please refer to Hansen et al. 2018

Now let’s add ketamine to the mix. Ketamine appears to have a high affinity for the GlUN2D subunits of NMDAR’s which appear to be highly exressed in forebrain inhibitory interneurons. Inhibition of NMDARs on GABAergic inhibitory interneurons seems to lead to increased glutamatergic activity in the medial prefrontal cortex (mPFC). Murrough et al. 2017 and Zanos et al. 2018

The Zanos paper proposes 4 different possible mechanisms for ketamines antidepressant effects.

A) Disinhibition

  • Ketamine antagonism of GABAergic interneurons (leads to) Glutamate release (leads to) AMPA activation (leads to) BDNF release (Brain Derived Neurtrophic factor) (leads to) Activation of TRKB (tropomyosin receptor kinase B receptor) (leads to) Activation of mTORC (mechanistic target of rapamycin complexes) (leads to) Increased protein synthesis

B) Inhibition of extra-synaptic NMDAR’s

  • Ketamine antagonism of Glu2NB containing NMDAR’s not found in the post-synaptic density (leads to) Disinhibition of MTORC1 (leads to) Increased protein synthesis

C) Blockade of spontaneous NMDAR activation

  • Ketamine antagonism of NMDAR (leads to) Inhibition of eukaryotic elongation factor 2 kinase (eFF2K) (leads to) Blocking phosphorylation of eFF2 substrate (leads to) Increased BDNF translation (leads to) Activation of TRKB (tropomyosin receptor kinase B receptor) (leads to) Activation of mTORC (mechanistic target of rapamycin complexes) (leads to) Increased protein synthesis

D) Ketamine hydroxynorketamine (HNK) metabolites

  • Ketamine is metabolized to (2R, 6R)- HNK and (2S,6S)-HNK. (leads to) Direct potentiation of AMPA receptors

  • As you can see protein synthesis appears to be a common final pathyway. This then leads to synaptogeneis which is thought to be related to clinical improvement.

  • It is this increased protein synthesis that may lead to increased activity in certain areas of the cortex that are aberrantly functioning in derpession. For instance, chen et al. 2018 showed increased activation in the supplementary motor area (SMA) and the dorsal anterior cingulate cortex (dACC) after patients received a ketamine dose of 0.5 mg/kg.

  • According to Williams et al 2018. giving naltrexone (opioid receptor antagonist) prior to giving ketamine seems to interfere with the effectiveness of ketamine. It appears ketamine’s anti depressive effects are linked to opioid receptors as well as NMDA and AMPA receptors.

Ketamine Pharmacology:

Per Up to Date:

  • “Onset of action:

  • IV: Anesthetic effect: Within 30 seconds

  • IM: Anesthetic effect: 3 to 4 minutes; Analgesia: Within 10 to 15 minutes

  • Intranasal: Analgesic effect: Within 10 minutes (Carr 2004); Sedation: Children 2 to 6 years: 5 to 8 minutes (Bahetwar 2011)

  • Oral: Analgesia: Within 30 minutes; Sedation: Children 2 to 8 years (Turhanoglu 2003):

  • 4 mg/kg/dose: 12.9 ± 1.9 minutes

  • 6 mg/kg/dose: 10.4 ± 2.9 minutes

  • 8 mg/kg/dose: 9.5 ± 1.9 minutes

  • Duration:

  • IV: Anesthetic effect: 5 to 10 minutes; Recovery: 1 to 2 hours

  • IM: Anesthetic effect: 12 to 25 minutes; Analgesia: 15 to 30 minutes; Recovery: 3 to 4 hours

  • Intranasal: Analgesic effect: Up to 60 minutes (Carr 2004); Recovery: Children 2 to 6 years: 34 to 46 minutes (Bahetwar 2011)

  • Distribution: Vdss: 2.1 to 3.1 L/kg (Clements 1981)

  • Protein binding: 27% (Brunton 2006)

  • Metabolism: Hepatic via N-dealkylation (metabolite I [norketamine]), hydroxylation of the cyclohexone ring (metabolites III and IV), conjugation with glucuronic acid and dehydration of the hydroxylated metabolites to form the cyclohexene derivative (metabolite II); metabolite I (norketamine) is 33% as potent as parent compound. When administered orally, norketamine concentrations are higher compared to other routes of administration due to extensive first-pass metabolism in the liver (Blonk 2010; Soto 2012).

  • Bioavailability:

  • IM: 93%

  • Oral: 20% to 30% (Miller 2010)

  • Intranasal: Children, Adolescents, and Adults: Mean range: 35% to 50% (Malinovsky 1996; Miller 2010; Nielsen 2014)

  • Rectal: Children 2 to 9 years: 25% (Malinovsky 1996)

  • Half-life elimination: Alpha: 10 to 15 minutes; Beta: 2.5 hours

  • Time to peak, plasma:

  • IM: 5 to 30 minutes (Clements 1982)

  • Intranasal: 10 to 14 minutes (Huge 2010); Children 2 to 9 years: ~20 minutes (Malinovsky 1996)

  • Oral: ~30 minutes (Soto 2012)

  • Rectal: Children 2 to 9 years: ~45 minutes (Malinovsky 1996)

  • Excretion: Urine (91%); feces (3%) (Ghoneim 1977)”

Important Considerations:

  • There has been no human clinical trial that directly compares s- ketamine to r-ketamine.

  • Animal models indicate the metabolism of (2S,6S;2R,6R)- HNK is required for ketramines antidepressant responses. Zanos et al 2016.

  • BDNF appears essential to antidepressant effects as animal models show decreased antidepressant response in BDNF knock out genes and BDNF -neurtralizing antibody administration. Lepack et al. 2014

  • The importance of mTOR as a common final pathway is certainly not the answer as there is evidence that inhibition of mTOR with rapamycin actually improved response and remission rates when given with ketamine. According to Abdallah et al. 2020, “Two weeks following ketamine administration, we found higher response (41%) and remission rates (29%) following rapamycin + ketamine compared to placebo + ketamine (13%, p = 0.04, and 7%, p = 0.003, respectively). In summary, single dose rapamycin pretreatment failed to block the antidepressant effects of ketamine, but it prolonged ketamine's antidepressant effects.”

References:

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  • Hansen KB, Yi F, Perszyk RE, Furukawa H, Wollmuth LP, Gibb AJ, Traynelis SF. Structure, function, and allosteric modulation of NMDA receptors. J Gen Physiol. 2018 Aug 6;150(8):1081-1105. doi: 10.1085/jgp.201812032. Epub 2018 Jul 23. PMID: 30037851; PMCID: PMC6080888.

  • Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. 2018 Apr;23(4):801-811. doi: 10.1038/mp.2017.255. Epub 2018 Mar 13. PMID: 29532791; PMCID: PMC5999402.

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  • Hardingham, G. E. & Bading, H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat. Rev. Neurosci. 11, 682–696 (2010).

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