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Mental HealthNasal SprayRx Only

Ketamine

Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that was initially developed to be used as an anesthetic. It has since shown promise in addressing chronic pain conditions and psychiatric disorders.

Usual dose

Ketamine nasal spray: Use nasally as directed. Typically used on an as-needed basis per provider instructions

Insert the tip of the spray bottle into one nostril, blocking the other nostril gently with the other hand. Relax and breathe out slowly. Squeeze the pump with your index and middle finger and breathe in slowly, just enough to keep the medication in place. Repeat steps in the other nostril. The effects of the ketamine nasal spray can typically be observed about 10 minutes after administration.

Ketamine troche: Use troche buccally 2 to 3 times a week as directed

Ketamine troches are administered by placing them under your tongue or in between your cheek and gums for 15-20 minutes without swallowing, and then any saliva that has accumulated is spit out. Avoid swallowing because ketamine ingested may have a longer onset time, increase the adverse effects and may extend the time required for you to return to your baseline physical and mental states. The effects of the ketamine troches can typically be observed about 10 minutes after administration,

IMPORTANT INFORMATION ABOUT COMPOUNDED MEDICATIONS

This medication has been compounded (custom-prepared) by a pharmacy. Compounded medications are specially prepared for individual patient needs based on a valid prescription from a prescribing healthcare practitioner and, as such, are not reviewed or approved by the U.S. Food and Drug Administration (FDA) for safety or efficacy. Compounded drugs are intended for patients whose prescriber has determined their medical needs are not met by an available FDA-approved drug. These statements have not been evaluated by the FDA.

This compounded preparation:

Has not been approved by the FDA
Has not undergone FDA review for safety, effectiveness, or quality
Is prepared specifically for you based on your prescriber's order
Individual outcomes may vary

Dosing is determined by the prescribing provider based on patient-specific factors. Always follow your healthcare provider's instructions. Compounded medications are not subject to FDA approval and lack the same safety and efficacy data as FDA-approved commercial medications. This medication should be prescribed and monitored by a licensed healthcare professional familiar with the condition being addressed and the specific applications of the medication.

This compounded medication is only available when the commercially available product is unavailable or when a prescriber determines that there is a clinically significant difference for the patient.

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Medicine Information

Ketamine may cause serious side effects, including sedation, dissociation, psychiatric issues (particularly in those with schizophrenia or severe personality disorders), substance dependence, anxiety, increased blood pressure or heart rate, respiratory depression, urinary and bladder symptoms, altered sense of time, dry mouth, elevated intraocular or intracranial pressure, loss of appetite, confusion, nausea, vomiting, blurred vision, and slurred speech.

Note: administration of ketamine at home may pose additional risks, as there is no healthcare provider present to monitor for adverse effects.

For both chronic pain and depression, ketamine’s actions stem from the antagonism of NMDA receptors, which mediate the neurotransmitter glutamate. We are learning that ketamine metabolites also exert a favorable pharmacological effect.

DEPRESSION: The NMDA antagonism of ketamine triggers a biochemical cascade that results in decreased neurotoxic metabolites of tryptophan, decreased neuroinflammation, decreased neuronal cell death, and improved neuronal synaptic connectivity and neuroplasticity.¹
CHRONIC PAIN: The NMDA antagonism of ketamine decreases the neuronal detection and encoding processes at an injury site (nociception) and the hyperexcitability of neurons in the spinal cord.

IMPORTANT INFORMATION ABOUT COMPOUNDED MEDICATIONS

This compounded preparation:

Has not been approved by the FDA
Has not undergone FDA review for safety, effectiveness, or quality
Is prepared specifically for you based on your prescriber's order
Individual outcomes may vary

McIntyre RS, Alsuwaidan M, Baune BT, Berk M, Demyttenaere K, Goldberg JF, Gorwood P, Ho R, Kasper S, Kennedy SH, Ly-Uson J, Mansur RB, McAllister-Williams RH, Murrough JW, Nemeroff CB, Nierenberg AA, Rosenblat JD, Sanacora G, Schatzberg AF, Shelton R, Stahl SM, Trivedi MH, Vieta E, Vinberg M, Williams N, Young AH, Maj M. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. 2023 Oct;22(3):394-412. doi: 10.1002/wps.21120. PMID: 37713549; PMCID: PMC10503923.

Correia AS, Cardoso A, Vale N. Oxidative Stress in Depression: The Link with the Stress Response, Neuroinflammation, Serotonin, Neurogenesis and Synaptic Plasticity. Antioxidants (Basel). 2023 Feb 13;12(2):470. doi: 10.3390/antiox12020470. PMID: 36830028; PMCID: PMC9951986.

Bell, Charles JM, et al. “Glutathione alterations in depression: a meta-analysis and systematic review of proton magnetic resonance spectroscopy studies.” Psychopharmacology (2024): 1-8.

Kopra E, Mondelli V, Pariante C, Nikkheslat N. Ketamine’s effect on inflammation and kynurenine pathway in depression: A systematic review. J Psychopharmacol. 2021 Aug;35(8):934-945. doi: 10.1177/02698811211026426. Epub 2021 Jun 26. PMID: 34180293; PMCID: PMC8358579.

Aleksandrova, Lily R., and Anthony G. Phillips. “Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics.” Trends in pharmacological sciences 42.11 (2021): 929-942.

Jelen LA, Young AH, Stone JM. Ketamine: A tale of two enantiomers. J Psychopharmacol. 2021 Feb;35(2):109-123. doi: 10.1177/0269881120959644. Epub 2020 Nov 6. PMID: 33155503; PMCID: PMC7859674.

Ballard, Elizabeth D., and Carlos A. Zarate Jr. “The role of dissociation in ketamine’s antidepressant effects.” Nature communications 11.1 (2020): 6431.

Zacharias N, Musso F, Müller F, Lammers F, Saleh A, London M, de Boer P, Winterer G. Ketamine effects on default mode network activity and vigilance: A randomized, placebo-controlled crossover simultaneous fMRI/EEG study. Hum Brain Mapp. 2020 Jan;41(1):107-119. doi: 10.1002/ hbm.24791. Epub 2019 Sep 18. PMID: 31532029; PMCID: PMC7268043.

Nogo, Danica, et al. “The effect of ketamine on anhedonia: improvements in dimensions of anticipatory, consummatory, and motivation-related reward deficits.” Psychopharmacology 239.7 (2022): 2011-2039.

Rosenbaum SB, Gupta V, Patel P, et al. Ketamine. [Updated 2024 Jan 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470357/

U.S. Food and Drug Administration. FDA warns patients and health care providers about potential risks associated with compounded ketamine.

Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Science. 2012 Oct 5;338(6103):68-72. doi: 10.1126/ science.1222939. PMID: 23042884; PMCID: PMC4424898.

Bharadwaj A. Does ketamine show tolerance? Indian J Pharmacol. 2023 Nov-Dec;55(6):410-411. doi: 10.4103/ijp.ijp_230_23. PMID: 38174540; PMCID: PMC10821698.

Kalsi, S. S., Wood, D. M., & Dargan, P. I. (2011). The epidemiology and patterns of acute and chronic toxicity associated with recreational ketamine use. Emerging Health Threats Journal, 4(1). https://doi.org/10.3402/ehtj.v4i0.7107

Oliver PA, Snyder AD, Feinn R, Malov S, McDiarmid G, Arias AJ. Clinical Effectiveness of Intravenous Racemic Ketamine Infusions in a Large Community Sample of Patients With Treatment-Resistant Depression, Suicidal Ideation, and Generalized Anxiety Symptoms: A Retrospective Chart Review. J Clin Psychiatry. 2022 Sep 12;83(6):21m14336. doi: 10.4088/JCP.21m14336. PMID: 36112599.

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Subramanian S, Haroutounian S, Palanca BJA, Lenze EJ. Ketamine as a therapeutic agent for depression and pain: mechanisms and evidence. J Neurol Sci. 2022 Mar 15;434:120152. doi: 10.1016/j.jns.2022.120152. Epub 2022 Jan 14. PMID: 35092901.

Q. What is ketamine used for?

A. Though approved by the FDA primarily for anesthesia, our compounded ketamine options are most often used to help alleviate depression and chronic pain. Ketamine is also being explored for use in addressing post-traumatic stress disorder (PTSD), bipolar disorder, migraines, and substance use disorders.

Q. How can one minimize dissociation in a patient?

A. Dissociation is a discontinuity in the normal integration of consciousness, memory, identity, emotion, perception, body representation, motor control, and behavior.

At initiation of therapy, a provider should have a patient come to the clinic for dose administration to determine how a patient responds to ketamine and what is the lowest successful dose with the fewest unwanted effects. Dissociative doses will typically be higher than what is required for pain or depression management. Inadvertent swallowing of a ketamine troche dose may also change its pharmacokinetics and lead to prolonged dissociation (which is why we advise patients to spit out any troche residue after 20 minutes).

Q. Is dissociation needed to achieve a therapeutic effect?

A. Dissociation is not required to address chronic pain or depression. Neuroplasticity benefits of ketamine can be gleaned without dissociation. However, some providers may incorporate elements of ketamine’s pleasure-inducing or dissociative effects into a well-crafted psychotherapy regimen to make a patient more receptive or malleable to counseling.

Q. Are there any health conditions that would prevent me from using ketamine?

A. Ketamine should not be used in patients with schizophrenia or uncontrolled blood pressure. Avoid ketamine in patients with conditions where elevated blood pressure may increase the risk of complications, such as aortic dissection, myocardial infarction, or aneurysms.

Q. Should ketamine be cycled? How often is it used?

A. Ketamine exerts its effects when used approximately twice a week. Taking it more frequently does not afford better outcomes and may even increase the risk of drug tolerance. In case of a reduced response to ketamine’s desired effects, discuss taking a short break from ketamine with your provider.

Q. How long do the effects last?

The onset of desired antidepressant effects can be within a few hours, making the medication useful in addressing suicidal ideation. Any mental side effects, such as confusion or dissociation, if present, usually last an hour but could be up to 4 hours in some patients. The ketamine from a single dose will be out of one’s system by 10 hours. However, the antidepressant effects are durable and may last up to a week.

Q. Does ketamine become less successful with prolonged use?

The literature notes an up-regulation of enzymes that metabolize ketamine with use, and a diminished effect of desirable outcomes is possible with long-term use. However, this build-up of tolerance to ketamine appears to be pronounced in recreational users who use high doses. Doses that lead to dissociation or sedation, or frequent administration, would be more likely to result in drug tolerance. Strive recommends the lowest appropriate dose taken approximately twice a week. The risk of developing drug tolerance with such a regimen would be minimal.^2,3

Q. How successful is ketamine for depression?

A. Most of the data we have suggestive of racemic ketamine’s success is from IV infusion studies. They show a response rate of around 70%, a remission rate of around 38%, and a 50% reduction in suicidal or self-harm ideation.⁴ Ketamine is often successful in patients who have failed standard antidepressant therapies.

Selective serotonin reuptake inhibitors (SSRIs), in comparison, may not work in up to 30% of patients, and the most recent high-quality trials show them to be nominally more successful than placebo. SSRIs can take up to 8 weeks to work, whereas ketamine is shown to have marked antidepressant effects within hours, and benefits may last up to a week. Ketamine is notable for not only reversing sadness, but bringing a sense of joy to activities a patient is generally fond of (positive affect). Its fast onset of action may be useful in addressing suicidal ideation.^4-6

Q. What medications interact with ketamine?

A. Medications that increase neuroinhibition may counteract ketamine’s effect of stimulating neural connections in the prefrontal cortex. Benzodiazepines, which are commonly prescribed in patients with concurrent depression and anxiety, may significantly decrease the success of ketamine therapy.

Q. Do I need to stop taking other antidepressants?

A. No. One may continue taking other antidepressants while on ketamine. In fact, up until January 2025, ketamine therapy such as Spravato was approved only in conjunction with another standard oral antidepressant.

Q. What are the differences between ketamine dosage forms, such as troche versus spray, and how do I choose which to use for a patient?

Both forms may be used in depressed patients. The troche form takes about 20 minutes to be absorbed through the mouth mucosa. The nasal spray has a quicker onset that can be used for depression with acute anxiety. It is also used off label for migraines. Please be aware the nasal form, due to its quick onset, has a higher potential for abuse.

Q. Is there a difference between Spravato and Strive’s ketamine nasal spray?

Spravato is the S-enantiomer of ketamine which was shown to have a stronger affinity for the NMDA receptor. In order to have an efficient response at the lowest possible doses, S-enantiomer was pursued as the choice of active ingredient. However, evidence has been mounting that racemic ketamine (S and R enantiomers) is more successful than the S-enantiomer alone. R-ketamine, despite its lower affinity for the NMDA receptor, may have longer-lasting antidepressant effects, alongside fewer side effects and a lower abuse potential. These advantages appear to be conferred through ketamine’s metabolites via the AMPA pathway.^6,7 Strive’s ketamine is racemic, drawing on the strengths of both S and R enantiomers.

Q. Are there any supplements that may assist ketamine therapy?

A. Low serum magnesium levels have been linked to depression and magnesium deficiency may be fairly widespread in the general population. However, magnesium also has an antagonistic effect on the NMDA receptor, and administering it in ketamine users may have a synergistic effect on glutamate neurotransmitter activity. A patient may want to use a form with relatively good bioavailability, such as magnesium glycinate, for general supplementation. ⁸