Ketamine

Ketamine has shown potential in addressing individuals with psychiatric disorders and chronic pain conditions.

• Post-traumatic stress disorder (PTSD)
• Chronic pain
• Migraine
• Depression
• Suicidal ideation

To view Strive dispensing and dosing protocol for providers:

Pharmacokinetics

Recommended maximum dosing: 1.5 mg/kg/dose OR 5 mg/kg/day

• Bioavailability of Troche: 30%
• Duration of possible altered cognition/alertness following TROCHE dose: 1 to 4 hours
• Bioavailability of Nasal Spray: 50%
• Duration of possible altered cognition/alertness following NASAL SPRAY dose:: 1 to 2 hours

Plasma Concentration for Dissociative (50-100 μg/L) and Hypotonic (>2000 μg/L)

Terminal half-life of 183 min

Dose Dependent Activity:

• Low dose: 0.2-0.5mg/kg (empathogen, psycholytic)
• Moderate dose: 0.5-1mg/kg (entheogen)
• High dose: >1mg/kg (anesthetic)

Risk of addiction: Yes, particularly with nasal route of administration

Examples of appropriate codes on prescriptions

• F33.1 Major Depressive Disorder (MDD)
• F41.1 Generalized Anxiety Disorder
• F43.1 Post Traumatic Stress Disorder (PTSD)
• M79.2 Neuralgia, unspecified
• G90.50 Complex Regional Pain Syndrome (CRPS)
• G43.919 Intractable Migraine
• F10.20 Alcohol Use Disorder/Dependence

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. 

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

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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. 

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

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