Ketamine is a dissociative class compound, with an FDA schedule III designation. It is indicated for and commonly used as an anesthetic medication. Ketamine has been found to be helpful for treating depression, even in individuals who have not responded to other interventions. It has a unique effect, in that it can work very rapidly, with individuals frequently seeing improvement in their depression within hours. However, ketamine response is not guaranteed and even in responders, there can be a high rate of relapse back to the depressed, state, even with repeat dosing that increases over time.
The ongoing beneficial effects of ketamine that can be realized include general mood improvement, lessening of anhedonia and reduction/resolution of suicidal ideation. Improvements to levels of anxiety and behavioral pattern of sleep, appetite and energy can also be realized. Ketamine has also demonstrated benefit in anxiety conditions, including PTSD, and may yield gains to patterns of obsessive thinking or rumination. Coupling these biological effects with psychotherapy and behavioral change is designed to maximize benefit and sustained gains.
Ketamine does not have an indication for treatment of depression, anxiety of any other psychiatric condition by the FDA. Therefore, the provision of ketamine for these conditions is an ‘off-label’ use. This is a legal prescribing practice and occurs quite commonly. Almost twenty percent of all medications prescribed in the United States are prescribed for off-label use.
FDA warns patients and health care providers about potential risks associated with compounded ketamine products, including oral formulations, for the treatment of psychiatric disorders
What Patients and Health Care Providers Should Know
There is increased interest in compounded ketamine products (including oral formulations) for the treatment of psychiatric disorders. When considering use of compounded ketamine products, patients and health care providers should know:
Ketamine is not FDA approved for the treatment of any psychiatric disorder. FDA is aware that compounded ketamine products have been marketed for a wide variety of psychiatric disorders (e.g., depression, anxiety, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder); however, FDA has not determined that ketamine is safe and effective for such uses.
Compounded drugs, including compounded ketamine products, are not FDA approved, which means FDA has not evaluated their safety, effectiveness, or quality prior to marketing. Therefore, compounded drugs do not have any FDA-approved indications or routes of administration. Although compounded drugs can serve an important medical need for certain patients when an FDA-approved drug is not medically appropriate, they also present a risk to patients and should only be used under the care of a health care provider.
Use of compounded ketamine products without monitoring by a health care provider for sedation (sleepiness), dissociation (disconnection between a person’s thoughts, feelings, and sense of space, time, and self), and changes in vital signs (such as blood pressure and heart rate) may put patients at risk for serious adverse events.
Known safety concerns associated with the use of ketamine products include abuse and misuse, psychiatric events, increases in blood pressure, respiratory depression (slowed breathing), and lower urinary tract and bladder symptoms. For FDA-approved ketamine (see Ketalar prescribing information), the expected benefit outweighs these risks when used at appropriate doses for FDA-approved indications and routes of administration.
Despite increased interest in the use of compounded ketamine, we are not aware of evidence to suggest that it is safer, is more effective, or works faster than medications that are FDA approved for the treatment of certain psychiatric disorders.
Ketamine hydrochloride (referred to here as “ketamine” interchangeably) is a Schedule III controlled substance that is FDA approved as an intravenous or intramuscular injection solution for induction and maintenance of general anesthesia. Ketamine, like many drug products, is a mixture of two mirror-image molecules, R-ketamine and S-ketamine (arketamine and esketamine, respectively). Spravato (which includes only the esketamine molecule), is approved as a nasal spray for treatment-resistant depression in adults and for depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior (in conjunction with an oral antidepressant).
On February 16, 2022, FDA published a compounding risk alert describing the potential risks associated with at-home use of compounded ketamine nasal spray and several adverse event reports. The February 2022 compounding risk alert also provided information about Spravato, which is subject to a Risk Evaluation and Mitigation Strategy (REMS) as part of its FDA approval. A REMS is a drug safety program that FDA can require for certain approved medications with serious safety concerns to ensure the benefits of the medication outweigh its risks. The Spravato REMS requires esketamine to be dispensed and administered in medically supervised health care settings that are certified in the REMS and agree to monitor patients for a minimum of two hours following administration because of possible sedation and dissociation and the potential for misuse and abuse. Compounded ketamine products are not FDA approved for any indication, including psychiatric disorders, and are, therefore, not part of a REMS program. This does not mean compounded ketamine products are safer for patients. In fact, because compounded ketamine products are not subject to monitoring requirements under a REMS, they may be less safe.
Since the publication of the February 2022 compounding risk alert, FDA has become aware of increasing public interest in the use of sublingual and oral dosage forms of compounded ketamine for the treatment of psychiatric disorders. FDA understands that the ability to obtain such products through telemedicine platforms and compounders for at-home use may be attractive to some patients. However, the lack of monitoring for adverse events, such as sedation and dissociation, by an onsite health care provider may put patients at risk. Additionally, FDA has identified safety concerns associated with compounded ketamine products as discussed below. Furthermore, FDA has not established safe or effective dosing of ketamine for any psychiatric indication because ketamine has not been approved for these uses. These factors may place the patient at risk for serious adverse events, misuse, and abuse.
Potential Safety Risks Associated with Compounded Ketamine Products
Patients who receive compounded ketamine products from compounders and telemedicine platforms for the treatment of psychiatric disorders may not receive important information about the potential risks associated with the product. As previously noted, safety concerns that may be associated with ketamine products include, but are not limited to, risks of sedation, dissociation, psychiatric events or worsening of psychiatric disorders, abuse and misuse, increases in blood pressure, respiratory depression (breathing becomes slower and shallower and the lungs fail to exchange carbon dioxide and oxygen efficiently), and lower urinary tract and bladder symptoms. At-home administration of compounded ketamine presents additional risks because a health care provider is not available onsite to monitor for serious adverse outcomes resulting from sedation and dissociation.
In April 2023, FDA received an adverse event report of a patient who experienced respiratory depression after taking compounded oral ketamine outside of a health care setting for the treatment of PTSD. The patient’s ketamine blood level appeared to be twice the blood level typically obtained for anesthesia.
In addition to the potential risks associated with compounded ketamine products, patients and health care providers should be aware that information about use of these products is lacking. For example, FDA has not established safe or effective dosing of ketamine for any psychiatric indication. Furthermore, the dosages of the sublingual and oral compounded ketamine products marketed by compounders and telemedicine platforms may vary, which makes it challenging to predict which potential risks may be associated with these products. In addition to the concerns regarding the short-term use of compounded ketamine, the overall benefit-risk profile of ketamine for treatment of psychiatric disorders is unknown.
FDA is aware of increased interest in the at-home use of compounded ketamine products, including oral formulations, for the treatment of psychiatric disorders. Patients and health care providers should be aware that FDA has identified potential safety concerns associated with the use of compounded ketamine products from compounders and telemedicine platforms, including abuse and misuse, psychiatric events, increases in blood pressure, respiratory depression, and lower urinary tract and bladder symptoms. Home use of compounded ketamine products presents additional risk because onsite monitoring by a health care provider is not available. Ketamine is not FDA approved for the treatment of any psychiatric disorder, and additional clinical studies are needed to adequately investigate ketamine’s benefit-risk profile and safe-use conditions in the treatment of psychiatric disorders.
FDA encourages compounders, patients, and health care providers to report adverse events associated with compounded ketamine products to FDA’s MedWatch Adverse Event Reporting program.
Complete and submit the report online at MedWatch: The FDA Safety Information and Adverse Event Reporting Program; or
Download and complete the form, then submit it via fax at 1-800-FDA-0178.
Ketamine operates on a receptor level as NMDA antagonist and regulates the availability of the neurotransmitter glutamate in the brain. The antidepressant effect appears to be mediated by downstream signal effects of AMPA receptors. A variety of other receptors are targeted and contribute to the acute and ongoing effects of treatment.
Route of Administration
Ketamine can be administered in a variety of ways: via an intravenous ketamine infusion (IV), an intramuscular injection (IM), a subcutaneous injection (SC) intranasally, sublingually and orally as a dissolving troche or oral dissolving tablet. Routes vary in the onset of action, bioavailability and clearing time through the system for each individual. While there is generally a predictable response based on past administration, it is possible that patient maybe experience variable physiological and subjective experiences with the same dose.
Route IV IM Nasal Oral Sublingual
Bioavailability 100% 93% 25-50% 17-24% 24-30%
Onset 1 min 1-5 min 30 min
There are a variety of dosing protocols in practice. Much research and attention has been focused on the provision of 0.5mg/kg of ketamine by IV infusion over 45 minutes, in a repeated series consisting of 2/week for 3 weeks. Other described protocols include provision of a single infusion, daily or weekly dosing by IV, IM, sublingual, or oral routes.
There is significant ongoing research into the initial and maintenance protocol to define optimal response. Much attention is focused on the maintenance of response, noting that the drop off in response can approach 90% following a positive response. Combining psychotherapy with ketamine dosing serves to prolong effect by addressing behavioral and psychological factors that can perpetuate depression, anxiety and other distress states.
Ketamine effects can be designated as occurring at time of dosing – acute, and ongoing – beyond the time it takes for ketamine to metabolize physically, noting that longer acting metabolites persist up to a week.
The acute subjective effects of ketamine dosing can range from sub perceptual disturbances in cognitive processing and body sensation to full dissociative states in which one feels separate from the body and thoughts dissolve fully. Research has shown that ketamine treatment without dissociation is as effective as treatment with dissociation. Dissociation is not required to achieve treatment success.
These experiences are classified as non-ordinary states of consciousness, and may represent novel experiences for patients. It is possible that some patients may experience a departure from their usual mind and physical state aschallenging or unsettling in the moment. The treatment environment, supportive therapist stance and dosing protocol is designed to optimize the positive nature of the subjective experiences.
The most common treatment dosages administered by Ketamine Treament Services for the majority of patients are in the range of 100-400mg sublingually. Studies have shown that higher doses do not increase the success rate of treatment. Most patients do not dissociate or have unpleasant feelings at this dose. Most patients have an empathogenic experience with the symptoms described below
A more comprehensive description of dosing ranges and effects.
Ketamine Psychedelic Psychotherapy: Focus on its Pharmacology, Phenomenology, and Clinical Application: Journal of Transpersonal Studies. Volume 33. Issue 2.
Medical clearance for treatment
Prior to administration of ketamine, a patient will need to be medically cleared for treatment by one of our providers. Unstable medical conditions may need to be addressed before starting ketamine teatment. Clearance by the patients cardiologist may be required in instances where there has been arrhythmia or a history of cardiovascular issues. Patient with a history of cystitis or other bladder issues may need to be cleared by their urologist, noting the rare but potential significant adverse effect of cystitis.
Adverse and side effect associated with treatment
The most common side effects associated with ketamine are nausea, vomiting, dizziness, diplopia, drowsiness, dysphoria, and confusion. There are reports of emergence phenomenon for approximately 6% to 12% of patients. Rarely, patients experience hallucinations.
A complete list of side effects follows:
Allergic: anaphylaxis, breathing difficulties, facial, lip, throat and tongue swelling, hives
Cardiovascular: arrhythmias, blood pressure, is frequently elevated, bradycardia, hypotension, left ventricular dysfunction in patients with heart failure, respiratorycardiac arrest
Gastrointestinal: anorexia, nausea, and vomiting
Muscular: muscle stiffness and spasms/tonic-clonic movements resembling seizures, enhanced skeletal muscle tone
Neurologic: confusion, seizures
Ophthalmologic: diplopia, increased intraocular pressure, nystagmus Psychiatric: amnesia, anxiety, confusion, depression, disorientation,
dysphoria, dissociative state (patients may not be able to speak or respond purposefully to verbal commands), emergence phenomena/delirium (6% to 12% in different studies and can last for up to 3 hours) including hallucinations, flashbacks, unusual thoughts, extreme fear, excitement, and irrational behavior, insomnia, physical and psychological dependence, addiction when used recreationally. (Drug dependence and tolerance may develop after prolonged use. Withdrawal symptoms may occur if stopping ketamine suddenly.)
Respiratory: apnea, increased laryngeal, and tracheal secretions, laryngospasm, airway obstruction in infants (may not be drug-related),
Skin: (infrequently) at the site of injection, local pain, and erythema, morbilliform rash
Ketamine increases sympathetic tone in the vasculature and can raise blood pressure, which has associated risks with adverse outcomes linked to stroke and arrhythmias, resulting in loss of function and possibly death.
Ketamine has limited suppression of respiratory drive, however it is rarely reported to cause laryngospasm, particularly in pediatric populations.
Ketamine has been associated with cystitis, a painful and potentially irreversible bladder condition. Cystitis has been generally reported in higher doses and more frequent uses, particularly in substance abusing population. Ketamine has a risk of abuse and tolerance. It generally has low reinforcement properties and no physiological withdrawal syndrome. Therefore, it is atypical for patients to crave use and demonstrate behaviors to obtain it. Some patients exhibit tolerance (needing higher doses for the same effect).
An emergence phenomena, in approximately 10-20% of cases, has been reported in which a patient may experience subjective distress with psychological or physical restlessness. In these instances, treatment with low dose anxiolytic medication has been beneficial.
There are also rare psychological and psychiatric risks associated with treatment, notable switching into mania for bipolar patients, who may not yet be diagnosed as such. While rarely described, it is possible that sustained perceptual disturbances, alternations in cognition, reality testing or subjective distress stemming from treatment may persist beyond that acute treatment.
Management of Adverse Effects:
Intervention may include prescribing of anti-hypertensive medication, medication for nausea, or medication for anxiety. Management of cardiorespiratory symptoms is beyond the scope of our practice and should be handled by activation of the EMS system in coordination with the local Emergency Department. In the event of psychological distress, treating provider may prescribe an anxiolytic medication or antipsychotic medication. The treating provider reserves the right to activate emergency response systems, ie. call 9-11, if it is determined by clinical judgment that patient safety requires a higher level of care.
Prior to treatment:
Patients are expected to abstain from all substance use for a period of 48 hours; including alcohol tobacco, cannabis, illicit substances.
No dietary intake for least 1 hour prior treatment. A small intake of water is permitted
Hold medication that may raise blood pressure – ie. stimulants
Continue on anti-hypertension and diabetic medication, with dose of adjustment of insulin based on dietary intake adjustment.
Standard course experience with treatment
Preparation: 0-15 minutes
Completion of depression and related screening forms
Review of this consent form prior to treatment
Evaluation of mindset and readiness for treatment
Having a patient sitter present
Dosing: Onset 15-30 minutes
Self administration of Ketamine troche, tablet or suppository.
Trance state: 30-45 minutes:
Generally restful, volitionally non-verbal, supported by soothing music and eye shade to minimize light effect
Patient will typically experience a heaviness in the physical body, possibly with the loss of sensation, followed by a separation from the usual state of cognitive processing, such that verbal expression may become limited and even absent.
Patients are generally rousable to an alert and interactive state, and may be checked in on by verbal cue to determine if there are any concerns.
Some patients may experience unfamiliarity with this state that is disconcerting – perhaps in the heaviness/floating sensation, vertigo like sensation, physical discomfort (nausea), the presentation of distressing psychological material
Integration Phase: 30-45 minutes
Opportunity for reflection and discussion
Patient are encouraged to describe experience and potentially engage in discussion of thoughts, emotional states and physical sensations with another person or by writing in a journal. Patients may prefer silence in this period, and thoughts recorded by notations, or use of a the patient’s private recording device – ie. audio on phone.
Disengagement from treatment
At any point in the treatment course, the patient may disengage from the defined and recommended process – ie. sit up and take off the eye shade.
Patients agree to use the medication at the end of the day before going to sleep for the evening. Any activities affected by sedation should be avoided until the following day.
The patient may be engage in an ongoing and concurrent treatment with a medical provider at Integration Healthcare, and/or a psychiatrist or psychologist, as deemed appropriate. The termination or interruption of this collaborative treatment may result in termination of ketamine associated therapy.
In signing this agreement, I recognize that:
I have an established a treatment relationship with a provider at Integration Healthcare.
I agree to use the medication only as it is prescribed.
I understand that sharing or selling my prescribed medications to another person is a crime and grounds for immediate dismissal from treatment.
I understand that I have alternative treatment options beside ketamine for my condition.
I understand that I may not respond or have a favorable response to ketamine treatment and there are risks associated with the treatment, some of which may be permanent.
I understand the FDA warning related to the use of ketamine at home and assume all responsibility for injury, adverse outcome related to possible oversedation, or death related to use of ketamine at home.
Treatment may be terminated by Integration Healthcare based on clinical factors, including and not limited to concerns for poor fit with treatment, likelihood of response, lack of compliance with care, concern for diversion, patient behaviors and risk factors exceeding tolerance of his practice, and lack of sufficient collaborative support by the treatment team. Provision of treatment does not automatically imply future treatment.