Ketamine - Guidelines
We've explored how ketamine works, its potential benefits, and its safety in treating mental health conditions.
But what happens when it comes to applying that knowledge in real-life care?
There's a crucial gap between research and standardized care.
Clear guidelines for ketamine therapy in mental health are still emerging.
In this post, we'll try to provide a detailed and thorough comparison of existing guidelines for ketamine use in mental health treatments, mainly focusing on Treatment-Resistant Depression (TRD).
Each section breaks down key similarities and differences between the guidelines, offering insights into definitions, patient inclusion/exclusion criteria, dosing protocols, and evidence supporting ketamine use in clinical settings.
Key Organizations in Ketamine Guidelines
AANA (American Association of Nurse Anesthesiology)
This professional organization represents Certified Registered Nurse Anesthetists (CRNAs), who often play a key role in administering ketamine.
APA (American Psychiatric Association)
This is the main professional organization for psychiatrists in the United States, involved in setting standards for mental health care.
CANMAT (Canadian Network for Mood and Anxiety Treatments)
This organization develops clinical guidelines for the treatment of mood and anxiety disorders in Canada.
Edmonton Ketamine Program
This is a specialized program within Alberta Health Services in Canada, focused on providing ketamine therapy for treatment-resistant depression.
JPP (Journal of Psychedelic Psychiatry) -
“Ethical Guidelines for Ketamine Clinicians”
This peer-reviewed journal guideline focuses on ethical ketamine practice rather than clinical aspects.
New Zealand SMHS (New Zealand Ministry of Health, Specialist Mental Health Services)
This government agency provides guidance and resources for mental health services in New Zealand.
Mclntyre and Sanacora et. al.
This refers to a group of researchers and clinicians led by Dr. Gerard Sanacora, a leading figure in ketamine research and clinical practice at Yale University.
Texas HHS (Texas Health and Human Services)
This state government agency oversees health services in Texas, including mental health care regulations.
VA (Department of Veterans Affairs)
This federal agency provides healthcare services to veterans, including mental health treatment.
1. Definitions and Criteria for Treatment-Resistant Depression (TRD)
Commonalities
Ketamine is recognized as a treatment for TRD, which refers to patients who have not responded to at least two antidepressants from different pharmacological classes, administered at adequate dosages for an appropriate duration.
The failure of these antidepressants is measured by the lack of clinical remission or a significant reduction in depressive symptoms.
Differences
AANA
While the guidelines focus on patients who have failed standard antidepressant treatments, they do not explicitly define TRD as strictly as other protocols.
APA Task Force
Requires that patients experience a major depressive episode without psychotic features and fail to respond to two or more antidepressants.
Texas HHS
“The strongest data are in its use in patients with MDD without psychotic features”
VA
This is the most stringent guideline, requiring patients to have failed at least FOUR antidepressants or psychotherapy treatments, or to have severe suicidal depression where the rapid onset of treatment is crucial.
CANMAT
Defines TRD as failure after two first-line antidepressants and one adjunctive therapy.
New Zealand SMHS
Includes both medication (two failed antidepressants) and evidence-based psychotherapy (if available) failure in its definition of TRD.
Edmonton Ketamine Program
Designed for patients with TRD, defined as failure to respond to two or more trials of “appropriate pharmacotherapy”.
Mclntyre and Sanacora et. al.
These guidelines recommend ketamine only for patients who have failed “adequate trials of more standard antidepressant treatments”, stressing a comprehensive risk-benefit analysis before use.
JPP Ethical Guidelines
Focuses primarily on ethical considerations, with the implication that ketamine should only be used for “psychiatric indication, psycho-spiritual exploration, and/or psychological work”.
2. Patient Inclusion Criteria
Commonalities
Ketamine is broadly recommended for patients with MDD who have not responded to conventional therapies (TRD).
Most guidelines focus on adult populations (patients over 18 years of age).
Differences
AANA
The inclusion criteria are not deeply specified, focusing more broadly on patients with TRD.
VA
Opens eligibility to those who have failed multiple treatments, including those with severe suicidal depression.
Edmonton Ketamine Program
Bipolar TRD patients are included in their protocol.
Mclntyre and Sanacora et. al.
Strongly recommends individual risk-benefit analysis before including any patient, especially those with complex treatment histories.
JPP Ethical Guidelines
These ethical guidelines lean more on the side of patient autonomy and informed consent, allowing flexibility based on individualized treatment needs.
3. Patient Exclusion Criteria
Commonalities
Psychotic disorders, active substance use disorders, and uncontrolled medical conditions (e.g., cardiovascular, hepatic, and renal issues) are common exclusion criteria across all guidelines.
Pregnancy and breastfeeding are contraindicated for ketamine treatment due to insufficient safety data.
Differences
Psychiatric Exclusion Criteria
APA Task Force
Explicitly excludes patients with psychotic features and severe personality disorders due to the risk of exacerbating psychosis.
AANA
Patients with Delirium, current or previous abuse of ketamine should be excluded.
New Zealand SMHS
Dementia and Inability to consent for treatment are mentioned.
“Significant Comorbid Personality Disorder” is also mentioned, without clarification.
Mclntyre and Sanacora et. al.
“Preliminary evidence suggests that persons with psychotic depression or a primary psychotic disorder may safely benefit from treatment with intravenous ketamine or esketamine.”
VA
Recent (<7 days) delirium
Dementia
Current or past history of schizophrenia, schizoaffective disorder, or bipolar disorder
Medical Exclusion Criteria
Cardiovascular conditions
As noted above, most guidelines exclude patients with uncontrolled hypertension or cardiovascular conditions.
CANMAT
Specifies a cutoff for baseline blood pressure above 140/90 mmHg.
Edmonton & Mclntyre and Sanacora et. al.
Patients with a recent cardiovascular event (e.g., heart attack within 6 weeks) and New York Heart Association class III heart failure.
VA and AANA
“Severe Cardiac Decompensation”
Renal and Other Conditions
New Zealand SMHS
Excludes patients with “severe bladder pathology”.
“Failed course of ketamine in the past 12 months”
4. Level of Evidence and Supporting Studies
Commonalities
All guidelines agree that ketamine’s short-term efficacy is supported by robust evidence from randomized controlled trials (RCTs), especially in TRD and depression with suicidal ideation.
All guidelines acknowledge the gap in long-term efficacy data and emphasize the need for need for further research.
Differences
APA Task Force
Cites 7 placebo-controlled, double-blind studies as strong evidence of ketamine’s effectiveness, focusing on its ability to alleviate symptoms in 24 hours.
CANMAT
Supports IV Ketamine use in single doses for short-term effects (level 1).
“But relapse occurs within 10 days for most patients”
“Limited Evidence” for efficacy for a course of 6 to 8 repeated infusions (level 3).
Oral Ketamine may be efficacious (level 3).
New Zealand SMHS
Oral Ketamine (ketamine mixed with orange juice and sipped over 30–60 min) appears beneficial.
Edmonton Ketamine Program
“In Canada … IV racemic ketamine has been acknowledged as a 3rd line treatment for both bipolar depression and adults with unipolar TRD.
5. Dosing Protocols
Commonalities
All guidelines broadly agree on the use of 0.5 mg/kg IV dose as the most common and accepted method of administration and dosing (exception: New Zealand SMHS).
This dose is considered effective for producing rapid antidepressant effects without significant anesthetic side effects.
Differences
Texas HHS & APA Task Force
Highlights the importance of adjusting treatment frequency based on the patient’s response.
Indirectly suggests IV 0.5 mg/kg for 40 minute dosing twice weekly x 4 weeks.
“The results of this trial suggest that twice-weekly administration is as efficacious as thrice-weekly for a period of up to four weeks.” (Texas HHS)
VA
“Ketamine infusion should be repeated no less 3 days apart and not more frequently than twice a week for 2 – 3 weeks.”
“After 2-3 weeks the frequency of infusion should be once a week to once every 3 weeks with the goal to extend the interval between infusions to as long as possible (usually monthly).”
CANMAT
As a single infusion, or as a course of repeated infusions administered 2 to 3 times per week for a total of 4 to 8 infusions (level 3).
Caution with repeated infusions given the limited long-term data on safety.
New Zealand SMHS
Focuses on alternative routes such as intramuscular (IM) and oral ketamine.
Recommends using two unique “Pathways”—
1. Rapid Test of Ketamine Response Pathway“If determining whether patient is responsive to ketamine is urgent, patients can be given 1 mg/kg IM ketamine at the clinic of the local psychiatric hospital (where medical monitoring and support is available).”
Only can be used ONCE as an alternative option to urgently test patient response.
“… But recognise that there may be situations when repeated doses of intramuscular ketamine are preferred (particularly severe suicidality).
“We chose the dose of 1 mg/kg because of recent clinical trial and ‘real-world’ evidence that 0.5 mg/kg is an ineffective dose for some, and to optimise the likelihood of response”.**
**Please be careful with this high initial dose.
1 mg/kg IM dose equates to around 0.93 mg/kg IV, meaning it’s 86% more potent than broadly accepted 0.5 mg/kg IV dose.
IV dosing can be stopped at anytime. IM dosing cannot be once injected.
There has been a report of patient respond too strongly to 0.4 mg/kg IV dose.
Make sure to vet your patient thoroughly if this dose is essential.
Document your risks vs. benefits prior to treatment.
Acquire additional informed consent on higher than normal bioavailable dose
Monitor tightly and have support and resources available for cardiovascular and/or psychological complications.
2. Standard Oral Ketamine Pathway
Initial: Oral 1 mg/kg.
“According to DASS-21 and clinical response, ketamine can be increased to 1.5 mg/kg and then 2 mg/kg if response is suboptimal.”
Oral ketamine can be administered up to twice weekly for 12 weeks depending on duration of response.
Edmonton Ketamine Program
Begins with the 0.5 mg/kg IV dose but allows for dose increases (by 0.25 mg/kg) up to 1.0 mg/kg if the patient does not respond to the standard dose.
Treatment typically occurs twice per week, with flexibility in dosing and frequency based on the patient’s progress.
The program also explores intranasal and sublingual options for long-term maintenance.
Mclntyre and Sanacora et. al.
Endorses the standard 0.5 mg/kg IV infusion, citing strong support in the literature.
Higher doses up to 1.0 mg/kg are also explored but must be used cautiously due to potential side effects.
6. Treatment Setting and Monitoring
Commonalities
Across all guidelines, there is a shared emphasis on the importance of administering ketamine treatments, especially intravenous (IV) infusions, in a controlled clinical setting.
The primary reason for this is to ensure patient safety, as ketamine can cause both physical and psychological side effects that require immediate intervention.
Most guidelines and protocols mandate continuous monitoring of vital signs like blood pressure, heart rate, and oxygen saturation during and after the treatment.
Most guidelines suggest a minimum 2-hour observation period after administration.
Differences
AANA
Ketamine infusions should be conducted in clinics equipped with monitoring equipment for Cardiovascular, hemodynamic, and respiratory function.
“ECG and measurement of oxygen saturation are essential”.
Crash cart and emergency airway management are also suggested.
APA Task Force & Texas HHS
Additional emphasis on behavioral and psychological side effects, including ketamine’s dissociative and psychotomimetic effects (e.g., level of consciousness).
“It is suggested that an on-site clinician be available and able to evaluate the patient for potential behavioral risks, including suicidal ideation, before discharge to home.”
VA
Ketamine should be administered within VA medical centers that have comprehensive facilities for managing cardiovascular and respiratory events.
“The facility must also be capable of administering oxygen, medication and/or restraints to manage potentially dangerous behavioral symptoms”
The ordering VA psychiatrist or VA licensed health-care provider (i.e., CPP, NP, PA) AND an ACLS certified physician or nurse will be present during the infusion and prior to discharge.
Rationale
Veterans receiving ketamine treatments may have complex comorbidities (e.g., PTSD, suicidal ideation).
Proper psychological assessments (i.e. CADSS) needed for discharge.
CANMAT
“Ketamine infusions should be administered in facilities that have secure storage for controlled medications, physiological monitoring requirements, and available medications to manage adverse events.”
Generally, an on-site Anesthesiologist is not required for low-risk patients, but trained medical staff must be available for any necessary interventions.
New Zealand SMHS
Oral ketamine is briefly discussed.
Can be administered at home by case manager and/or team nurse.
Edmonton Ketamine Program
Conducts ketamine administration in acute care hospitals where rapid response teams are on hand in case of emergencies.
Nurses trained in advanced airway management administer the ketamine
Patients are on the unit for 90 minutes after the infusion to ensure side effects have resolved before they are discharged.
“However, our critical assessment of risks and benefits concludes that in office monitoring need not be routinely required”
JPP Ethical Guidelines
Highlight the need for a multidisciplinary approach to ketamine administration, involving both medical professionals (for physical monitoring) and mental health professionals (for psychological support).
The guidelines emphasize that ketamine’s dissociative effects can be particularly challenging.
Summary
All guidelines agree that ketamine administration requires a clinical setting equipped with continuous monitoring for cardiovascular and respiratory events.
Each guideline addresses various psychological monitoring and the level of on-site staffing.
7. Clinician Training and Certification
Commonalities
Across all guidelines, there is a consistent emphasis on the need for trained professionals to administer ketamine, particularly due to its medical and psychological risks.
Most guidelines recommend or require clinicians to be certified in Advanced Cardiac Life Support (ACLS) to handle potential cardiovascular emergencies.
Differences
AANA
Certified Registered Nurse Anesthetists (CRNAs) should administer ketamine, as they are trained in both anesthesia and emergency management.
Emphasizes interdisciplinary team approach, especially with psychiatric specialists.
APA Task Force & Texas HHS
Clinicians administering ketamine should be licensed to handle Schedule III medications and ACLS certification.
Calls clinicians to be experienced with “The method of ketamine administration” (i.e. IV admin. technique)
New Zealand SMHS
“It is intended that psychiatrists will observe three intramuscular treatments to ensure familiarity with the dissociative ketamine experience before overseeing intramuscular ketamine administration for future patients.”
Edmonton Ketamine Program
Ketamine should be administered by nurses trained in advanced airway management, with physicians available if necessary.
Reflects the program’s approach of using acute care hospitals as treatment centers.
JPP Ethical Guidelines
Strong emphasis on psychiatric training
“It is simply not possible to provide a truly informed consent, including risks, benefits, and alternatives, if the provider does not have psychiatric training”.
8. Safety Protocols and Side Effect Management
Commonalities
All guidelines require continuous monitoring of vital signs (i.e. BP, HR, and oxygen saturation) during ketamine infusions, given the risks of cardiovascular side effects.
General BP cutoff for treatment initiation is around 140/90 mmHg.
Most guidelines recommending psychological monitoring and support both during and after treatment.
Monitor for at least 2 hours after the infusion and prohibit patients from driving themselves home.
Most guidelines do not list specific medications or procedures for managing side effects.
Pre-treatment assessments to evaluate the patient’s psychiatric and medical suitability are a universal recommendation (i.e. toxicology screening).
Differences
APA Task Force
Assessment of urinary discomfort
Texas HHS & VA
Cutoff for treatment initiation
BP: Systolic 150 mmHg or Diastolic 95 mmHg
SpO2: 94
HR : < 60 bpm or > 100 bpm
Edmonton Ketamine Program
“Conversely, transient hypertension is not treated in an emergency medicine scenario unless there are symptoms of hypertensive emergency which include..”
Crushing chest pressure
Syncope
Severe abdominal pain
Decreased (not just altered) level of consciousness
Shortness of breath
Suggests pre-treatment with clonidine, beta blockers, or calcium channel blockers if elevated BP is a concern.
Mclntyre and Sanacora et. al.
Recommends additional assessment of…
Anxiety (GAD-7)
Psychosocial function
Self-rated cognitive function (PDQ-D-5)
Well-being (WHO-5 Well-being Index)
9. Long-Term Efficacy and Follow-Up Care
Commonalities
All guidelines agree that the short-term benefits of ketamine in reducing depressive symptoms are well documented, particularly for patients with treatment-resistant depression (TRD).
However, there is a collective recognition of the limited data regarding its long-term efficacy and safety.
Most guidelines suggest stopping treatment if there’s no improvement of 20-50% in baseline depression scores after 4 to 6 sessions.
All emphasize the need for regular follow-up assessments to monitor for potential relapse, side effects, and the development of tolerance or dependency.
Differences
APA Task Force & Texas HHS
The APA places significant emphasis on the uncertainty surrounding ketamine’s long-term effects and advises clinicians to exercise caution.
Maintenance therapy should be customized to the individual patient’s needs.
“Discontinuation of ketamine treatment is recommended if the dosing cannot be spaced out to a minimum administration of 1 dose per week by the second month of treatment.”
VA
After 2-3 weeks, reduce the frequency to once every 1–3 weeks, aiming to extend intervals as much as possible (ideally monthly).
Similar to above, the goal should be 1 dose per week by the second month of treatment.
CANMAT
The need for maintenance ketamine should be assessed on a case-by-case basis and reserved only for individuals who have exhausted other treatment options (Level 4).
A previously untried antidepressant or adjunctive medication should be started concurrently with a course of ketamine infusions or shortly after (Level 4).
New Zealand SMHS
Recommends the use of oral ketamine for up to 12 weeks.
Sufficient time for “behavioural activation and the reinforcement of mood improvements by behavioural change”.
Does not endorse long-term or maintenance treatment.
Edmonton Ketamine Program
Maintenance may be a “more inevitable consideration” for individuals with “higher level of treatment resistance”
What’s Next?
What happens when a treatment with so much promise is tangled up in rules, regulations, and business interests?
Even with established clinical data and various expert guidelines,
Access remains a struggle.
Ketamine use for psychiatric disorder poses unique legal and logistical challenges—
Controlled substance regulations
Off-Label Use
Provider training and credentialing
Insurance coverage
Ethical considerations
Can we really make it available to everyone who needs it?
In the next post, we'll peel back the layers on the current state of ketamine therapy—
What the experts are saying,
Where the laws stand, and
Why providing and getting treatment isn’t as simple as it sounds.
I’ll try to cover legal loopholes, practical challenges of running a clinic, and compliance tips.
Comparative Summary of Ketamine Therapy Guidelines for TRD
| Guideline | TRD Definition | Inclusion Criteria | Exclusion Criteria | Level of Evidence |
|---|---|---|---|---|
| Commonalities |
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| AANA |
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| APA Task Force |
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| CANMAT |
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| Edmonton Ketamine Program |
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| JPP Ethical Guidelines |
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| New Zealand SMHS |
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| Mclntyre & Sanacora et al. |
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| Texas HHS |
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| VA |
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| Guideline | Dosing Protocols | Routes of Administration | Treatment Setting & Monitoring | Clinician Training | Safety Protocols | Long-Term Efficacy & Follow-Up |
|---|---|---|---|---|---|---|
| Commonalities |
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| AANA |
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| APA Task Force |
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| CANMAT |
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| Edmonton Ketamine Program |
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| JPP Ethical Guidelines |
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| New Zealand SMHS |
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| Mclntyre & Sanacora et al. |
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| Texas HHS |
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| VA |
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References
American Association of Nurse Anesthesiology (AANA). (2024). Practice considerations for ketamine therapy for psychiatric disorders and chronic pain management. American Association of Nurse Anesthesiology. https://issuu.com/aanapublishing/docs/7_-_ketamine_infusion_therapy_for_psychiatric_diso?fr=sNTFhMjU2NDAxMjU.
Beaglehole, B., Glue, P., Clarke, M., & Porter, R. (2023). Multidisciplinary development of guidelines for ketamine treatment for treatment-resistant major depression disorder for use by adult specialist mental health services in New Zealand. BJPsych open, 9(6), e191. https://doi.org/10.1192/bjo.2023.577.
Chrenek, C., Duong, B., Khullar, A., McRee, C., Thomas, R., & Swainson, J. (2024). Use of ketamine for treatment resistant depression: updated review of literature and practical applications to a community ketamine program in Edmonton, Alberta, Canada. Frontiers in psychiatry, 14, 1283733. https://doi.org/10.3389/fpsyt.2023.1283733.
McIntyre, R. S., Rosenblat, J. D., Nemeroff, C. B., Sanacora, G., Murrough, J. W., Berk, M., Brietzke, E., Dodd, S., Gorwood, P., Ho, R., Iosifescu, D. V., Lopez Jaramillo, C., Kasper, S., Kratiuk, K., Lee, J. G., Lee, Y., Lui, L. M. W., Mansur, R. B., Papakostas, G. I., ... Stahl, S. (2021). Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: An international expert opinion on the available evidence and implementation. American Journal of Psychiatry, 178(5), 383–399. https://doi.org/10.1176/appi.ajp.2020.20081251.
Ryan, W. C., & Bennett, R. G. (2020). Ethical guidelines for ketamine clinicians. Journal of Psychedelic Psychiatry. https://shamynds.com/wp-content/uploads/2021/10/JPP-Ethical-Guidelines-for-Ketamine-Clinicians.pdf.
Sanacora, G., Frye, M. A., McDonald, W., Mathew, S. J., Turner, M. S., Schatzberg, A. F., Summergrad, P., Nemeroff, C. B., & American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments (2017). A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. JAMA psychiatry, 74(4), 399–405. https://doi.org/10.1001/jamapsychiatry.2017.0080.
Swainson, J., McGirr, A., Blier, P., Brietzke, E., Richard-Devantoy, S., Ravindran, N., Blier, J., Beaulieu, S., Frey, B. N., Kennedy, S. H., McIntyre, R. S., Milev, R. V., Parikh, S. V., Schaffer, A., Taylor, V. H., Tourjman, V., van Ameringen, M., Yatham, L. N., Ravindran, A. V., & Lam, R. W. (2021). The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Recommendations for the Use of Racemic Ketamine in Adults with Major Depressive Disorder: Recommandations Du Groupe De Travail Du Réseau Canadien Pour Les Traitements De L'humeur Et De L'anxiété (Canmat) Concernant L'utilisation De La Kétamine Racémique Chez Les Adultes Souffrant De Trouble Dépressif Majeur. Canadian journal of psychiatry. Revue canadienne de psychiatrie, 66(2), 113–125. https://doi.org/10.1177/0706743720970860.
Texas Health and Human Services. (2019). Ketamine (Ketalar) monograph. https://www.hhs.texas.gov/sites/default/files/documents/doing-business-with-hhs/provider-portal/facilities-regulation/psychiatric/monograph/ketamine-ketalar-monograph.pdf
U.S. Department of Veterans Affairs. (2022). Ketamine infusion for treatment resistant depression: National protocol guidance. VA Pharmacy Benefits Management Services, Medical Advisory Panel, VISN Pharmacist Executives, and Office of Mental Health Somatic Treatment Field Advisory Committee.https://www.va.gov/formularyadvisor/DOC_PDF/CRE_Ketamine_Infusion_for_Treatment_Resistant_Depression_Rev_Jul_2022.pdf.
