Doctor talking consulting man with depression about use of ketamine

Ketamine and Depression: Understanding its use and risks

Ketamine has been getting more attention as a potential fast-acting treatment for severe, treatment-resistant depression and suicidal thoughts.

Medically reviewed by Dr. John Ogrodniczuk – Written by Aiden Simard and the HeadsUpGuys Team

Posted June 1, 2021. Updated September 16, 2024.

"Despite the risks of its usage, the limited amount of research seems to suggest that ketamine may have the potential to be an effective treatment for severe and chronic depression."

1. What is ketamine?

Originating in the 1960s, ketamine was developed as an anesthetic used on the battlefield and was later adapted for veterinary and human surgeries. With its pain-reducing effects, ketamine has also been used more frequently for acute and chronic pain management.

Since its initial development, ketamine and its derivatives have been used (and abused) for various purposes. Ketamine gained popularity as a ‘club drug’, known as ‘Special K’, in the late 80s because of the dissociative and ‘out of body’ experiences it causes when used. Because of its sedative effects, ketamine has also been used as a date-rape drug. When abused in these ways, ketamine poses several risks to the user’s mental and physical health, and can result in addiction, withdrawals, and several other adverse effects.

More recently, ketamine has been getting more attention from researchers, drug manufacturers, and health professionals as a potential fast-acting treatment for severe, treatment-resistant depression and suicidal thoughts. (1) The most common antidepressants used today are SSRIs (selective serotonin reuptake inhibitors). Unlike SSRIs, ketamine appears to act on another neurotransmitter (glutamate), opening up the potential for new treatments for depression. By binding and blocking certain receptors in the brain, ketamine may strengthen new neural pathways that can positively affect mood, reinforce various cognitive processes, and reduce depressive symptoms. (2)

The intriguing possibility for a new approach in treating depression sparked the development of a new ketamine derivative, esketamine, which works as a nasal spray. (3) So far, esketamine has been approved in the US (2019), Canada (2020), and the UK (2020) as a treatment for depression. It is only administered to patients with treatment-resistant depression.

So how can ketamine act as both a dissociative, addictive club drug and a potentially groundbreaking treatment of depression? Research is still quite limited, and experts remain divided. However, current evidence and clinical usage suggest that a strict, controlled drug administration may be an effective treatment option for patients suffering from persistent and seemingly untreatable depression. (4)

2. Ketamine as a Last-Resort Treatment of Depression

In the US, Canada, and the UK, the drug must be administered in the presence of a health care provider at a registered doctor’s office/clinic. Patients are given low, controlled doses and must be closely monitored and discharged by the physician. Administration to those with alcohol and substance use disorders is prohibited. Evidence indicates decreases in depressive symptoms directly following usage and acute relief for those with unbearable, unchanging depressive symptoms (5) and those with suicidal thoughts (1).

3. Risks of Ketamine as an Abused Substance

Despite the potential for ketamine to function as a fast-acting antidepressant, its abuse as a recreational drug carries severe risks.

  • Highly addictive and potential for strong withdrawal symptoms. (6)
  • May lead to worsened depressive state and increased prevalence of suicidal thoughts. (7)
  • Risk of entering the “K-hole”: an altered state of consciousness characterized by hallucinations and an inability to move. (6)
  • Risk of developing high blood pressure and cystitis (inflammation of the bladder). (8)

4. The Bottom Line

Using ketamine as an antidepressant is still a very new practice, and carefully conducted research on it is limited. It is important to be aware of the potential effects, risks, and eligibility regarding ketamine usage.

  • If you are using recreationally:
    • Understand the risk you are taking; un-regulated ketamine usage may result in worsened depressive symptoms, hallucinations, inability to move, and other serious adverse effects. (6)
    • Inform your doctor that you are using ketamine.
  • If you are wondering about its use to treat depression:
    • Ketamine and esketamine will only be prescribed to you if a physician deems your depression untreatable by traditional, evidence-based medicines. It may be used to provide acute relief for entrenched depressive symptoms and suicidal thoughts, but also carries the risk for various severe side effects. (8)
  • Do not self-medicate:
    • There are strict eligibility requirements that must be met before ketamine is recommended for treatment.
    • Consult your doctor for treatment options.

Despite the risks of its usage, the limited amount of research seems to suggest that ketamine may have the potential to be an effective treatment for severe and chronic depression. For those who have been fighting depression for years and have already tried various antidepressants, without success, ketamine may be an option to consider with your physician.

On the advice of an international expert panel, it “should be administered only at centres with the appropriate infrastructure and multidisciplinary personnel with expertise in the assessment and treatment of adults with mood disorders.” (9) Otherwise, there is risk of worsening depression, and a wide range of harmful side effects.

References:

  1. Krystal, J., Abdallah, C., Sanacora, G., Charney, D., & Duman, R. (2019). Ketamine: a paradigm shift for depression research and treatment. Neuron, 101(5), 774-778.
  2. Newport, D., Carpenter, L., McDonald, W., Potash, J., Tohen, M., & Nemeroff, C. (2015). Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. The American Journal of Psychiatry, 172(10), 950-966.
  3. Daly, E., Trivedi, M., Janik, A., Li, H., Zhang, Y., Li, X., Lane, R., Lim, P., Duca, A., Hough, D., Thase, M., Zajecka, J., Winokur, A., Divacka, I., Fagiolini, A., Cubala, W., Bitter, I., Blier, P., Shelton, R., … Singh, J. (2019). Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry, 76(9), 893-903.
  4. Fava, M., Freeman, M., Flynn, M., Judge, H., Hoeppner, B., Cousin, C., Ionescu, D., Matthew, S., Chang, L., Iosifescu, D., Murrough, J., Debattista, C., Schatzberg, A., Trivedi, M., Jha, M., Sanacora, G., Wilkinson S., & Papakostas, G. (2019). Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Molecular Psychiatry, 25, 1592-1603.
  5. Phillips, J., Norris, S., Talbot, J., Birmingham, M., Hatchard, T., Ortiz, A., Owoeye, O., Batten, L., & Blier, P. (2019). Single, repeated, and maintenance ketamine infusions for treatmentresistant depression: a randomized controlled trial. The American Journal of Psychiatry, 176(5), 401-409.
  6. Ketamine: Modern Drug of Abuse? (n.d.). Drugs.com.
  7. FDA approves new nasal spray medication for treatment-resistant depression; available only at certified doctor’s office or clinic. (2019, March 05). U.S. Food and Drug Administration.
  8. Perez-Esparza, R., Kobayashi-Romero, L., Garcia-Mendoza, A., Lamas-Aguilar, R., Fonseca-Perezamador, A. (2019). Promises and concerns regarding the use of ketamine and esketamine in the treatment of depression. Acta Psychiatrica Scandinavica, 140(2), 182-183.
  9. Roger S. McIntyre, Joshua D. Rosenblat, Charles B. Nemeroff, Gerard Sanacora, James W. Murrough, Michael Berk, Elisa Brietzke, Seetal Dodd, Philip Gorwood, Roger Ho, Dan V. Iosifescu, Carlos Lopez Jaramillo, Siegfried Kasper, Kevin Kratiuk, Jung Goo Lee, Yena Lee, Leanna M.W. Lui, Rodrigo B. Mansur, George I. Papakostas, Mehala Subramaniapillai, Michael Thase, Eduard Vieta, Allan H. Young, Carlos A. Zarate, Jr., and Stephen Stahl. 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 2021 178:5, 383-399. doi: 10.1176/appi.ajp.2020.20081251.

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