Ketamine-assisted psychotherapy

Ketamine is a short-acting, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that was discovered by Parke-Davis Labs and Dr. Calvin Lee Stevens in 1962 during research into derivatives of phencyclidine (PCP).{{Cite journal |last1=Mathai |first1=David S. |last2=Mora |first2=Victoria |last3=Garcia-Romeu |first3=Albert |date=2022 |title=Toward Synergies of Ketamine and Psychotherapy |journal=Frontiers in Psychology |volume=13 |page=868103 |doi=10.3389/fpsyg.2022.868103 |issn=1664-1078 |pmc=8992793 |pmid=35401323 |doi-access=free }} It was first used clinically as a veterinary anesthetic that was first given to a human in 1964 as a potential replacement for PCP. Soon after, Parke-Davis filed a patent for the utilization of the anesthetic.{{Cite web |title=History of Ketamine |url=https://tonydagostino.co.uk/history-of-ketamine-other-dissociative-anaesthetics/ |access-date=2023-12-05 |website=TD Consultancy |language=en-GB}}{{Cite journal |last1=Le Daré |first1=B. |last2=Pelletier |first2=R. |last3=Morel |first3=I. |last4=Gicquel |first4=T. |date=January 2022 |title=[History of Ketamine: An ancient molecule that is still popular today] |journal=Annales Pharmaceutiques Françaises |volume=80 |issue=1 |pages=1–8 |doi=10.1016/j.pharma.2021.04.005 |issn=0003-4509 |pmid=33915159|doi-access=free }} With this patent, ketamine began to be used on the battlefield where it was considered the "buddy drug" because soldiers were able to administer it to one another.{{Cite journal |last=Mercer |first=S. J. |date=2009 |title='The Drug of War'--a historical review of the use of Ketamine in military conflicts |url=https://pubmed.ncbi.nlm.nih.gov/20180434/ |journal=Journal of the Royal Naval Medical Service |volume=95 |issue=3 |pages=145–150 |doi=10.1136/jrnms-95-145 |issn=0035-9033 |pmid=20180434}} Given its hallucinogenic properties, interest rapidly rose in the possibility of broader avenues of application, including within the field of psychiatry as a treatment for depression, substance use dependence, and more.{{Cite journal |last1=Dore |first1=Jennifer |last2=Turnipseed |first2=Brent |last3=Dwyer |first3=Shannon |last4=Turnipseed |first4=Andrea |last5=Andries |first5=Julane |last6=Ascani |first6=German |last7=Monnette |first7=Celeste |last8=Huidekoper |first8=Angela |last9=Strauss |first9=Nicole |last10=Wolfson |first10=Phil |date=2019-03-15 |title=Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data and Outcomes in Three Large Practices Administering Ketamine with Psychotherapy |journal=Journal of Psychoactive Drugs |volume=51 |issue=2 |pages=189–198 |doi=10.1080/02791072.2019.1587556 |issn=0279-1072 |pmid=30917760|s2cid=85543704 |doi-access=free }} Thus, soon after discovery, ketamine has been used as an off-label medication for a diverse group of psychiatric symptoms across Europe and the United States, and a topic of robust investigation. The US Food and Drug Administration (FDA) first approved the use of intranasal esketamine (Spravato)—an enantiomer of ketamine—for the use of ketamine-derived therapy for treatment-resistant depression, in 2019,{{Cite journal |last=Research |first=Center for Drug Evaluation and |date=2022-02-16 |title=FDA alerts health care professionals of potential risks associated with compounded ketamine nasal spray |url=https://www.fda.gov/drugs/human-drug-compounding/fda-alerts-health-care-professionals-potential-risks-associated-compounded-ketamine-nasal-spray |journal=FDA |language=en}} leading to the creation and expansion of telemedicine-based companies that practice ketamine-assisted psychotherapy, such as the Psychedelic Institute of Mental Health & Family Therapy.{{cite news |last=DeMarco |first=Michael |title=Psychedelic Cognitive Behavioral Therapy: On Ketamine, Context and Competencies in "Assisted-Psychotherapy" |url=https://psychedelicmentalhealth.net/psychedelic-therapy-cognitive-behavioral-therapy-ketamine-context-competencies/ |work=Psychedelic Institute of Mental Health & Family Therapy |date=11 May 2024}} Ketamine is currently one of three injected general anesthetics that the World Health Organisation includes in its Model List of Essential Medicines along with propofol and thiopental, and is listed as safe to use for children.{{Cite web |title=eEML - Electronic Essential Medicines List |url=https://list.essentialmeds.org/recommendations/5 |access-date=2025-03-12 |website=list.essentialmeds.org}}

File:Ketmine Injection.jpg

As of 2023, the World Health Organization reported 230 million people worldwide as having depression, or around 3.8% of the human population.{{Cite web |title=Depressive disorder (depression) |url=https://www.who.int/news-room/fact-sheets/detail/depression |access-date=2025-03-12 |website=www.who.int |language=en}} The current therapy for depression includes, but is not limited to, psychotherapy, antidepressant medications, transcranial magnetic stimulation, electroconvulsive therapy, and lifestyle approaches. However, antidepressant treatment is heavily limited by its delayed onset of efficacy, with noticeable effects only appearing over a period of months. The Sequenced Treatment Alternatives to Relieve Depression Study (STAR*D) Trial{{Cite journal |last1=Sinyor |first1=Mark |last2=Schaffer |first2=Ayal |last3=Levitt |first3=Anthony |date=March 2010 |title=The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Trial: A Review |url=http://journals.sagepub.com/doi/10.1177/070674371005500303 |journal=The Canadian Journal of Psychiatry |language=en |volume=55 |issue=3 |pages=126–135 |doi=10.1177/070674371005500303 |pmid=20370962 |s2cid=19442084 |issn=0706-7437}} also found that patients had low response rates to alternative compounds after the failure of the first antidepressant.{{Cite journal |last1=Naughton |first1=Marie |last2=Clarke |first2=Gerard |last3=O′Leary |first3=Olivia F. |last4=Cryan |first4=John F. |last5=Dinan |first5=Timothy G. |date=2014-03-01 |title=A review of ketamine in affective disorders: Current evidence of clinical efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of action |url=https://www.sciencedirect.com/science/article/pii/S0165032713008252 |journal=Journal of Affective Disorders |language=en |volume=156 |pages=24–35 |doi=10.1016/j.jad.2013.11.014 |pmid=24388038 |issn=0165-0327}} Thus, interest sparked for a more rapid treatment option that could also be used as an adjunct to previous therapies in treatment-resistant depression. Ketamine's neuroplasticity-promoting effects appear to strengthen the cognitive restructuring that takes place through traditional psychotherapy, thereby leading to long-lasting behavioral change,{{Cite journal |last=Krystal |first=John H. |date=2007-10-15 |title=Neuroplasticity as a Target for the Pharmacotherapy of Psychiatric Disorders: New Opportunities for Synergy with Psychotherapy |url=https://www.biologicalpsychiatryjournal.com/article/S0006-3223(07)00825-6/fulltext |journal=Biological Psychiatry |language=English |volume=62 |issue=8 |pages=833–834 |doi=10.1016/j.biopsych.2007.08.017 |issn=0006-3223 |pmid=17916459 |s2cid=41034050}}{{Cite journal |last1=Greenway |first1=Kyle T. |last2=Garel |first2=Nicolas |last3=Jerome |first3=Lisa |last4=Feduccia |first4=Allison A. |date=2020-06-02 |title=Integrating psychotherapy and psychopharmacology: psychedelic-assisted psychotherapy and other combined treatments |url=https://doi.org/10.1080/17512433.2020.1772054 |journal=Expert Review of Clinical Pharmacology |volume=13 |issue=6 |pages=655–670 |doi=10.1080/17512433.2020.1772054 |issn=1751-2433 |pmid=32478631 |s2cid=219169886}} making it a compound of recent interest.

Research evidence has found that combining psychotherapy and antidepressant medications enhances the effects of both.{{Cite journal |last1=Walsh |first1=Zach |last2=Mollaahmetoglu |first2=Ozden Merve |last3=Rootman |first3=Joseph |last4=Golsof |first4=Shannon |last5=Keeler |first5=Johanna |last6=Marsh |first6=Beth |last7=Nutt |first7=David J. |last8=Morgan |first8=Celia J. A. |date=January 2022 |title=Ketamine for the treatment of mental health and substance use disorders: comprehensive systematic review |journal=BJPsych Open |language=en |volume=8 |issue=1 |pages=e19 |doi=10.1192/bjo.2021.1061 |pmid=35048815 |pmc=8715255 |issn=2056-4724}} This combination of pharmacotherapy and psychotherapy has historically been efficacious in numerous instances, such as the pairing of psychotherapy with conventional antidepressants for mood and anxiety disorders, with naltrexone for alcohol and opioid dependence, and with bupropion for smoking cessation. Ketamine offers a notable advantage as opposed to currently-approved antidepressants, as it has a rapid onset{{Cite journal |last=Hasler |first=Gregor |date=June 2020 |title=Toward specific ways to combine ketamine and psychotherapy in treating depression |journal=CNS Spectrums |language=en |volume=25 |issue=3 |pages=445–447 |doi=10.1017/S1092852919001007 |pmid=31213212 |s2cid=195067658 |issn=1092-8529|doi-access=free }} (2–24 hours post-infusion){{Cite journal |last1=Singh |first1=Jaskaran B. |last2=Fedgchin |first2=Maggie |last3=Daly |first3=Ella J. |last4=De Boer |first4=Peter |last5=Cooper |first5=Kimberly |last6=Lim |first6=Pilar |last7=Pinter |first7=Christine |last8=Murrough |first8=James W. |last9=Sanacora |first9=Gerard |last10=Shelton |first10=Richard C. |last11=Kurian |first11=Benji |last12=Winokur |first12=Andrew |last13=Fava |first13=Maurizio |last14=Manji |first14=Husseini |last15=Drevets |first15=Wayne C. |date=August 2016 |title=A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression |journal=American Journal of Psychiatry |language=en |volume=173 |issue=8 |pages=816–826 |doi=10.1176/appi.ajp.2016.16010037 |pmid=27056608 |issn=0002-953X|doi-access=free }} of temporally limited, but sustained, antidepressant and analgesic effects (typically lasting 4–7 days). Its dissociative, psychedelic effects could also provide patients with increased neuroplasticity and cognitive flexibility that would enable more effective participation in therapy sessions. Therapy could, in turn, reinforce the effects and improvements facilitated by ketamine to provide longer-lasting treatment.{{Cite journal |last1=Doblin |first1=Richard E. |last2=Christiansen |first2=Merete |last3=Jerome |first3=Lisa |last4=Burge |first4=Brad |date=2019-03-15 |title=The Past and Future of Psychedelic Science: An Introduction to This Issue |journal=Journal of Psychoactive Drugs |volume=51 |issue=2 |pages=93–97 |doi=10.1080/02791072.2019.1606472 |issn=0279-1072 |pmid=31132970|s2cid=167220251 |doi-access=free }} Supplementing ketamine use with cognitive behaviour therapy (CBT), in particular, has the potential to help patients reverse their inaccurate beliefs and maladaptive processing of information, that lead to depressive mental states.{{Cite journal |last1=Joneborg |first1=Isak |last2=Lee |first2=Yena |last3=Di Vincenzo |first3=Joshua D. |last4=Ceban |first4=Felicia |last5=Meshkat |first5=Shakila |last6=Lui |first6=Leanna M. W. |last7=Fancy |first7=Farhan |last8=Rosenblat |first8=Joshua D. |last9=McIntyre |first9=Roger S. |date=2022-10-15 |title=Active mechanisms of ketamine-assisted psychotherapy: A systematic review |url=https://www.sciencedirect.com/science/article/pii/S0165032722007984 |journal=Journal of Affective Disorders |language=en |volume=315 |pages=105–112 |doi=10.1016/j.jad.2022.07.030 |pmid=35905796 |s2cid=251141313 |issn=0165-0327}}

File:Ketamine.svg

There are several hypotheses as to the underlying neural and cognitive mechanisms responsible for the psychiatric effects of ketamine. Its mechanism of action is as an NMDA receptor antagonist. As such, glutamate modulation is a well-known effect, which is specifically believed to confer increased synaptic excitability. Notably, however, the effects of ketamine are now believed to be larger in scope than previously thought, ultimately leading to greater synaptogenesis and neuroplasticity. As demonstrated in animal models, the administration of ketamine propagates signaling pathways surmised to augment neuroplasticity. Key among these are mammalian target of rapamycin (mTOR), glycogen synthase kinase-3 (GSK3), and elongation factor 2 (eEF2) kinase. Ketamine has also demonstrated its ability to increase brain-derived neurotrophic factor levels within the brain in animal studies, which ameliorates the effects of acute and chronic stress.{{Cite journal |last1=Du |first1=Rui |last2=Han |first2=Ruili |last3=Niu |first3=Kun |last4=Xu |first4=Jiaqiao |last5=Zhao |first5=Zihou |last6=Lu |first6=Guofang |last7=Shang |first7=Yulong |date=2022 |title=The Multivariate Effect of Ketamine on PTSD: Systematic Review and Meta-Analysis |journal=Frontiers in Psychiatry |volume=13 |page=813103 |doi=10.3389/fpsyt.2022.813103 |issn=1664-0640 |pmc=8959757 |pmid=35356723 |doi-access=free }} The subsequent increase in both synaptic excitation and neuroplasticity is believed to precipitate the powerful and immediate symptom reduction ketamine elicits for a variety of conditions. It has additionally been theorized that ketamine disrupts the reconsolidation of dysfunctional memories and, through doing so, diminishes the burden of those associated with trauma, anxiety, substance use, and so on.{{Cite journal |last1=Stein |first1=Murray B. |last2=Simon |first2=Naomi M. |date=2021-02-01 |title=Ketamine for PTSD: Well, Isn't That Special |url=http://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2020.20121677 |journal=American Journal of Psychiatry |language=en |volume=178 |issue=2 |pages=116–118 |doi=10.1176/appi.ajp.2020.20121677 |pmid=33517752 |s2cid=231752701 |issn=0002-953X}}

File:A session with a psychotherapist (751707089).jpg

{{Main|treatment-resistant depression}}

The use of ketamine as an antidepressant has mainly been studied for the treatment of treatment-resistant depression(TRD). Single-dose use has been found to have noticeable and rapid anti-depressive effects that tend to last up to a week, accompanied by acute side-effects that resolve spontaneously.{{Cite journal |last1=Corriger |first1=Alexandrine |last2=Pickering |first2=Gisèle |date=2019-12-31 |title=Ketamine and depression: a narrative review |journal=Drug Design, Development and Therapy |volume=13 |pages=3051–3067 |doi=10.2147/DDDT.S221437 |pmc=6717708 |pmid=31695324 |doi-access=free }} It has also been shown to have a moderate-to-large effect in reducing suicidality in some patients suffering from suicidal ideation,{{Cite journal |last1=Nowacka |first1=Agata |last2=Borczyk |first2=Malgorzata |date=2019-10-05 |title=Ketamine applications beyond anesthesia – A literature review |url=https://www.sciencedirect.com/science/article/pii/S0014299919304996 |journal=European Journal of Pharmacology |language=en |volume=860 |pages=172547 |doi=10.1016/j.ejphar.2019.172547 |issn=0014-2999 |pmid=31348905 |s2cid=198934018}} with visible efficacy within two hours of administration. This is in sharp contrast with currently-approved treatment options, whose delayed onset poses an increased risk for suicidality in patients. However, this potency cannot currently be generalised for non-depressed patients experiencing suicidal ideation.

Repeated sessions of ketamine-assisted psychotherapy have also been found to be an effective method for facilitating clinically-significant reduction in anxiety and depression, when conducted in private practice settings. Sessions may last up to three hours, with provisions for supervised recovery towards the end. The time-to-relapse after ketamine treatment is typically 2–4 weeks, which is why a repeated dosage paradigm is used to increase its efficacy on treatment-resistant depression. Currently only 20% of the 2,500 ketamine clinics in the United States offer ketamine-assisted psychotherapy.{{Cite web|title=About Healing Maps|url=https://healingmaps.com/about-healing-maps/}}

The mode of ketamine administration is a crucial consideration in the use of ketamine-assisted psychotherapy for depression. It employs a dosage escalation strategy to achieve different levels of dissociative effects, depending on the amount of alteration of consciousness needed for treatment. Lower-dose sublingual administration is recommended for sessions that require active therapist-patient communication, and higher-dose intramuscular administration takes place when an inward focus is needed, with eye coverings and music provided. There is no notable difference in efficacy, however.{{Cite journal |last=Andrade |first=Chittaranjan |date=2017-08-23 |title=Ketamine for Depression, 4: In What Dose, at What Rate, by What Route, for How Long, and at What Frequency? |url=https://www.psychiatrist.com/jcp/depression/ketamine-for-depression-dosing-administration-and-duration/ |journal=The Journal of Clinical Psychiatry |language=English |volume=78 |issue=7 |pages=e852–e857 |doi=10.4088/JCP.17f11738 |pmid=28749092 |issn=0160-6689|doi-access=free }} Guidelines for the provision of psychotherapy are also variably defined, depending on the application, with it being delivered either simultaneously, or following the infusion of ketamine.

{{Main|Bipolar disorder}}

Multiple studies have identified the beneficial effect of combining a mood-stabilizing agent with intravenous ketamine infusions for controlling the depressive phase of bipolar disorder.{{Cite journal |last1=Bahji |first1=Anees |last2=Zarate |first2=Carlos A. |last3=Vazquez |first3=Gustavo H. |date=2021-07-23 |title=Ketamine for Bipolar Depression: A Systematic Review |journal=The International Journal of Neuropsychopharmacology |volume=24 |issue=7 |pages=535–541 |doi=10.1093/ijnp/pyab023 |issn=1469-5111 |pmc=8299822 |pmid=33929489}} Notably, depressive symptoms including suicidal ideations were improved rapidly within around 40 minutes,{{Cite journal |last1=Zarate |first1=Carlos A. |last2=Brutsche |first2=Nancy E. |last3=Ibrahim |first3=Lobna |last4=Franco-Chaves |first4=Jose |last5=Diazgranados |first5=Nancy |last6=Cravchik |first6=Anibal |last7=Selter |first7=Jessica |last8=Marquardt |first8=Craig A. |last9=Liberty |first9=Victoria |last10=Luckenbaugh |first10=David A. |date=2012-06-01 |title=Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial |journal=Biological Psychiatry |volume=71 |issue=11 |pages=939–946 |doi=10.1016/j.biopsych.2011.12.010 |issn=1873-2402 |pmc=3343177 |pmid=22297150}}{{Cite journal |last1=Diazgranados |first1=Nancy |last2=Ibrahim |first2=Lobna |last3=Brutsche |first3=Nancy E. |last4=Newberg |first4=Andrew |last5=Kronstein |first5=Phillip |last6=Khalife |first6=Sami |last7=Kammerer |first7=William A. |last8=Quezado |first8=Zenaide |last9=Luckenbaugh |first9=David A. |last10=Salvadore |first10=Giacomo |last11=Machado-Vieira |first11=Rodrigo |last12=Manji |first12=Husseini K. |last13=Zarate |first13=Carlos A. |date=August 2010 |title=A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression |journal=Archives of General Psychiatry |volume=67 |issue=8 |pages=793–802 |doi=10.1001/archgenpsychiatry.2010.90 |issn=1538-3636 |pmc=3000408 |pmid=20679587}} which is difficult with current antidepressant therapy. However, a few patients did experience dissociative and/or manic symptoms during therapy in multiple studies, and the long-term effects of ketamine therapy and alternative modes of ketamine administration (other than intravenous) remains unclear, prompting further research into the area before efficacy and safety can be determined. Furthermore, research remains mixed on whether or not ketamine infusions are more effective than esketamine.{{Cite journal |last1=Johnston |first1=Jenessa N. |last2=Kadriu |first2=Bashkim |last3=Kraus |first3=Christoph |last4=Henter |first4=Ioline D. |last5=Zarate |first5=Carlos A. |date=January 2024 |title=Ketamine in neuropsychiatric disorders: an update |journal=Neuropsychopharmacology|volume=49 |issue=1 |pages=23–40 |doi=10.1038/s41386-023-01632-1 |issn=1740-634X |pmc=10700638 |pmid=37340091}}

{{Main|Anxiety disorder}}

Studies on the effect of ketamine on anxiety disorders remains sparse in number. However, limited studies have shown significantly improved symptoms of anxiety with ketamine, with various modalities of administration including intravenous, intramuscular, and oral.{{Cite journal |last1=Whittaker |first1=Elizabeth |last2=Dadabayev |first2=Alisher R. |last3=Joshi |first3=Sonalee A. |last4=Glue |first4=Paul |date=2021 |title=Systematic review and meta-analysis of randomized controlled trials of ketamine in the treatment of refractory anxiety spectrum disorders |journal=Therapeutic Advances in Psychopharmacology |volume=11 |pages=20451253211056743 |doi=10.1177/20451253211056743 |issn=2045-1253 |pmc=8679040 |pmid=34925757}} In these studies, ketamine appeared to be an effective method to lower anxiety rapidly, but its long-term effects and combinations with other modes of therapy remain unclear.{{Cite journal |last1=Tully |first1=Jamie L. |last2=Dahlén |first2=Amelia D. |last3=Haggarty |first3=Connor J. |last4=Schiöth |first4=Helgi B. |last5=Brooks |first5=Samantha |date=October 2022 |title=Ketamine treatment for refractory anxiety: A systematic review |journal=British Journal of Clinical Pharmacology |volume=88 |issue=10 |pages=4412–4426 |doi=10.1111/bcp.15374 |issn=1365-2125 |pmc=9540337 |pmid=35510346}}

{{Main|Obsessive–compulsive disorder}}

Ketamine appears to significantly improve symptoms of obsessive-compulsive disorders short-term, with improved effects when used in conjunction with cognitive behavioral therapy.{{Cite journal |last1=Martinotti |first1=Giovanni |last2=Chiappini |first2=Stefania |last3=Pettorruso |first3=Mauro |last4=Mosca |first4=Alessio |last5=Miuli |first5=Andrea |last6=Di Carlo |first6=Francesco |last7=D'Andrea |first7=Giacomo |last8=Collevecchio |first8=Roberta |last9=Di Muzio |first9=Ilenia |last10=Sensi |first10=Stefano L. |last11=Di Giannantonio |first11=Massimo |date=2021-06-27 |title=Therapeutic Potentials of Ketamine and Esketamine in Obsessive-Compulsive Disorder (OCD), Substance Use Disorders (SUD) and Eating Disorders (ED): A Review of the Current Literature |journal=Brain Sciences |volume=11 |issue=7 |pages=856 |doi=10.3390/brainsci11070856 |doi-access=free |issn=2076-3425 |pmc=8301752 |pmid=34199023}} Of note, mild to moderate symptoms of obsessive thoughts and compulsions were treated with significant efficacy, even in patients with psychiatric comorbidities.{{Cite journal |last1=Ferguson |first1=Asila A. |last2=Khan |first2=Aujala Irfan |last3=Abuzainah |first3=Baraa |last4=Chaudhuri |first4=Dipabali |last5=Khan |first5=Kokab Irfan |last6=Al Shouli |first6=Roba |last7=Allakky |first7=Akhil |last8=Hamdan |first8=Jaafar A. |date=April 2023 |title=Clinical Effectiveness of N-Methyl-D-Aspartate (NMDA) Receptor Antagonists in Adult Obsessive-Compulsive Disorder (OCD) Treatment: A Systematic Review |journal=Cureus |volume=15 |issue=4 |pages=e37833 |doi=10.7759/cureus.37833 |doi-access=free |issn=2168-8184 |pmc=10198239 |pmid=37213965}}

{{Main|Substance use disorder}}

Ketamine has been shown to significantly affect treatment rates and reduce cravings in multiple modalities of substance use disorder, including that of alcohol, cocaine, and opioids.{{Cite journal |last1=Famuła |first1=Anna |last2=Radoszewski |first2=Jakub |last3=Czerwiec |first3=Tomasz |last4=Sobiś |first4=Jarosław |last5=Więckiewicz |first5=Gniewko |date=March 2024 |title=Ketamine in Substance Use Disorder Treatment: A Narrative Review |journal=Alpha Psychiatry |volume=25 |issue=2 |pages=206–211 |doi=10.5152/alphapsychiatry.2024.241522 |issn=2757-8038 |pmc=11117434 |pmid=38798813}} Ketamine therapy used in conjunction with psychotherapy also appeared to decrease cannabis use. However, the mechanisms of action for these effects remain unknown, and the addictive effects of ketamine on patients prone to substance use disorder has not been studied.

{{Main|Eating disorder}}

Eating disorders have been a challenge to treat due to varying degrees of effectiveness of current treatments and high rates of remission,{{Cite journal |last1=Monteleone |first1=Alessio Maria |last2=Pellegrino |first2=Francesca |last3=Croatto |first3=Giovanni |last4=Carfagno |first4=Marco |last5=Hilbert |first5=Anja |last6=Treasure |first6=Janet |last7=Wade |first7=Tracey |last8=Bulik |first8=Cynthia M. |last9=Zipfel |first9=Stephan |last10=Hay |first10=Phillipa |last11=Schmidt |first11=Ulrike |last12=Castellini |first12=Giovanni |last13=Favaro |first13=Angela |last14=Fernandez-Aranda |first14=Fernando |last15=Il Shin |first15=Jae |date=November 2022 |title=Treatment of eating disorders: A systematic meta-review of meta-analyses and network meta-analyses |journal=Neuroscience and Biobehavioral Reviews |volume=142 |pages=104857 |doi=10.1016/j.neubiorev.2022.104857 |issn=1873-7528 |pmc=9813802 |pmid=36084848}} and is often a combination of psychotherapy with various psychotropic medications.{{Cite journal |last1=Ragnhildstveit |first1=Anya |last2=Slayton |first2=Matthew |last3=Jackson |first3=Laura Kate |last4=Brendle |first4=Madeline |last5=Ahuja |first5=Sachin |last6=Holle |first6=Willis |last7=Moore |first7=Claire |last8=Sollars |first8=Kellie |last9=Seli |first9=Paul |last10=Robison |first10=Reid |date=2022-03-12 |title=Ketamine as a Novel Psychopharmacotherapy for Eating Disorders: Evidence and Future Directions |journal=Brain Sciences |volume=12 |issue=3 |pages=382 |doi=10.3390/brainsci12030382 |doi-access=free |issn=2076-3425 |pmc=8963252 |pmid=35326338}} Ketamine has been shown to be an effective treatment for eating disorders, particularly for anorexia nervosa.{{Cite journal |last1=Calder |first1=Abigail |last2=Mock |first2=Seline |last3=Friedli |first3=Nicole |last4=Pasi |first4=Patrick |last5=Hasler |first5=Gregor |date=October 2023 |title=Psychedelics in the treatment of eating disorders: Rationale and potential mechanisms |url=https://pubmed.ncbi.nlm.nih.gov/37352816 |journal=European Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology |volume=75 |pages=1–14 |doi=10.1016/j.euroneuro.2023.05.008 |issn=1873-7862 |pmid=37352816}} While ketamine's effects on treating eating disorders appear positive, especially in patients who have failed previous therapies, the limited number of clinical studies may indicate that more research must be done to demonstrate its efficacy and safety across the diverse modalities of eating disorders.

The most common side effects of both intravenous ketamine and intranasal esketamine include, but is not limited to: dissociation, disorientation, dizziness, nausea, and hypertension.{{Cite web |title=SPRAVATO® (esketamine) {{!}} Official Patient Website |url=https://www.spravato.com/safety-and-tolerability/ |access-date=2025-03-15 |website=SPRAVATO® (esketamine) {{!}} Official Patient Website |language=en}}{{Cite web |title=Ketamine |url=https://www.dea.gov/factsheets/ketamine |archive-url=http://web.archive.org/web/20250313121519/https://www.dea.gov/factsheets/ketamine |archive-date=2025-03-13 |access-date=2025-03-15 |website=DEA |language=en}} However, recent research has demonstrated a sublingual type of ketamine therapy that is both efficacious, able to be used from home, and low-risk.{{Cite journal |last1=Hull |first1=Thomas D. |last2=Malgaroli |first2=Matteo |last3=Gazzaley |first3=Adam |last4=Akiki |first4=Teddy J. |last5=Madan |first5=Alok |last6=Vando |first6=Leonardo |last7=Arden |first7=Kristin |last8=Swain |first8=Jack |last9=Klotz |first9=Madeline |last10=Paleos |first10=Casey |date=2022-10-01 |title=At-home, sublingual ketamine telehealth is a safe and effective treatment for moderate to severe anxiety and depression: Findings from a large, prospective, open-label effectiveness trial |journal=Journal of Affective Disorders |volume=314 |pages=59–67 |doi=10.1016/j.jad.2022.07.004 |issn=1573-2517 |pmid=35809678|doi-access=free }} Further research is needed to assess the long-term side effects of ketamine therapy in multiple modalities.

In the United States, ketamine is approved by the FDA as an anesthetic agent. However, use of compounded ketamine for any psychiatric disorder is not approved by the FDA due to concerns for safety and efficacy, despite off-label prescriptions by healthcare professionals.{{cite journal | url=https://www.fda.gov/drugs/human-drug-compounding/fda-warns-patients-and-health-care-providers-about-potential-risks-associated-compounded-ketamine | title=FDA warns patients and health care providers about potential risks associated with compounded ketamine products, including oral formulations, for the treatment of psychiatric disorders | journal=FDA | date=10 October 2023 }} Since 2019, Only esketamine (Spravato) has been approved by the FDA since 2019 as a nasal spray for depression that is treatment-resistant or to control acute behaviors of suicidality. Esketamine is under strict regulation and guidance from FDA and the Risk Evaluation and Mitigation Strategy (REMS), requiring patient monitoring after administration for safety. Despite FDA's lack of approval, ketamine has been prescribed off-label by healthcare professionals to patients with a variety of psychiatric conditions, particularly in settings of treatment-resistant conditions.{{Cite web |date=2024-01-26 |title=What to Know About Ketamine {{!}} Johns Hopkins {{!}} Bloomberg School of Public Health |url=https://publichealth.jhu.edu/2024/what-to-know-about-ketamine |access-date=2025-03-13 |website=publichealth.jhu.edu |language=en}}{{Cite journal |last1=Wilkinson |first1=Samuel T. |last2=Sanacora |first2=Gerard |date=2017-09-05 |title=Considerations on the Off-label Use of Ketamine as a Treatment for Mood Disorders |journal=JAMA |volume=318 |issue=9 |pages=793–794 |doi=10.1001/jama.2017.10697 |issn=1538-3598 |pmc=6248331 |pmid=28806440}} In the United States, ketamine is able to be given off-label by healthcare professionals only, and over 2000 clinics have legally been prescribing ketamine under medical supervision for psychiatric care.{{Cite web |last=Tafra |first=Karla |date=2023-12-27 |title=Where Is Ketamine Legal In 2024 |url=https://healingmaps.com/where-is-ketamine-legal/ |access-date=2025-03-24 |website=HealingMaps |language=en-US}} Other countries also allow the use of ketamine as an off-label agent to treat resistant psychiatric conditions under medical supervision, including Canada, Germany, and United Kingdom. Potential risks associated with it include dissociation, sedation and abuse. Esketamine cannot be distributed outside of certified clinical settings.

Ketamine-assisted psychotherapy has the potential to show significant efficacy in the treatment of treatment-resistant depression and suicidality, among other mental disorders. But, extensive further research is needed for its effects and mechanisms of action to be properly understood. Currently, the lack of large, replicated clinical trials prevent existing results from being generalizable to the larger population, and many clinical trials have used different administrations of treatment, making a standardized review difficult. The current model of ketamine-assisted psychotherapy also uses repeated administration of ketamine, the long-term side effects of which are not fully known yet. High doses of ketamine could also have potentially toxic effects in patients.{{Cite journal |last1=Short |first1=Brooke |last2=Fong |first2=Joanna |last3=Galvez |first3=Veronica |last4=Shelker |first4=William |last5=Loo |first5=Colleen K |date=January 2018 |title=Side-effects associated with ketamine use in depression: a systematic review |url=https://linkinghub.elsevier.com/retrieve/pii/S2215036617302729 |journal=The Lancet Psychiatry |language=en |volume=5 |issue=1 |pages=65–78 |doi=10.1016/S2215-0366(17)30272-9|pmid=28757132 }} Given that existing studies only have short-term follow-up, the long-term safety of patients who undergo repeated dosing is, therefore, unknown. Future trials should be of larger scale, with repeated ketamine dosing, regular monitoring and follow-up. They should also focus on integrating ketamine with other forms of therapy, including, but not limited to motivational enhancement therapy (MET) and functional analytic psychotherapy (FAP).

Category:Psychotherapy