Ketamine Treatment for Depression: Benefits & Risks to Consider

Ketamine-assisted psychotherapy (KAP) uses ketamine as a tool that allows clients to access psychologically distressing materials and promotes a state of openness and flexibility. Interest in using ketamine for depression has increased over the past two decades due to its fast-acting antidepressant and anti-suicidal properties and the higher response rate for those struggling with treatment-resistant depression and bipolar depression.

What Is Ketamine Therapy?

Psychedelic therapies are a hot and somewhat controversial topic, especially in recent years. While ketamine is not considered a classic psychedelic—as its mechanism of action differs from classical psychedelic compounds such as psilocybin, lysergic acid diethylamide (LSD), or mescaline—it has similar effects in altering one’s state of consciousness and is currently the only psychedelic legally used in the mental health field outside of research.

The History of Ketamine Therapy

Ketamine is a molecule originally synthesized in 1962 by the chemist Calvin Stevens, for Parke-Davis (a Pfizer subsidiary), as an anesthetic alternative to phencyclidine (PCP). Also synthesized by Parke-Davis, PCP was an effective general anesthetic, yet had psychomimetic side effects like hallucinations, postoperative delirium and confusion. Ketamine was developed as a shorter-acting PCP, with reduced undesired psychomimetic effects.

Domino and Corssen first administered an anesthetic dose of ketamine to healthy prisoners in 1964. In 1966, they published a study of 130 patients who underwent ketamine anesthesia for a surgical procedure. They found that Ketamine was able to produce effective analgesic and anesthetic effects, along with a unique state of altered state of consciousness, which was described as being disconnected from one’s own body. Thus, the drug was referred to as a dissociative anesthetic.^{1, 2} In 1970, ketamine was approved by the FDA for anesthetic purposes, with a good margin of safety, as it does not cause respiratory depression and thus was utilized to treat pediatric and geriatric populations along with being used on the battlefield, where the safety of analgesics was a paramount consideration.^{1, 2, 3}

Since then, the antidepressant qualities of Ketamine were observed. Currently, there is strong support for ketamine treatment for unipolar and bipolar depression and generalized anxiety disorder. There is also moderate support for ketamine treatment for OCD and PTSD. There is also some support for the treatment of eating disorders and substance use, with much more research is being done.

What Is Treatment-Resistant Depression?

Depression is characterized by persistent feelings of sadness or irritability or loss of interest and pleasure in once-liked activities (i.e., anhedonia), among other symptoms. Although there is no consensus on what constitutes treatment-resistant depression (TRD), the most common definition of TRD is a failure of two previous psychopharmacological treatments in unipolar depression, and one failed treatment in bipolar depression.⁴

Depression is an extremely debilitating condition that may lead to an inability to function and perform activities of daily living, as well as substantial health problems and even death. ⁵ For those who struggle with difficult-to-treat depression, life can feel unbearable, and the hopelessness that characterizes depression can feel insurmountable when common treatments have failed to facilitate a healing process. While additional treatments for TRD like Electroconvulsive Therapy (ECT) and Transcranial Magnetic Stimulation (TMS) are currently available, many people are deterred by the potential adverse effects and the procedures themselves, which may seem daunting.

Ketamine Therapy Vs. Antidepressants for Depression

Ketamine therapy for depression may offer symptom relief within hours of treatment, and while transient, the effect lasts up to seven days, and for others, up to 2-4 weeks.This starkly contrasts the delayed relief of symptoms with other available antidepressant medications like SSRIs, which take 4-6 weeks for an initial response and need to be taken daily for continuous effect.

The first clinical trial that used a sub-anesthetic dose of ketamine for depression was published in 2000.⁶ In that and subsequent placebo-compared double-blind studies, it was shown that ketamine had a much higher response rate of symptom alleviation in those who struggle with treatment-resistant depression and bipolar depression. In addition, rapid relief in feelings of anhedonia and suicidal thoughts was reported; the treatment’s impact on suicidal behavior was not reported. There is still much to understand as we navigate the various proposed mechanisms of action of ketamine.⁷

Ketamine is an NMDA receptor inhibitor, which impacts an increase in GABA neurotransmitter, leading to an experience of relaxation, along with an increase in glutamate which is implicated in shaping memory and learning. While there is more to elucidate about the mechanisms of action of ketamine, we know that it allows for increased brain plasticity, flexibility, increased/novel connectivity, and neurogenesis.⁸ On an experiential level, ketamine induces an altered state of consciousness that is characterized by feelings of being in a dream-like state, dissociation from one’s body, other perceptual alterations (e.g., time and space), increased openness and flexibility of thought, connection to the symbolic realm, reduction in negative, obsessive and ego-based thinking. It may also induce mystical and transpersonal experiences.⁹

How Is Ketamine Therapy Administered?

Ketamine can be administered via several routes that differ in the level of bioavailability and produce different experiential and psychological effects at different doses.

• Intravenous (IV): Allows for 100% bioavailability, done under medical supervision. Onset is immediate, and administration duration is usually 40-60 minutes. The intensity of dose can be adjusted with prolonged administration.
• Intramuscular (IM): Close to 100% bioavailability. Administered by a medical provider with an onset of several minutes post administration and experience lasting between 1-3 hours. May elicit a more intense experience as the medicine absorption of IM is rapid.
• Intranasal: about 45% bioavailability. Currently offered in the form of Spravato nasal spray. Offered under medical supervision in specialty clinics as an ancillary treatment with an additional antidepressant.
• Sublingual/Oral: about 25-30% bioavailability. Usually self-administered in a clinician’s office or in the context of at-home treatment. Experience lasting between 40 minutes to about 2 hours and is dose-dependent.

Ketamine-Treatment Models

Currently there is no clear evidence to favor one route of administration over another.^{10, 11}At this time, there is also no one standard protocol for ketamine treatment. It is also important to differentiate between Ketamine as a stand-alone pharmacological intervention and ketamine as part of Ketamine Assisted Psychotherapy (KAP).

Some possible Ketamine-treatment models include:

• The medical model: utilizes the biological effects of ketamine to achieve symptom reduction relying on the pharmacological effects of ketamine. Most common routes of administration within this model will be IV, IM, and intranasal (i.e., Spravato). Usually treatment will focus on the pharmacological impact of the medicine and will not include a psychotherapy component.
• The psycholytic model: capitalizes on the psychological effects of the medicine, including a sense of openness and lowering of defenses, to allow increased access to distressing materials and the facilitation of the psychotherapeutic process to deepen and enhance the work done in psychotherapy. This model aims to keep the client in touch with the present moment and the therapist. The most commonly used routes of administration within this model are lozenges and intranasal ketamine. This treatment focuses on the psychotherapy process augmented by the psychological effects of ketamine and includes a preparation process and integration sessions to digest the effects of ketamine. Different theoretical orientations may be employed when utilizing this model, including—but not limited to—psychoanalytic, psychodynamic, IFS, CBT, art and somatic frameworks.
• The psychedelic model: focuses on the impacts of the transcendental and mystical experiences which may be induced by ketamine at higher doses. Most commonly administered IV, IM, or orally. Similar to the psycholytic model, preparation and integration therapy sessions are integral to this model. In this modality, dosing is usually higher, and the therapeutic process occurs towards the end of the experience and in weeks after. Within this framework, transpersonal psychology is the leading theoretical orientation for treatment, though not the only one, and the modalities mentioned in the psycholytic model are also often used.

Benefits of Using Ketamine for Depression

Some benefits of ketamine therapy include:

Rapid Symptom Relief

Ketamine has the potential to rapidly alleviate symptoms of depression, including suicidal ideation, as well as TRD. It may also alleviate anxiety symptoms, among other uses of ketamine (e.g., substance use disorder). Many controlled trial studies have shown the efficacy of ketamine in depression and anxiety-symptom reductions. This has been further confirmed in a real-world study looking at the effectiveness of ketamine, as opposed to the efficacy shown in controlled research trials.¹²

High Success Rate

While the data suggest that the treatment’s effectiveness is varied, ketamine treatment demonstrated significant effectiveness in reducing depressive symptoms and a less consistent yet significant reduction in suicidal ideation. While ketamine may lead to symptom reduction within a few hours, its sustained effects are unclear. Some research indicates that effects last for about a week, losing superiority to placebo after 10-12 days, while other findings suggest that there may be a prolonged effect with repeated administration of ketamine, with effects of symptom reduction a month post-last ketamine administration.^{13, 14}

Emotional Breakthroughs

Beyond the neurobiological mechanisms of symptom reduction, ketamine has psychological mechanisms that impact treatment effectiveness, including the potential to induce new experiences in the psyche. One of the proposed mechanisms of action of ketamine is its effect on the Default Mode Network (DMN), the system that is active when one is engaged in passive tasks that do not require focused attention and is related to self-referential processing and the experience of the “I.”¹⁵ With ketamine, this system is less activated and connected, allowing for new pathways and experiences to emerge.

For example, a person with depression who is ruminating about the idea that everyone is disappointed with them will have reduced connectivity in that ruminative pathway and will be able to have a new insight (e.g., that others are actually caring and worried for them). Another way to understand this is through a commonly used analogy of our habitual ways of perceiving the world as being like a repeatedly used ski slope, and ketamine plowing the ski slopes or being the fresh snow, allowing for new trails to be utilized.

Furthermore, mystical and transcendental experiences, which are commonly induced by ketamine in medium doses—including feelings of universal interconnectedness, ego dissolution, and one’s lack of boundaries—are also a potential psychological mechanism in Ketamine’s effects in depression relief.¹⁶ Some mystical experiences may increase acceptance and flexibility and lead to personal insights. Such emotional breakthroughs are likely to be implicated in the antidepressant effects of ketamine. With that, mystical experiences may also be experienced as very challenging to endure, like the dread of ego dissolution, which can be experienced as the annihilation of the self and feel similar to a near-death experience.

What to Expect From Ketamine Therapy for Depression

While ketamine has great potential to benefit those with TRD when done in the right mindset and a safe and secure setting, like with all psychedelics, each experience, even for the same person with the same dose and medicine, will look very different, depending on the set and setting one is in. Challenging and even distressing experiences with psychedelics happen, yet may be positively transformative if supported appropriately.

Ensuring you are entering treatment with a prepared mindset and being cared for adequately is paramount to gaining benefits and avoiding any potential harm of ketamine treatment.

Ketamine’s variability in sustained outcomes of symptom reduction, along with the potential for challenging experiences, calls for reconsidering the recent media claims and hype around ketamine being a cure for depression. While ketamine has its neurobiological benefits, those are not long lasting, and the psychological benefits may be elusive without the process of integration.

Evidence supports that in treating mental health issues, combining therapy with medication has increased effectiveness than just medication alone. With ketamine treatment, the same is true¹⁷. To attain increased benefits, it would be important to utilize the neurobiological and psychological effects of ketamine, and further enhance these bidirectional effects with a comprehensive treatment modality.

Comprehensive ketamine-assisted psychotherapy includes critical components such as:

• Consultation and preparation: The consultation assessment is critical to ensure safety in ketamine treatment. During the consultation, the provider should review your medical and psychosocial history to determine the appropriateness of the treatment. A thorough preparation will include a review of what one can expect during the treatment, a discussion of the potential risks and benefits, and other alternatives for treatment. Any concerns, hopes, and expectations one may have for treatment and clarification on internal and external resources for support during the treatment process are imperative. Since entering an altered state of consciousness during a ketamine treatment may feel extremely vulnerable, cultivating a sense of trust and safety with the provider is extremely important.
• Dosing session: Dosing session may look very different depending on the route of administration. Generally, some grounding techniques may be utilized after a quick check-in, and administration will begin. Your provider will remain with you throughout the experience and will be there to ensure your safety, support you through any challenging moments, and witness you in your experience.
• Integration: The integration aims to bring more awareness and meaning to what was experienced during the dosing session and to work on embodying any new insights to make desired changes in your life. Since experiences in an altered state of consciousness are often challenging to grasp, the first integration session usually occurs as close to the dosing session as possible. You and your provider will work together to try and make your experience whole, glean any insights, and anchor those, so you can then incorporate them into your day-to-day consciousness. Integration can be done through many mediums, verbal, movement and artistic practices.
• Repeating dosing and integration as necessary: Integration may take several sessions, and repeating dosing and integration sessions is recommended. Each dosing session may look very different and will likely deepen one’s process. It is important to take the time to digest and process each dosing experience before moving on to the next ketamine experience. The amount of time needed to integrate each experience is likely to vary.

What Are the Risks of Ketamine Treatment for Depression?

Ketamine treatment is considered safe if done under appropriate circumstances, with no severe or lasting adverse effects.¹⁸ Ketamine still carries some potential risks and is contraindicated under certain conditions.

Who Shouldn’t Receive Ketamine Treatment?

Individuals who are experiencing any of the following should avoid Ketamine treatment:

• Pregnancy: is a contraindication for ketamine treatment as it was shown that ketamine is not safe for unborn babies.¹⁹
• Current state of mania and psychosis: some findings suggest that Ketamine may induce and exacerbate symptoms of mania and psychosis, so those with active mania or psychosis should avoid Ketamine treatment. For those with mania in remission, ketamine treatment should be administered with additional considerations and monitoring of any early signs and triggers of a manic episode. Some findings show that similar care can be applied to those with psychosis in remission, yet as of now most research excluded those with a history of psychosis with the assumption that it will exacerbate the condition and will cause more harm than benefit.²⁰
• Cardiac disease and high blood pressure: Since ketamine increases blood pressure and heart rate, those who have symptoms of cardiac disease or are diagnosed with uncontrolled blood pressure should not be undergoing ketamine treatment.
• Glaucoma or recent ocular surgery: Ketamine may increase intraocular pressure and therefore is not recommended for those with these conditions.
• Substance use disorder: those who use substances to avoid experiencing challenging feelings may have fewer skills in coping with challenging experiences that may arise during a ketamine journey and may misuse ketamine as a way to avoid pain rather than work through it.

Potential Adverse Responses In Ketamine Treatment

Despite being considered a low-risk form of treatment, ketamine still carries the risk of side effects, such as:

• Increased heart rate and blood pressure: As ketamine increases both blood pressure and heart rate, these could be transient side-effects of treatment. Again, for those who suffer from cardiovascular problems, ketamine treatment is not recommended for this reason.
• Nausea, dizziness, and drowsiness: are common experiences to be felt during the treatment, these symptoms are transient and remit post-treatment.
• Dissociation—While it is suggested that dissociation may play a role in the antidepressant effects of ketamine, for some this could elicit a very unpleasant experience.²¹ This emphasizes the need for support from experienced providers when undergoing ketamine treatment.
• Distressing psychological experiences: may arise during the Ketamine journey. Remember, an unpleasant or challenging experience does not equal a bad experience. Many people report that the challenging experiences under psychedelic treatment, under certain circumstances and when supported by a therapeutic container, were meaningful and led to growth and overall positive outcomes.²²
• Laryngospasm: though rare, in higher doses, ketamine may cause a transient spasm of the vocal cords leading to difficulty breathing or speaking. Working with a trusted provider who will know how to assist if such a rare occurrence happens is important.
• Suicidality: While ketamine is shown to be effective in rapidly reducing suicidal thoughts, there is a risk that after the anti-suicidality effects are weakened, a “rebound” effect may occur. Therefore, close monitoring and supportive practices should be in place post-treatment.
• Mania induction: Ketamine has the potential to induce mania symptoms, and those who have a family history of mania should be monitored closely.
• Renal and bladder: With long-term use, ketamine may lead to declining renal and bladder functioning. In cases of prolonged ketamine treatment, medical monitoring of these functions should be continuously monitored.
• Substance misuse and addiction: Like some other medications, ketamine is a medicine with the potential to lead to addiction or substance use disorders. It is suggested that ketamine, as administered in therapeutic settings, does not lead to physiological dependency and can even be beneficial in treating substance use disorder. With that, psychological addiction (e.g., addiction to dopamine release or to psychic pain avoidance) may occur. It is very important for both the client and provider to be aware of and monitor the appropriate use of the medicine.

Finding a Therapist Specialized In Ketamine & Depression

Working with ketamine may feel very vulnerable and destabilizing, therefore, a sense of safety is paramount in ketamine-assisted psychotherapy. Choosing a therapist and provider you feel comfortable and open with is important, and you can start your search in an online therapist directory.

Ketamine treatments are more commonly offered these days, and since there is no one standard for treatment application, you must do your research and find the provider that offers the model that fits your needs and style. Ketamine is usually prescribed by anesthesiologists and psychiatrists. Many physicians’ clinics offer the medical model of ketamine treatment. If you choose to work in the psycholytic or the psychedelic model, it is important to work with a provider who is experienced in providing psychedelic-assisted psychotherapy. This can be a psychiatrist, psychologist, licensed mental health clinician, or art therapist, among others. While anyone who is licensed to work as a therapist in the mental health field, and has the appropriate training and experience, may provide ketamine-assisted psychotherapy, prescription of ketamine is done only by medical providers.

Mindbloom offers at-home ketamine treatment for those who are a good fit. It’s a unique way of harnessing the power of psychedelics from the comfort of your own home. Learn more in our full Mindbloom review, where one of our editors went through the program to see what it’s like.

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