Ketamine Therapy: What It Is, Who It Can Help, & Effectiveness

What Is Ketamine?

Ketamine is a psychedelic drug originally devised in the 1970s as a surgical anesthetic and analgesic. More recently, ketamine has shown promise psychiatrically to treat severe depression and post-traumatic stress disorder. However, it also has a dark history as an illicit street drug used for getting high.¹

Ketamine is composed of two mirror-image molecules: R-ketamine (arketamine) and S-ketamine (esketamine). R-ketamine and S-ketamine can be isolated and compounded independently; however, when these molecules are combined, they are referred to as the “racemic” form of ketamine.¹

How Does Ketamine Work?

Ketamine has diverse, dose-related effects on the brain and body. Its mechanism of action is complex and not fully understood, but it involves several interacting neurotransmitter systems. Ketamine increases glutamate and GABA but also acts on the opioidergic and endocannabinoid systems. Ketamine also stabilizes membrane potentials, regulating the flow of sodium and calcium ions, which may help to calm overexcited brain regions and stimulate underactive regions.^2,3,4

Ketamine’s many mechanisms of action are difficult to detangle but are collectively believed to result in disinhibition of one’s neuronal network, sedation, pain relief, improved mood, and ability to form new neural connections (enhancing neuroplasticity). Associated increases in dopamine and serotonin may underlie ketamine’s antidepressant “feel good” effects but also may hold potential for addiction.³

History of Ketamine

Ketamine was first synthesized in 1962 for use as a dissociative anesthetic and gained FDA approval in 1970 for use in surgery.⁵ It was extensively used to treat U.S. soldiers in the Vietnam War and gained popularity due to its believed safety profile (over phencyclidine – PCP); however, when residual delirium was discovered as a side effect, its use declined as a surgical anesthetic at high doses.⁶

In the 1980s, off-label ketamine use proliferated, with research exploring its efficacy for treating a wide range of psychiatric conditions.⁷ However, illicit, recreational use also increased across the U.S. until it was reclassified as a Schedule 3 controlled substance to control illicit use.

Over the past two decades, dissatisfaction with the time needed to respond to traditional psychiatric medications (like SSRIs and tricyclics) led to clinical research involving ketamine as a fast-acting, alternative treatment for depression and suicidality, with potential application to other psychiatric conditions as well. Additionally, recent animal studies suggest that ketamine’s psychiatric benefits may relate to its potential for neuroplasticity and neurogenesis as well as synaptogenesis and synaptic potentiation.^3,4,8,9

What Is Ketamine Therapy?

Ketamine therapy is a burgeoning treatment option with limited FDA approval for treatment-resistant depression with suicidal ideation but is also used off-label to treat other mental health conditions (e.g., PTSD, anxiety). It is fast-acting, relieving symptoms in as little as an hour but with potentially lasting effects, especially when combined with psychotherapy.

Is Ketamine Therapy Legal?

At present, racemic ketamine is not FDA-approved for psychiatric treatment; however, as of 2019, the S-ketamine form of the drug (marketed under the trade name “Spravato” as a nasal spray) attained limited FDA approval for adults with major depressive disorder with acute suicidal ideation under the Risk Evaluation and Mitigation Strategy (REMS) safety program. As such, the drug must be administered in certified, medically supervised healthcare settings where patients are closely monitored.

Though several other compounded forms of ketamine have been marketed and prescribed by physicians (usually psychiatrists) to treat various mental health disorders, this is done on an off-label basis and does not have FDA approval.

How Prevalent Is Ketamine Therapy?

Clinics and telehealth providers of ketamine (typically esketamine) have been popping up with increasing frequency. Over 400 ketamine therapy providers in the United States alone are registered with the American Society of Ketamine Physicians, Psychotherapists, and Practitioners (ASKP3), and there are likely even more.

Ketamine Therapy Vs. Ketamine Psychotherapy

When ketamine is administered as the healthcare provider monitors the patient but does not offer talk therapy, it is referred to as ketamine therapy. While ketamine alone can improve mental health symptoms, it can be enhanced when combined with psychotherapy. Ketamine psychotherapy is most effective when the client establishes a connection and trust with the therapist before the treatment.¹

What Disorders Can Ketamine Therapy Treat?

Ketamine (esketamine only) treatment for depression is the only mental health condition that holds FDA approval for treatment-resistant individuals or those at risk for suicide. Yet, there are several other mental health conditions that have been shown to benefit from (off-label) ketamine therapy, too. Most clinical research on ketamine therapy has focused on MDD and PTSD.

Mental health disorders and conditions that may benefit from ketamine therapy include:

• Include all disorders that may benefit
• Major depressive disorder (MDD)
• Bipolar depression
• Treatment-resistant depression
• Posttraumatic stress disorder (PTSD)
• Obsessive-compulsive disorder (OCD)
• Anxiety disorders
• Anorexia nervosa
• Alcohol use disorder
• Cannabis use disorder
• Cocaine use disorder
• Opioid use disorder

Is Ketamine a First or Last Resort?

Ketamine is considered only after traditional treatments, like psychotherapy and FDA-approved medications for depression (e.g., SSRIs), have not effectively relieved symptoms. However, ketamine may be considered earlier in treatment for severe cases of depression, especially if a suicide attempt or specific suicidal ideation is present.

Sometimes, in emergency situations, EMTs or ER physicians may administer ketamine as a sedative or anesthetic, which has anecdotally been reported to improve mood symptoms even though it wasn’t the intention. Since ketamine does provide relief significantly faster than traditional antidepressants, some mental health professionals believe that it should be considered earlier in treatment for severe mental health cases.

What Are the Potential Benefits of Ketamine Therapy?

The benefits of ketamine therapy can be divided into immediate, short-term, and long-term effects. Acute effects usually include relief of pain, anxiety, and depressive feelings. It’s been described as dissociating or separating oneself from uncomfortable thoughts and feelings, being able to acknowledge them from afar without being drowned in discomfort.

While ketamine can provide acute relief, it also can spur neuro-signaling changes that persist even after the drug has been eliminated from the body. When combined with psychotherapy, the formation of new thought patterns and the release of old maladaptive ones can lead to longer-term relief.

How Long Do the Benefits of Ketamine Treatment Last?

Just how long such effects last is not clear, as the majority of research studies follow-up with participants for one year at most. Although our knowledge about ketamine is continually updating, here’s what we know so far:

• Depending on the route of administration, effects can be felt about 15 minutes after the full dose is given.
• Acute treatment effects – like feeling dissociated – last for about 45 minutes and are followed by a come-down phase.
• The come-down phase varies greatly across people but can range from 20 minutes to the rest of the day.
• A single treatment session can relieve symptoms for up to 2 weeks but usually diminish gradually over that period. This will vary with the condition being treated and the dose given, among other factors.
• Treatment usually takes place across several sessions (often 6-8 biweekly), with the hope that longer-term and more permanent changes are taking place in the brain that will persist indefinitely. Maintenance or booster sessions may be needed if symptoms return.

Is Ketamine Therapy Effective?

Ketamine therapy for mental health disorders is fairly young. While clinical research is exploring its potential to treat a wide range of disorders and establishing ideal parameters (dose, administration route, frequency), it is not a cure-all. Ketamine therapy is most effective in treating depression and other mental health issues that are often comorbid with depression (e.g., PTSD, anxiety disorders, substance use disorders). Research on the efficacy of ketamine for anxiety, PTSD, and substance use shows promising results.

Effectiveness of Ketamine in Treating Depression

For depression, ketamine helps approximately 50% of patients who try it, with 30% achieving remission. 60% of those achieving remission experienced sustained relief for approximately 8 weeks without needing maintenance or a booster dose.¹⁶

To this point, there is limited data on ketamine’s ability to treat depression on a long-term basis. Ketamine is felt to be beneficial as a fast-acting treatment for suicidal ideation that starts working in as little as one hour and can lead to remission of suicidal ideation in close to 70% of individuals with weekly administration.

Effectiveness of Ketamine in Treating PTSD, Anxiety, & Bipolar

Similar improvements have been documented for PTSD (67-80% response rate), anxiety (50% reduction in symptoms), and bipolar depression.¹⁷ Preliminary studies have suggested a role for ketamine in the treatment of eating disorders and obsessive-compulsive disorder, too.¹⁶

Effectiveness Of Ketamine In Treating Substance Use Disorders

For the treatment of substance use disorders, ketamine has shown efficacy in sustaining abstinence for at least one year in people with alcohol use disorder (66% compared to only 24% of a control group) and heroin use disorder (50% abstinence rate).¹⁸ Other psychedelics – psilocybin in particular – have shown promise for treating similar addictions, including alcohol and, notably, smoking (nicotine), with less potential for abuse of the treatment drug itself.^19,20,21,22

Is Ketamine Therapy Safe?

Ketamine therapy is fairly safe and well-tolerated; however, it does come with its share of risks. Depending on the dose and a person’s comorbidities, ketamine can cause cardiovascular, psychotic-like symptoms or accidents (falling, car accidents, etc.). When administered in a controlled medical setting for psychiatric treatment, that risk is minimized because the on-site healthcare provider will monitor vital signs and mental status while under the influence.

Numerous risks are greater when ketamine is prescribed via telehealth and used in one’s home without clinical monitoring.¹² Even more risky is when ketamine is misused, as questionable sourcing, unsafe dosages, lacing with fentanyl or other substances, polypharmacy, and neglect of contraindications all have the potential to make illicit use dangerous and even deadly.

Risks of ketamine therapy include:

• Psychosis and the development of brief psychotic disorder:
• Addiction and substance misuse potential
• Cardiovascular events
• Bladder and urinary problems
• Memory impairment
• Physical injury from accident after treatment
• Brief psychotic disorder
• Exacerbation of transient psychotic symptoms in predisposed individuals

Who May Not Be A Good Fit for Ketamine Treatment?

Ketamine therapy is not a good fit for everyone. It may not be safe for people with certain medical or mental health conditions (including substance misuse disorder), or who are undergoing other treatment regimens. Aside from medical contraindications, some people may not like or tolerate the dissociative sensation that ketamine can induce, and ketamine therapy can feel anxiety-provoking or aversive.

Individuals who should not take ketamine treatment include:

• People with high blood pressure
• People with cardiovascular disease
• Individuals at risk for psychosis (e.g., schizophrenia)²⁶
• People who can not be monitored by medical staff during treatment (e.g., telehealth compounded prescriptions)
• Those who are anxious about dissociating
• Very young or very old individuals

Can Ketamine Treatment Be Addictive?

Ketamine and addiction have a paradoxical relationship. While ketamine is potentially addictive, it has also been shown to be therapeutic in treating other addictions (e.g., cocaine, heroin, and alcohol).¹⁸ As with any treatment, one must weigh the risk against the benefit. For conditions that have not responded to other traditional treatments, the benefits may outweigh the risks. The healthcare provider will have to consider the risk of ketamine addiction or misuse when assessing if someone is a candidate.

How Old Do You Have To Be To Start Ketamine Treatments?

Esketamine is only approved for adults with treatment-resistant depression or suicidality, but not children, adolescents, or teens. Research on the use of ketamine for teens has only recently started, and although initial studies demonstrate potential, it is still premature to draw conclusions about its efficacy and risk.²⁴ Given its risk profile for hypertensive events, it may not be recommended for older adults with such contraindications.

How Is Ketamine Therapy Administered?

There is a wide range of ketamine administration methods. It is recommended to educate yourself on the pros and cons of the different types and find a provider that offers a route, setting, and expertise that you are comfortable with.

Forms & Dosages of Ketamine Treatment

Ketamine (and its variants like esketamine) can be administered in several ways, including non-invasively through oral (sublingual, pill, lozenge) and nasal routes and invasively through injection (subcutaneous, intramuscular, intravenous). There are pros and cons to consider for different routes of administration, including bioavailability, onset and duration time, environment (clinic, hospital, office, home), and expense.

Common forms of Ketamine treatment include:

• Intranasal: Esketamine (i.e., Spravato), which is the only FDA-approved form of ketamine for psychiatric use, is only available by nasal spray in a certified healthcare provider’s office or clinic. A typical intranasal dose of Spravato can range from 28 mg (i.e., one set of sprays) to 84 mg (i.e., 3 sets of sprays), though it is not uncommon for 140 mg of Spravato (i.e., 5 sets of sprays) to be administered. Some psychiatrists, however, offer racemic ketamine compounds off-label, and dosing for the nasal spray of this form is different due to racemic ketamine being less potent. With racemic ketamine, each set of sprays is 20 mg, and it is not uncommon, depending on a patient’s absorption and tolerance, for as many as 15 sets of sprays (i.e., 300 mg) to be given in a single session.
• Oral Ketamine: Sublingual, tablet, lozenge; oral forms have lower bioavailability (20-25%) than intravenous (close to 100%) or intranasal esketamine (50%).¹² Higher doses (sublingual doses of 150-250mg) due to lower bioavailability can result in increased adverse side effects. The FDA does not approve oral ketamine and related compounds to treat mental health conditions, but it is the form offered for off-label, at-home administration by several telehealth companies.
• Extended-release oral: One proof-of-concept study found that an extended-release oral ketamine tablet designed to release ketamine over 10 hours gradually had fewer side effects (only minor dissociative effects) and no alterations to blood pressure or heart rate but still relieved symptoms to a similar degree as other methods, albeit longer onset time.¹³
• Intravenous (“ketamine infusion”): Although administration through IV requires additional medical staff, equipment (e.g., infusion pump), and is more invasive than oral or intranasal routes, dosage can be fine-tuned with more accuracy to a patient’s optimal level and works faster than other routes.¹⁴ Although not yet approved by the FDA for treating psychiatric conditions, it is nonetheless used off-label. Most clinical research trials studying IV ketamine for mental illness used 0.5mg/kg of IV ketamine.
• Subcutaneous injection: Ketamine injected under the skin (around 0.5mg/kg) has antidepressant effects comparable to other methods like IV, except it is more cost-effective and convenient than IV.¹⁵
• Intramuscular injection: This method of administration is faster, easier, and less expensive than IV; however, the sustained level in the bloodstream can not be titrated as with IV. Most clinical research trials studying intramuscular injectable ketamine for mental illness used 2.0mg/kg.

What Not to Do Post-Administration

Ketamine effects can linger beyond the therapy session, and one should not drive or operate heavy machinery for 6-12 hours following an outpatient, non-surgical ketamine administration, and should avoid these things, regardless of the time frame, for however long a person is feeling disoriented.

Ketamine Treatment Side Effects

At sub-anesthetic doses, most side effects of ketamine are transient and usually resolve in an hour. The most common side effects are sleepiness, dizziness, and blurred vision. Side effects will vary with dose, route of administration, and the individual. One study found that with subcutaneous and oral dosing, nearly 60% of patients had no side effects, 14% had one side effect, and 27% had up to three side effects.²⁵

Potential common side effects of Ketamine treatment include:

• Sleepiness
• Dizziness/Lightheadedness
• Blurred vision
• Palpitations
• Flushing
• Poor concentration
• Nausea
• Paresthesia (pins and needles sensation)
• Dry mouth
• Headache
• Dissociation
• Perceptual distortions
• Psychotic-like symptoms

Potential serious side effects of Ketamine treatment include:

• Elevated blood pressure
• Increased heart rate
• Respiratory depression
• Urinary and bladder symptoms
• Memory impairment
• Psychiatric events
• Ketamine misuse
• Interactions with other comorbidities and medications

What to Expect in Ketamine Therapy

While ketamine can be used acutely for relieving symptoms like suicidal ideation within an hour of administration, it is more commonly administered repeatedly, over weeks or months, to treat depression and other mental health conditions. The process begins before the first administration and ends beyond the last active treatment session, sometimes requiring maintenance or “booster” sessions as needed.

Here is what you can expect during ketamine therapy:

Initial Assessment & Evaluation

To receive ketamine therapy, an individual is required to undergo an assessment. The assessment is conducted by a healthcare professional, usually a psychiatrist, and begins with a psychiatric evaluation. The healthcare professional will obtain information from the patient to assess eligibility and explain what treatment entails, including in-office visits ranging from once per month to several times per week and administration methods.

Ketamine is usually only recommended when a patient has not responded to other typical antidepressants (e.g., SSRIs). There are contraindications that would disqualify someone from ketamine therapy, such as a history of psychotic symptoms or severe hypertension.

Preparation

To prepare for ketamine therapy, the psychiatrist administering the ketamine may consult (with permission) with a patient’s other healthcare providers, including their regular psychiatrist, psychologist, and any other physicians treating the patient for existing medical conditions (e.g., cardiologist, internist, etc.).

The psychiatrist and patient will also set intentions for the ketamine session, select auditory stimuli (background music, progressive or guided meditation), position (sitting vs. laying down), and address any concerns the patient may have, as well as explain what to expect during the active session.

Instructions are given in advance for things to do — like taking one’s routine medication, especially for blood sugar and blood pressure if necessary— and things to avoid — like eating within 4 hours of treatment. It’s also very important that arrangements are made in advance for an individual’s transportation home after each session.

Sometimes, joint sessions between a psychiatrist and psychologist are arranged so that a ketamine-assisted psychotherapy session can be scheduled. Such sessions have the potential to achieve more progress than either ketamine or psychotherapy alone.¹

Setting

The administration room may vary between practitioners but is often set with dim lighting, limited ancillary sounds, and comfortable furniture for sitting or lying down. If an individual has a history of sexual trauma, it is recommended to have a friend or family member present during the treatment.

Administration

Administration type may vary, but since the only FDA-approved form of the drug is the nasal spray administration of esketamine (i.e., Spravato), this has become the most common administration method. However, off-label, non-FDA-approved ketamine use may sometimes involve injection, IV drip, or oral administration. For the first session, a smaller dose is given to see if it is well-tolerated. Doses are then adjusted in subsequent sessions based on the patient’s response and intention.

Monitoring

Regardless of administration type, when performed in a medical setting, it is typical for the physician on staff to regularly monitor the patient’s blood pressure and vital signs and ask them at multiple points if the patient is feeling okay. Sometimes, during a ketamine procedure, a patient will be unable to verbalize their responses and may need to respond with a head or hand gesture. It is possible, though rare, that a patient may experience fainting (especially if they had not eaten at all that day). If this happens, the appropriate emergency medical care is administered.

Timing

A ketamine session typically lasts around 75 minutes, with the main thrust of the drug’s effects beginning about 15 minutes after the full dose and lasting an additional 45 minutes. The come-down phase of the session — beginning after the peak effects start to diminish — can last anywhere from 20 minutes to the rest of the day.

Post-Treatment

As noted above, the come-down phase of a ketamine session begins just as the peak effects start to diminish and can last the entire rest of that day. When effects are experienced after the day of a session, it is sometimes referred to as the “afterglow” phase. During this period, a person is more amenable to changes in their thinking and behavior than usual.

It is not uncommon for the afterglow period to extend for several days following treatment. During this time, one’s ketamine provider and psychologist may check in with a patient to assess their mood and physical state, and this is an excellent period for a therapy session of any kind — individual, group, or couples.

Microdosing Ketamine

Microdosing psychedelics involves taking a daily dose so low that it doesn’t elicit psychotropic effects (e.g., dissociation, perceptual distortions, etc.). Microdosing is more typical with psilocybin use and research, and there is scant research on ketamine microdosing. The smallest doses used in human ketamine research studies did not have the desired effect and did still lead to dissociation in some participants.

Another reason why ketamine microdosing may be uncommon is that a “consensus among researchers and practitioners seems to be forming around the need for a psychedelic/dissociative/trance experience to be achieved during a psychedelic-assisted session (regardless of which psychedelic drug is used) for it to achieve maximum efficacy.”¹ However, such a ‘psychedelic/dissociative/trance experience’ is not possible with microdoses of ketamine, and thus, larger doses are likely required to obtain the intended antidepressant effect.

Ketamine Vs. Psilocybin Therapy

Ketamine and psilocybin are both psychedelics. Ketamine has been approved for medical use as a general anesthetic since 1970 and can be used off-label by physicians for treating psychiatric conditions. Psilocybin, on the other hand, is not widely legal, and thus, the availability of psilocybin therapy is much more limited. With the exception of psilocybin used specifically in clinical research studies, sourcing the substance is questionable and not regulated, at least in the U.S.

While psilocybin is rarely addictive, ketamine does carry some potential for addiction.^3,23 Both psychedelics have shown efficacy in treating other addictions, like alcohol, cocaine, nicotine, and heroin.

How to Find a Therapist Trained In Ketamine Treatment

Like any medication, ketamine must be administered by a physician (medical doctor or psychiatrist) or nurse practitioner. While psychologists cannot prescribe medication, some do collaborate with psychiatrists to conduct psychotherapy sessions during ketamine treatments.

If you have a long-term relationship with a therapist that you trust, you can ask if a ketamine-assisted psychotherapy session would be possible. An established relationship is ideal for such sessions; however, if not, you can find a therapist using an online therapist directory or find a medical ketamine practitioner through directories like The American Society of Ketamine Physicians, Psychotherapists, and Practitioners directory.

How to Get a Ketamine Prescription

It is recommended only to get a ketamine prescription through a ketamine clinic or physician who will administer it on-site and monitor you during treatment. Typically, vitals like oxygen saturation, blood pressure, and heart rate are consistently monitored during ketamine treatments. Several telehealth companies do offer compounded forms of ketamine for home use; however, such unmonitored use and potential for misuse can pose serious health and safety risks.

Cost of Ketamine Treatment

The cost of ketamine treatment can vary greatly with administration route (IV, oral, intranasal), frequency, insurance type, and whether on-label or off-label use is being done. When insurance does cover treatment, it is only for adults with treatment-resistant depression and suicidal ideation who have already been unresponsive to at least two other pharmacotherapies.

As a reference, telehealth companies (like Mindbloom) charge $100-200 per session. Psychiatrists administering intranasal esketamine charge $150-$1,000 for a session ranging from 60 to 90 minutes. Some psychiatrists may offer talk therapy during the session, while others may collaborate with a psychotherapist who may charge for a session separately.