What is ketamine? How is it used to treat depression and how does it work?

Ketamine is a long used anesthetic medication that in the early 2000s was found to be helpful for treating depression, even in individuals who have not responded to other interventions.  It can be administered in a variety of ways: via an intravenous ketamine infusion (IV), an intramuscular injection (IM), intranasally, sublingually, or even orally.  It is unique in that it works very rapidly, with individuals frequently seeing improvement in their depression within hours.  Ketamine administrations take place only in the office and are medically monitored by Dr. Ryan the entire time.  These treatments take place in a comfortable office, with a couch, music, and optional use of blindfolds—in contrast to a post-op recovery room as is done in many other clinics. These 90 minute ketamine sessions include several components: medication management, ketamine administration, and psychotherapy, and can be combined with regular psychiatry follow-up visits where other medications are adjusted. Please see below for more in-depth discussion of the psychotherapy component of these visits; the majority of other clinics administer ketamine on its own without psychotherapy, but that addition of psychotherapy component is thought to provide much more benefit.

What about ketamine-assisted psychotherapy?

Combining ketamine with psychotherapy, as done here, can yield an even greater benefit than ketamine treatments alone.  The psychedelic aspects of the ketamine experience provide for more material to work with in therapy, especially in the context of a long term psychotherapeutic relationship. While studies examining this particular application of ketamine are limited, work with compounds that create similar states of consciousness--such as MDMA, LSD, and psilocybin--suggest a role of altered states and psychotherapy that is independent of the well established biochemical antidepressant effects of ketamine.  Research into applications of the so called "classical hallucinogens" (LSD, psilocybin, mescaline, DMT, ayahuasca) drastically slowed in the 1970s due to political pressure, but have in recent years resumed with promising preliminary findings.  Similarly, the well known entheogen MDMA (methylenedioxymethamphetamine), which is one of the active ingredients of the street drugs molly and ecstasy, was used by psychiatrists in the 1980s to augment psychotherapy.  Results were quite promising, but research essentially halted after the DEA scheduled MDMA as a controlled substance in 1985, resuming only recently. Studies of MDMA-assisted psychotherapy suggest efficacy in treatment of PTSD, even in individuals who exhausted all other available treatment methods. Perhaps most exciting is the study that suggests benefits from such assisted psychotherapy last for years after the initial course of therapy, as seen in Mithoefer's landmark follow up study.  Ultimately, patients who undergo ketamine sessions are encouraged to continue with or begin their own psychotherapy, although this is not an absolute requirement to treatment.  Individuals with an existing therapist are welcome to continue seeing them, and those without have the option to be seen by Dr. Ryan for psychotherapy.  

How is ketamine different from esketamine (Spravato)? Do you offer esketamine (Spravato)?

Ketamine, like many molecules, is actually made up of a 50:50 mixture of left and right hand versions of the molecule (AKA enantiomers). Such “chirality”, as it is called, is a property of many molecules and medications, and can be measured by the rotation of polarized light shined through a solution of the molecule. These different orientations of the molecule can have subtly different pharmacological effects on the body. In this case esketamine (S-ketamine), the right handed version of the ketamine molecule, is far more potent of the two; the other being called arketamine (R-ketamine), the left handed version. Since much of the pharmacological activity of ketamine comes from the esketamine component, it has been purified and used in and of itself. Ketamine has seen clinical use since the 1960s, while esketamine came into use much later, in the 1990s, and only in Europe. In the eyes of the FDA, ketamine and esketamine are different molecules, while practically they are very similar (mirror images of each other on the molecular level). The use of esketamine, and enantiomers in general, may offer some slight advantages over the parent molecule in terms of lower incidence of side effects or duration of action, though head to head clinical trials of ketamine against esketamine have not been performed and so this is not clear (such a clinical trial is actually being planned).

Additional considerations include route of administration, cost, insurance coverage, efficacy, and monitoring requirements. Esketamine, in the form approved by the FDA, is only available as a nasal spray (Spravato), where as the older ketamine is available in nasal as well as other forms (see above). Different routes of administration, such as nasal versus intramuscular injection, have differing bioavailabilities; nasal administration (in contrast to intramuscular administration) results in less of the active medication affecting the body, due to absorption and metabolism. In terms of cost, ketamine itself is quite inexpensive, typically totaling a few dollars per dose, while nasal esketamine (Spravato) is reported to have a wholesale price of approximately $600-900 per dose (depending on if one is using the lower 56mg dose versus the higher 84mg dose). This higher cost of Spravato is because it is a branded medication being marketed by Johnson & Johnson, a pharmaceutical company. After patent protection of the Spravato formulation expires in several years, it will likely be available in generic form for a much lower cost, similar to ketamine currently. As of March 2019, health insurance providers are discussing requirements to cover Spravato for their enrollees, but my speculation is that they will likely ask that individuals have tried and failed at least two antidepressant trials of adequate dose and duration in the current depressive episode. When insurance companies start to cover Spravato, and if prior newly approved medications are any indication, they will likely enforce arbitrary requirements on its use. In terms of efficacy, or the ability to provide relief from depression, the two are probably the same with the caveat that ketamine itself can be used in higher dosages, which means both greater potential for benefit as well as for side effects. Such comparatively higher dosages are not possible with Spravato due to an FDA-mandated program called REMS (risk evaluation and mitigation strategy), which among limits to dose options, also requires a two hour period of monitoring after administration.

Ultimately they are both effective in the treatment of depression, though esketamine is more costly, requires longer appointments (due to FDA monitoring requirements), and is more tightly regulated. I am able to provide either treatment, and can discuss your options with you during the initial visit. Please remember that both treatments are administered only in the office (not for take home use), and in a frequency of twice per week. Similar to ketamine treatment, people should not drive the rest of the day and only after getting a restful night’s sleep.

Should I receive ketamine treatments from a psychiatrist or an anesthesiologist?  What are Dr. Ryan's qualifications?

Ketamine treatments are offered by psychiatrists, anesthesiologists, and emergency room physicians. Each medical specialtiy has its own unique qualifications; while anesthesiologists are well versed in the physiological effects of ketamine (such as blood pressure, heart rate), they do not receive any psychiatry or psychotherapy training. Psychiatrists, conversely, are extensively trained in psychotherapy and specialize in the treatment of mental health conditions including depression, anxiety disorders, and addiction. It is important to know that psychiatrists are medical doctors and so are well qualified to safely administer such sub-anesthetic doses of ketamine. Indeed, doses used in such treatments have a much more favorable safety profile than the higher anesthetic-level doses used in surgery.  A large advantage of receiving your ketamine treatments from a psychiatrist involve the addition of psychotherapy, which boosts efficacy, and the greater knowledge around treatment of depression that only specialized clinical training can provide (residency training in psychiatry).

Further benefits of having a psychiatrist manage one's ketamine treatments include the option to consolidate all of your psychiatric care with one provider, including medication management / ongoing mental health prescriptions, psychotherapy, and ketamine treatments.  Dr. Ryan is uniquely qualified given his extensive academic, clinical, and research experience, including double board certification in psychiatry and addiction psychiatry, years of psychodynamic psychotherapy and motivational interviewing training, as well as various presentations and publications on treatment of depression, ketamine for treatment resistant depression, MDMA-assisted psychotherapy, cannabis, club drugs, hallucinogens, and addiction. He also has extensive experience working with individuals in altered states of consciousness as a medical/lead at the Zendo Project, which provides psychedelic harm reduction at various festivals.

Is ketamine safe? What are some reasons I would not be eligible (contraindications)?

Ketamine is a unique among anesthetic medications in that it is extremely safe, having been used in various settings for more than fifty years, even in poorly monitored settings such as the battlefield and developing countries: "ketamine has a good safety profile and is easy to use, especially in under-resourced health systems and emergency settings where clinical conditions and medical equipment are generally not available" (World Health Organization).  Ketamine has an even higher margin of safety when used to treat depression because such doses are much lower than those used in surgery. Patients typically remain conscious the entire time, though will likely feel somewhat altered (“dissociated”) and experience perceptual changes.  When used in much higher anesthetic level doses, ketamine puts people into a temporary coma such that they can undergo medical procedures and surgery; such coma-level doses of ketamine require the presence of an anesthesiologist for full airway and cardiac monitoring, while the lower doses used in depression do not.  There are specific reasons you would not be eligible for ketamine, including recent myocardial infarction (heart attack), cerebrovascular accident (stroke), recent psychosis (hallucinations, delusions), or recent bladder inflammation (cystitis). Administration of ketamine and medical monitoring throughout the session is performed by Dr. Ryan, and not by nurses or personnel with less medical training.   

What is the best route of administration for treatment of depression?

As noted above, ketamine can be administered in several different ways: by an intravenous infusion, an intramuscular injection, intranasally, sublingually, and orally. These different routes of administration come with a higher or lower bioavailability; in practice intravenous and intramuscular administration allows the most ketamine to affect the body, while the other routes result in lower effective doses due to metabolism and other factors. Intravenous ketamine infusions, typically over 40 minutes, have been most studied because of their historical use and the original FDA approval of ketamine for anesthesia in the 1960s. Pharmacokinetic data suggest an intramuscular injection results in active drug levels very similar to a forty minute long infusion, and empirically studies have shown equivalent efficacy (or benefit) with intramuscular administration.  It is unlikely that intravenous ketamine infusions are more effective than other routes of administration, but this certainly results in greater patient discomfort, greater resource utilization, and ultimately higher cost.  For this reason I provide ketamine as an intramuscular injection, and in the context of psychotherapy. For an in-depth discussion I invite you to read the review article I authored for the International Journal of Transpersonal Studies: Ketamine and depression: a review.

Am I a good candidate?  How are ketamine treatments structured?

Prior to initiating ketamine treatments, potential patients are scheduled for an initial psychiatric evaluation.  On this first meeting, we will determine a diagnosis, develop a treatment plan, and assess for any medical or psychiatric issues that may interfere with ketamine treatment. Please note that we can discuss other potential options that do not necessarily involve ketamine, or even medications at all. Indeed, it is important to know about the various options so that you can make the best choice. If we mutually agree that ketamine could be beneficial, then we can schedule a subsequent visit for the actual administration.  The greatest benefit of ketamine is attained with multiple administrations over the first few weeks of treatment, which is then followed by periodic booster treatments to maintain freedom from depression.  I ask patients to commit to a series of 6 administrations over 3 weeks, and then return for periodic bimonthly to monthly booster treatments thereafter to prevent depression from returning. Please note, it is always your option to stop treatment at any time, though I recommend that people try at least three before concluding it is not working for them. Driving after a treatment is not allowed as ketamine temporarily impairs one's balance, and so arrangements must be made to get a ride home, such as from family, a friend, or taxi/ride sharing company. Ketamine sessions are scheduled for 90 minutes in duration, and involve a brief medication management visit, the actual ketamine administration, followed by psychotherapy, all of which is integrated into one visit.

For individuals interested in ketamine treatments, please print out the informed consent (see forms page) and bring it with you to our appointment.  I will have you sign it after an in depth discussion about the risks, benefits, and alternatives available to you.

Are there any precautions?

Individuals receiving ketamine should abstain from any food or drink for the 6 hours prior to receiving the medication, and furthermore, should not drive for the remainder of the day. This is a necessary precaution because the subtle after effects of ketamine can linger for hours after the treatment and impair the ability to drive.  Effects typically resolve after a night of restful sleep, after which driving is allowed. Typically patients arrange a ride home with a friend, family member, or taxi / ride sharing service.

What is the cost of ketamine and esketamine (Spravato) treatments? Do insurance companies cover it?

Current fees can be found on the new patient intake form, available here. I do not directly contract with insurance companies, but instead collect the full fee at time of the visit and provide patients with a detailed receipt (“superbill”) with fees and CPT codes that can be submitted to their insurance provider for reimbursement. Visits coverage very much depends on the insurance plan and can vary greatly from person to person.  The initial psychiatric consultation visit (AKA evaluation or intake)is typically coded as 99205, where as the typical 90 minute long ketamine treatment session involves several components which may be reimbursed for: the medication management portion (99213, 99214, or 99215), psychotherapy aspect (90836 or 90838), and intramuscular injection administration.

Esketamine (Spravato) requires 2 hours of monitoring after administration, so visits are typically 2.5 hours in duration and the cost is proportionally greater. Please understand that esketamine (Spravato) is much more costly unless your insurance covers the medication. Ketamine itself is several dollars or less and so is combined with the above fees, while the cost of a dose of nasal esketamine (Spravato) is a separate $600-900 which is due to the pharmacy or health insurance company.

To get a good idea of coverage, I recommend potential patients check with their insurance provider to see what their out-of-network coverage benefits are for the above procedures/CPT codes.  PPO type insurances usually allow for out-of-network benefits, while HMO plans generally do not. I do not accept medi-cal (CA state) and medicare (federal) insurances, and there is no possibility of reimbursement from those.

What can you tell me about the use of ketamine for treatment of addiction or substance use disorders?

Ketamine has been studied for treatment of addiction, specifically to the opiate and street drug, heroin.  Findings suggest that ketamine, as part of a structured therapy program, is effective for the treatment of addiction, perhaps due to biochemical properties as an NMDA receptor antagonist. While studies examining this particular application of ketamine are more limited than those examining treatment of depression, work with compounds that create similar states of consciousness--such as the "classical hallucinogens": LSD, psilocybin, mescaline, DMT, and ayahuasca--suggest a role for altered states independent of the biochemical effects of ketamine.  Such compounds seem to work to treat addiction via their ability to produce spiritual or mystical experiences. While such "classical hallucinogens" are not currently available for clinical use, there exists a growing literature detailing successful and robust treatment of tobacco and alcohol addiction. Use of the aforementioned compounds outside of a research setting is however illegal, except for ketamine which has been FDA approved for other indications and is consequently available for off-label use to treat such diagnoses as depression, post-traumatic stress disorder, and addiction / substance use disorders.

What other psychiatric conditions has ketamine been used for?

Treatment resistant depression is, by far, the most extensively studied psychiatric application of ketamine, and has a wealth of data to support its use.  Other indications (or reasons to use ketamine) include drug or alcohol use disorders (specifically for opioid or cocaine use disorders),  Post-Traumatic Stress Disorder (PTSD), and eating disorders such as anorexia or bulimia.  On the other hand, data suggests ketamine is less effective for treatment of Obsessive-Compulsive Disorder (OCD), but may be worth pursuing on a case by case basis.

Where can I learn more?

You are invited to read a review article I authored on ketamine for depression.  The full text is available free of charge from the California Institute of Integral Studies [ full text ].  An updated version of this review is available as a book chapter in a larger publication on ketamine.  The book, entitled The Ketamine Papers--Science, Therapy and Transformation, is published by the non-profit Multidisciplinary Association for Psychedelic Studies (MAPS) and available for purchase through their website and amazon [ order the book via MAPS, or via amazon ].  Also available is a video recording of a presentation on ketamine that I gave for the Aware Project [ YouTube video ].