Ketamine is a fast-acting and well-tolerated synthetic compound that has been used as an anesthetic and pain management medicine for over 50 years. It acts at the N-methyl-D-aspartate (NMDA) receptor in the central nervous system (CNS). This receptor is a key part of the glutamate pathway, which is the most extensive excitatory neuropathway in the CNS.
Medical evidence also demonstrates that ketamine is extremely effective for treatment resistant depression and suicidality that is resistant to other treatment modalities. Recent studies have also shown promising results for ketamine as a therapy for several other common mental health issues as well as depression. When used for the management of mental health concerns, ketamine is administered at doses that are significantly lower than those used for anesthesia. In this context, ketamine sometimes causes dissociative, transcendent and/or psychedelic experiences that can be valuable when paired with structured psychotherapy and other therapies.
Ketamine Assisted Therapy (KAT) is a broader term that includes KAP. It recognizes that ketamine may facilitate improved outcomes when used in combination with a range of treatment modalities wider than just psychotherapy. KAT is an emerging area of practice that will continue to evolve as more research is conducted.
Ketamine Assisted Psychotherapy (KAP) is a primarily talk therapy aided by the use of ketamine. It is used to treat various mental health conditions. Emerging evidence demonstrates that KAP may be effective for conditions such as depression, post-traumatic stress disorder, obsessive-compulsive disorder, and substance use disorders.
Every chemical compound exists in two mirror image structures, this is the same for ketamine. S-ketamine is referring to the left handed molecule and R-ketamine to the right. To date there has been very little research conducted on the isolated R-ketamine form. Racemic ketamine contains both S- and R-ketamine (see below for more details).
Racemic ketamine is otherwise known as generic ketamine which is the form that has been widely used in medicine and anesthesia since the 1960’s, it is very inexpensive. It contains both S & R (left and right handed) molecules. Esketamine or Spravato® is a drug that was created by Janssen Pharmaceuticals in an effort to patent by isolating only the S-ketamine molecule. This was US FDA approved in 2019 as a nasal spray for treatment resistant depression to be used under the supervision of a medical professional. Esketamine was approved by Health Canada in 2020 but remains very expensive.
Ketamine is legal when prescribed by a medical doctor.
Health Canada approves medicines for specific medical uses. Ketamine is currently licensed as an anesthetic in Canada and has been for a long time. It is also a controlled substance under Schedule I meaning that it has a high potential for harm and abuse, similar to opioids or stimulants. It is illegal to sell, possess, or produce ketamine unless authorized for medical or scientific purposes.
Due to the Schedule 1 status of ketamine, the provincial health authorities require that proper handling, storage and documentation be followed, uses for ketamine outside of an anesthetic are regulated by provincial colleges and in many provinces its use falls under the regulations and guidelines for Alternative and Complementary Medical Treatments (each provincial College of Physicians and Surgeons has its own guidelines) and is considered to be off-label.
In July of 2020, Janssen’s esketamine was licensed by Health Canada and so became “on-label” for the treatment of Major Depressive Disorder, it is only available through a controlled distribution program called the Janssen Journey™ Program. All providers of Spravato® will need to follow these guidelines as they are product specific. Please see the Canadian Spravato® product monograph and your provincial College website for further information. Prior to July 2020, there was no on-label way to use any type of ketamine outside of anesthesia. Racemic ketamine was and is still being used by physicians and psychiatrists off-label for indications outside of its Health Canada approved use for anesthesia.
Off-label use is considered common practice and many medicines end up being used for things for which they were not originally intended i.e., “off-label.” For example, antipsychotics are used to augment antidepressants.
In order to use a medication off-label it is recommended that you refer to your provincial Complementary and Alternative Medicine Policy. Below is a non-exhaustive list of recommendations to follow when using a medication off-label.
- Ensure that its use is informed by evidence
- Justify the use and explain that you have tried other approved methods of treatment,
- Explain both the indications and contraindications,
- Obtain informed consent from the patient,
- Show that the off-label use is up to the medical community standards of practice,
- Demonstrate that the off-label use is reasonable and there are other practitioners using it in the same manner
The Colleges have not been clear in defining the size of the medical community of practice that can be used to justify off-label uses (i.e., where the physicians who are using this substance must reside). For example, ketamine is used off-label extensively across the globe, despite having less active use in Canada.
Depending on the jurisdiction you practice in, there are different rules and regulations restricting how and where you can use ketamine in your practice.
In Canada, the use of racemic ketamine for mood or psychiatric conditions and disorders is considered an off label use. However, recently provincial colleges are making statements and putting out guidelines for its use. For example, more recently, in BC, a new draft standard was circulated by the CPSBC outlining proposed new regulations for all ketamine use, and was invited to have commentary in early 2021. See here for more details on the process.
In other jurisdictions across Canada, such as Ontario, similar regulations are being proposed and discussed. Due to the fact that there is not a substantial body of randomized double blind controlled studies for Racemic ketamine for its off label uses, including mental health conditions, ketamine falls under the Complementary and Alternative Medicine policy (CAM). This policy is currently under review by the College of Physicians and Surgeons of Ontario (CPSO) and feedback was collected until March 2021. As of April 2021, there has been no further announcements from the College.
Racemic ketamine has been available and used safely in a variety of practice settings internationally for a very long time, it was originally invented in 1962 by an organic chemist Calvin Stevens. Because of the length of time of its use it cannot be patented, therefore it is a generic drug resulting in a lack of financial incentive to do randomized double blind controlled studies at this time. Therefore, there is instead a large body of observational, anecdotal, and clinical evidence, as well as clinical practice groups and practitioner collectives, spanning across the globe.
The routes of administration for ketamine are Oral (PO), Intranasal (IN), Sublingual (SL), Transdermally (TD), Rectally (PR), Subcutaneous (SC), Intramuscular (IM) and Intravenous (IV). The amount of ketamine absorbed into the blood varies by route, necessitating specific dosing strategies. The route also determines how quickly ketamine enters and leaves the body, and the resulting duration of effect.
Ketamine has a well established safety profile in both anesthetic and subanesthetic dose ranges. For the latter, common side effects include increased blood pressure, increased heart rate, dizziness, agitation, and nausea. These are usually mild and transient. Occasionally, these are addressed with medication in certain hospital and non-hospital settings.
Rare side effects include low heart rate, low blood pressure, or a transient change in heart rhythm. Ketamine can rarely cause laryngospasm (notably associated with ENT procedures). While alarming, this complication resolves spontaneously, and can be managed with bag-mask ventilation and application of the Larson maneuver.
Ketamine has been found to cause lower urinary tract problems in recreational users consuming larger quantities and with increased frequency. This has not been seen in patients who have been administered ketamine in a medical setting, although some mild increase in urgency has been reported in some clinical settings.
Safety profiles for ketamine are supported by evidence in emergency, pediatric, paramedic, psychiatric literature and clinical practice, including recommendations from the WHO.
IV (intravenous) ketamine is administered directly into the venous blood stream of the body, while IM (intramuscular) ketamine is administered into the muscle tissue, which is highly vascularised. IM ketamine has a 93% bioavailability compared to IV which is 100%. Bioavailability is the rate and extent of which a medicine accesses the site of action, in this case, the brain. IM ketamine is significantly less expensive and most practitioners in the field agree that it does not require extensive cardiorespiratory monitoring from a clinical standpoint; however it may be required by your specific regulatory body.
IM dosing is useful because once it is administered, it has a predictable and relatively set arc or timeline where peak concentrations reach the brain, and then gradually diminish. Whereas with IV infusion the level of effect can be maintained at a more consistent or steady dose over a determined period providing two unique treatment approaches.
Generally, most regular medications can be continued, however there are some that reduce the effectiveness of treatment, such as lamotrigine and all benzodiazepines. Serotonergic antidepressants tend not to interfere with the transient effects of ketamine for therapeutic purposes, and are generally not contraindicated during treatment.
It is important that regular blood pressure medications are taken as prescribed and any sympathomimetic agents that increase blood pressure such as decongestants or stimulants likely should be stopped before receiving ketamine treatment. As-needed benzodiazepines and prescribed narcotics may need to be discontinued on the day of administration when using ketamine to assist with psychotherapy. As mentioned above, some ketamine protocols use benzodiazepines to reduce agitation and anxiety during treatment, in particular when not combining ketamine with psychotherapy.
If you are thinking about receiving ketamine assisted therapy, the above would be discussed and approved by both your primary care provider and your prescriber.
Officially, the absolute contraindications to receiving ketamine would include hypersensitivity or anaphylactic reaction to ketamine previously, or you have a condition where an increase in your blood pressure would be dangerous to your health. Relative contraindications to receiving ketamine include severe cardiovascular disease, poorly controlled hypertension, pregnancy, hydrocephalus, active psychosis, severe liver disease, and a history of hemorrhagic stroke. Other things to take into consideration before receiving therapy assisted by ketamine include uncontrolled hyperthyroidism or an active manic episode.
Approximately 30-40% of patients with major depressive disorder do not respond to antidepressant medications and more do not respond strongly. In those cases, off-label treatments or electroconvulsive therapy (ECT) are considered. Ketamine is an off-label medication that has been used at subanesthetic doses for treatment resistant depression. Studies have shown promising and robust evidence for improvement in depressive and suicidal symptoms. Individuals interested in ketamine assisted therapy will need to consider the benefits and risks, in discussion with healthcare providers, to see if they are candidates.
The exact pathway is not clear, however, ketamine has been found to have an antidepressant effect. It is likely that it works in a few ways for which studies are underway.
One possible pathway is that ketamine does bind to the NMDA receptors which increases the amount of glutamate, a neurotransmitter, in the space between neurons. Glutamate activates the AMPA receptor that releases molecules that help neurons communicate along these new pathways. The synaptogenesis most likely impacts mood, cognition and thought patterns.
While ketamine was originally made for anesthetic purposes, it has been used for decades by mental health professionals and psychiatrists for depression and other disorders. In recent years, ketamine’s rapid antidepressant effects have been studied and documented in many case reports, prospective open-label studies, and double-blind, randomized, controlled trials. Given the epidemic of mental illness, there is an effort from multidisciplinary healthcare providers to address and bring forth evidence-based and efficacious treatment modalities, such as ketamine for depression.
It is possible to build tolerance to ketamine when used frequently, where the individual would need to take more to have the same effects. Cases of ketamine dependence are comparatively infrequent. However, patients should have a conversation with their prescribing physician if they are considering ketamine therapy, especially if there is a personal history of substance use disorder.
In most major cities, there are harm reduction resources available. Some of the services that they may provide include, education, sterile supplies, narcan kits, and drug testing. Given the risk of drug poisoning, overdose, and supply contamination, it is recommended that individuals pick up a narcan kit where available and never use alone. If you don’t know where to get a narcan kit, ask a local healthcare provider.
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*This FAQ will focus on racemic ketamine and refers to this as “ketamine”, see below for definition of racemic and esketamine.