By Dr. Christopher Fischer MD

Board Certified Psychiatrist

Sacramento

November 30, 2022

What Is Ketamine And Why Can It help with Mood Disorders, Anxiety, And Chronic Neuropathic Pain

According to the World Health Organization, depression is a leading cause of disability worldwide.  Depression affects more than 360 million people every year globally (and counting).  Our current modalities to treat depression and anxiety are failing. With just under a 40% response rate with oral antidepressants, many patients are left wondering, “Do I have to live like this forever?”.

Ketamine has relatively recently entered the sphere of mental health and has shown overwhelmingly positive results.

When compared to oral antidepressant medications, which can sometimes take 4-6 weeks to begin working, ketamine therapy can improve symptoms rapidly in just a few infusions. There have been studies that show Ketamine can be a quick and efficacious anti-suicidal treatment as well.

Ketamine began its journey as a synthesized drug in 1962 when Parke Davis and Calvin Stevens combined a ketone with an amine. Ketamine replaced a drug by the name of phencyclidine (PCP) because it had a much better safety profile. Ketamine was initially used in veterinary medicine to sedate horses and dogs. It was first introduced into human clinical use in the mid 1960’s and was used extensively in the Vietnam War as a sole anesthetic.

Since its introduction into human use, and in addition to being used in mental health, ketamine is most often used as an adjunct to general anesthetics and in conscious sedation procedures. The population that ketamine is most often use in is for procedures is children because of its excellent safety profile and minimal side effects.

Although we do not have a complete understanding of how ketamine works, we do know that one of its main targets is the N- methyl – D – aspartate (NMDA) receptor. The NMDA receptor has been implicated in the mechanism of anesthesia, pain transmission, morphine tolerance, memory and cognitive function, long term potentiation, long term depression, neuronal toxicity, and inflammatory responses.  Most recently, animal studies are showing that ketamine can spur neuronal growth prompting research into ketamine and traumatic brain injuries.

By antagonizing the NMDA receptor, ketamine can control the influx of glutamate which is one of the most prevalent excitatory neurotransmitters. It is believed that the slower the rate of release of glutamate, the less sensitized the nervous system becomes which in turn helps decrease nervous system signal transmission.  To put this in context, an excited nervous system can lead to organ damage and dysfunction and is one component that is believed to be the cause of chronic neuropathic pain syndromes.

NMDA RECEPTOR:

Ketamine can also bind to a variety of other receptors and exert its effects. In addition to binding to the NMDA receptor, ketamine can interact with certain opioid receptors, muscarinic receptors, adenosine receptors, voltage gated calcium channels, and it also has local anesthetic properties.  Due to this unique ability to be non-selective in its receptor binding, ketamine has the capability to treat a wide range of pain and mood disorders such as Chronic Regional Pain Syndrome (CRPS), fibromyalgia, depression, anxiety, PTSD, and as well as other conditions.

IS KETAMINE A PSYCHEDELIC?

Although ketamine is commonly described as a psychedelic and placed in the same category as MDMA (ecstasy) and psilocybin, technically ketamine is not a psychedelic and is best classified as a dissociative anesthetic.  However, ketamine does possess some psychedelic properties as it can induce visual hallucinations and “out of body” sensations during its administration. Often patients will describe their ketamine journeys as profound experiences.  These journeys may involve different physical sensations, colors, sounds, thoughts, emotions, and insights.  These insights can help guide patients and stimulate a shift in perspective, break negative thinking patterns, and help patients overcome mental roadblocks to their recovery and healing.

HOW IS KETAMINE ADMINISTERED?

Ketamine comes in many formulations and its routes of administration include intravenous, oral, intramuscular, intranasal and rectal.

Of these routes of administration, the intravenous route is considered the gold standard because of its predictability and consistency which can be attributed to its 100% bioavailability. The bioavailability can be used to explain a lot about why certain routes of administration are superior.  For example, a popular way to administer ketamine is intranasally however its bioavailability is low and also variable. The same is true for orally administered ketamine. This means that administrations of the medications are unpredictable and variable from session to session. A disadvantage with the intranasal ketamine route of administration also stems from the availability of dry nasal passage membranes because the ketamine cannot penetrate through membranes covered in mucus.  Therefore, when prescribing or administering ketamine, the bioavailability should be an important consideration in the decision-making process.

Ketamine, when given intravenously, has a rapid onset due to its high lipid solubility. Its low protein binding allows the ketamine molecule to easily and rapidly diffuse into cell membranes and exert its effect. It can be more precisely dosed because 100% of the medication goes systemically unlike the oral/intranasal versions. Ketamine administered as an infusion also allows for a steady amount of ketamine to constantly enter the blood stream. This permits the experience to be more fluid and for the patient to spend the maximum amount of time in the therapeutic zone.  Most infusions last between 40 to 60 minutes. The immediate effects of intravenous ketamine are terminated similarly to other intravenous medications via redistribution to other less vascular organs. Although the immediate effects of ketamine can wear off in minutes to hours, ketamine does have metabolites of which many are believed also to be active.

KETAMINE BIOAVAILABILITY:

ROUTES	BIOAVAILABILITY
IV	100%
IM	93%
INTRANASAL	25-50%
SUBLINGUAL	25-50%
ORAL	17-24%
RECTAL	25-50%

 

HOW DOES KETAMINE HELP WITH PAIN AND PAIN SYNDROMES?

Ketamine is believed to alleviate pain through several pathways.  Ketamine can produce analgesia by the action of dissociation.  In this sense ketamine has commonly been employed in the emergency room for minor procedures and during short periods of extreme pain, for example, when setting broken bones or noses.

The chronic pain syndromes that ketamine is believed to be particularly effective in fall in the category of neuropathic pain syndromes. We believe that ketamine helps these pain syndromes via the modulation of the glutamate neurotransmitter. By decreasing the release and circulation of glutamate, an excitatory neurotransmitter, we achieve a decrease in the excitation of the nervous system.

The currently suggested protocols from the American Society of Anesthesia to treat chronic pain syndromes involve a series of 6 infusions to be completed two to three times per week. Each session lasts 3-4 hours and involves high doses of ketamine. Current research is showing that ketamine therapy for chronic pain likely has benefits however much more research is needed to identify the optimal protocols to render long lasting pain control.

The suggested protocols for mood disorders require intravenous infusions over 45-60 mins once or twice per week for six total infusions. Many of the studies that are coming out with administration protocols are showing that to achieve long lasting effects ketamine should be given in pulses or infusion clusters. Studies indicate that most individuals will respond to ketamine between infusion 4 and 8 and for this reason you see many clinics offering 6 session infusion packages.

The protocols for intranasal, intravenous, and oral ketamine can vary between clinics and the guidelines will likely evolve with time as more data becomes available through on-going studies.

Furthermore, there is research looking into the effects of ketamine when coupled with intention setting and integration therapy. The results are showing that ketamine when coupled with the right type of therapy and in the correct setting can achieve longer lasting effects.

HOW EFFECTIVE IS KETAMINE FOR MOOD/ANXIETY DISORDERS?

A large peer-reviewed retrospective analysis of intravenous ketamine therapy in real-world setting ORKA – 1 (Osmind Real-world Ketamine Analyses) looked at thousands of patient data points and concluded that symptom improvement occurs in 70% of patients. This is consistent with the outcomes that we see at our ketamine clinic, Propel Therapeutics.

WHO IS A CANDIDATE FOR KETAMINE THERAPY FOR MOOD AND ANXIETY DISORDERS?

Most patients that present for ketamine therapy can be treated safely if they meet the indications.  Indications for ketamine therapy include mood disorders, anxiety disorders, and PTSD that has not responded to other forms of treatment.  Patients should receive a thorough psychiatric evaluation to determine if they are an appropriate treatment candidate.  Psychiatric contraindications include mania and active psychosis.  Patients should also be motivated and prepared to come in for at least four ketamine therapy sessions.

While ketamine is very safe, there are a few medical contraindications to its use. Since the initial action on cardiovascular system is due to amine reuptake inhibition (ex: epinephrine, dopamine, serotonin), ketamine can cause an increase in heart rate and blood pressure. It is not advised to administer ketamine to individuals with uncontrolled hypertension and some arrythmias.  A pregnant patient should never be given ketamine as there is insufficient evidence at this time to assess its safety to an unborn fetus. Therefore, clinics should screen for pregnancy in women of childbearing age and give proper consent to patient who decline an in-office pregnancy test. Ketamine, like many other medications, is metabolized by the liver and excreted by the kidneys consequently patients with cirrhosis and end-stage-kidney disease are not considered suitable candidates for this therapy.

IS KETAMINE ADDICTIVE?

Ketamine has a very low addiction potential. The classic definition of highly addictive substances require they create a sense of euphoria and leads to withdrawal once the drug is withheld. Ketamine doesn’t fit into these criteria. In fact, recent research has shown to be favorable toward ketamine being used to treat addiction such as alcoholism. Generally, if someone is abusing other drugs and/or alcohol, practitioners would want to have a period of 30 day of sobriety before offering ketamine therapy as a form of treatment to maintain sobriety. These studies are all in their infancy and so more data is needed to accurately access the role of ketamine in addiction medicine.

Overall, ketamine is a highly effective treatment for mood disorders, anxiety, PTSD, and chronic pain. These are conditions that sometimes do not respond to first line treatment options and can leave patients with chronic disabilities and significant impairment in functioning.  Ketamine is a novel modality that has dramatically changed the landscape of mental health treatments available to these patients, giving new hope to these conditions.

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About the Author

REFERENCES:

1. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Acute Pain Management From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologist; Eric S Schwenk, Eugene R Viscusi, Asokumar Buvanendran ¹ , Robert W Hurley  ² , Ajay D Wasan  ³ , Samer Narouze  ⁴ , Anuj Bhatia  ⁵ , Fred N Davis  ⁶ , William M Hooten  ⁷ , Steven P Cohen  ⁸ PMID: 29870457 ; PMCID: PMC6023582 ; DOI: 10.1097/AAP.0000000000000806. 2018 Jul;43(5):456-466.
2. Mechanisms of Action of Ketamine and Esketamine; Alan F Schatzberg; . 2021 Dec;178(12):1130. doi: 10.1176/appi.ajp.2021.21060653.
3. The Effect of Ketamine Infusion in the Treatment of Complex Regional Pain Syndrome: a Systemic Review and Meta-analysis; Jianli Zhao  ^{1   2} , Yajing Wang  ¹ , Dajie Wang  ³ . 2018 Feb 5;22(2):12. doi: 10.1007/s11916-018-0664-x.
4. Efficacy and Safety of Ketamine in the Treatment of Neuropathic Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials; José Eduardo Guimarães Pereira  ^{1   2} , Lucas Ferreira Gomes Pereira  ³ , Rafael Mercante Linhares  ⁴ , Carlos Darcy Alves Bersot  ⁵ , Theodoros Aslanidis  ⁶ , Hazem Adel Ashmawi  ¹ . 2022 Apr 9;15:1011-1037. doi: 10.2147/JPR.S358070. eCollection 2022.
5. Low Dose Ketamine Infusions for Comorbid PTSD and Chronic Pain: A randomized Double-Blind Clinical Trial; Alisher R Dadabayev, Sonalee A Joshi, Mariam H. Reda, Tamar Lake, Mark S. Hausman, Edward Domino, Israel Liberzon; Chronic Stress 2020 Jan-dec4; 2470547020981670; DOI 10.1177/2470547020981670
6. Clinical Anesthesiology; 5^th edition; Lange; Butterworth; Mackey; Wasnick

Image References

NMDA receptor: Schematic diagram of NMDA receptor complex. The NMDA receptor is an… | Download Scientific Diagram (researchgate.net)