The beginning of Ketamine

Ketamine is a drug which first appeared in the 1950s when it was synthesized from PCP (phencyclidine). PCP itself was synthesized in 1956 and studied for its potential as an analgesic, or product to relieve pain. Initial studies showed that it was extremely effective in relieving pain in animals and research moved on to human trials in 1958.

Scientists published results of human trials in 1959, finding that this early compound (called Sernyl) was “the most potent general analgesic agent which had been used in clinical medicine”. The main advantage of using this newer agent to other analgesics was that it did not lower blood pressure or breathing rate. This made it more suitable for use with elderly patients and also made it safer to use an analgesic with patients who had suffered blood loss.

However using this analgesic agent did result in extreme excitation of some patients, with several becoming unmanageable post surgery or suffering psychotic reactions. Further research made it apparent that PCP was not actually a suitable analgesic agent for use in humans. A related compound called PCE was developed in the late 1950s in an attempt to refine PCP in order to make it suitable for use with humans. However given that it produced hallucinations in patients and the fact that ketamine was discovered at around the same time PCE was pushed to the side.

Other research focused on trying to synthesise related compounds that would be suitable for use in humans. In 1962 Professor of Organic Chemistry Calvin Lee Stevens in Wayne State University (Detroit, Michigan) and consultant to Parke-Davies and Company laboratories, synthesised a compound we now know as ketamine. This compound was an effective analgesic, short acting and did not have the same hypnotic properties as previous agents.

Ketamine as a medicine

Ketamine itself was first patented in Belgium as a veterinary anaesthetic in 1963 and soon approved by the FDA in 1970 for use with humans; just in time to be field tested on the battlefields of Vietnam. Unfortunately in 1969 ketamine was introduced to Britain and very quickly became a widely abused party drug due to its potential to give users potent hallucinations. This led to a negative public opinion of the drug which, along with its use in veterinary medicine (often thought of the ‘horse tranquilizer’), made patients wary and reluctant to agree to being treated with it.

Ketamine continued to be used in less wealthy countries and in battle zones for emergency treatments as it was a safe option for patients, as well as one which did away with the need for extra equipment or highly trained staff. In fact it was and is so well considered that the World Health Organisation placed ketamine on its Essential Medicines List in 1985, and continues to support unrestricted access to supplies for medical purposes.

Revival of interest

In the 1980s research into particular receptors in the brain (NMDA) showed that activation of these receptor channels was responsible for synaptic plasticity; or the ability of synapses to either strengthen or weaken. The consensus was that synaptic plasticity and the influence of these receptor channels was responsible for memory, thinking and consciousness. Further research into this topic revealed that ketamine had a non-competitive inhibition effect upon the NMDA and led to advances in the study of mental functioning.

In the 2000s research connected the effects of ketamine with effective treatment of depression and a reduction in suicidal thoughts and has since been heralded as what “might be the most important breakthrough in antidepressant treatment in decades”

Current Status

Since it was first discussed as a potential treatment for depression nearly 20 years ago many studies have continued to further explore the link between ketamine and NMDA receptors. Today the FDA has not yet approved ketamine as a treatment option but many clinics offer it “off-label” and have reported significant results. Kalypso Wellness states that up to 70% of patients feel relief of symptoms after one treatment, and patients who follow the further 4-6 treatments over 2-3 weeks feel a 90-95% relief of symptoms.

There are currently 2 ‘types’ of Ketamine being used as treatments: racemic ketamine and Esketamine (Spravato). Racemic ketamine is a combination of two mirror image molecules, the ‘R’ and the ‘S’ ketamine and is usually administered intravenously. This type has been approved by the FDA and used for decades as an anaesthetic before its modern reinvention as a treatment for depression. Esketamine (Spravato) is only the ‘S’ type of Ketamine and is usually administered by a nasal spray, it has recently (2019) been approved by the FDA for use.

Benefits of Ketamine treatment :

  • Can provide relief of symptoms in patients with treatment resistant depression
  • Is shown to provide relief of symptoms within hours of administration
  • Provides an alternative to electroconvulsive therapies
  • Triggers ‘regrowth’ of neural connections associated with depression

In summary, Ketamine was synthesized in the 1950s and has now been widely used for nearly 60 years. It has been continuously used and supported by the WHO as a safe and highly effective medicine for use in the treatment of humans.

The last 20 years of renewed interest and redirected study has shown the effectiveness of ketamine in treating depression, chronic pain and reducing suicidal thoughts. The success of current trials is driving further study into the mechanics of exactly how ketamine helps treat depression and has given hope to millions of sufferers who may have tried a variety of treatment options.

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