Ketamine – Shifting Depression one Glutamate Receptor at a Time

Have you ever taken something that left you seeing the world through a distorted lens, watching the world instead of directly experiencing it? You may have taken ‘Ket’ or ‘Special K’. Break your leg jumping on a trampoline? You may very well find that your paramedic will administer Ketamine to relieve the pain. Popular among recreational users and routinely used in the medical field, Ketamine is a unique compound which may be driving the next revolution in mental health treatment. Ketamine research has exploded in the past ten years and its findings are percolating into popular consciousness, with an ever-growing interest in how this compound could help improve our lives. In this article we briefly summarize the history of Ketamine, how it works and how it may be the biggest advance in mental health treatment yet. 

Ketamine’s story begins with the discovery of Phencyclidine, also known as PCP or Angel Dust, an anaesthetic first synthesized in the early 1960s. While an extremely effective anaesthetic, it also causes intense, distressing, and prolonged hallucinations. In search of an equally effective compound with fewer panic-inducing side effects, researchers eventually synthesized what was then known as CI-581. At one-tenth of the potency, this compound was a reliable anaesthetic with only very mild respiratory depressant effects. It still caused dissociative and altered states of perception in patients, but far less intense and frightening than its forbearer. Reliable, safe and with many routes of administration, the now-called Ketamine quickly became a drug routinely used for anaesthetic and pain-relieving purposes.

Ketamine’s ability to, at mild doses, produce feelings of dissociation or “out of body” experiences and perceptual alterations popularized it with recreational users. It is short-acting and has stimulant effects, increasing blood pressure and heart rate. When snorted, effects are experienced within 10-15 min, lasting no more than 30-45 min. At high doses, Ketamine can cause users to K-hole: to dissociate completely from their surroundings and experience intense psychedelic experiences as well as loss of feeling in limbs. Users can quickly develop tolerance to the desired effects, and this may cause users to take larger and more frequent doses. As a result, Ketamine can be liable to compulsive use and abuse and people can develop psychological dependence. Side effects of frequent ketamine use may include low mood and mild cognitive impairments such as attention deficit and frequent and chronic ketamine use has been associated with urinary tract and gastrointestinal issues.

Ketamine affects a number of systems in the brain, but its primary mechanism of action is believed to be through glutamate, one of the brain’s most prominent chemical messengers. Glutamate together with the NMDA receptor play an important role in many of our higher cognitive functions, particularly in memory and learning. When ketamine binds to the NMDA receptor and blocks glutamate from binding to the receptor, it causes a surge of glutamate in the brain. The surge activates the AMPA receptor, and this combined activity releases other molecules which are thought to help establish new communication routes between neurons (“synaptogenesis”) and trigger a rapid antidepressant response. 

It is this rapid antidepressant response which excites modern day clinicians and researchers. To date our most effective antidepressants primarily act on single monoamine neurotransmitters such as serotonin, dopamine or norepinephrine. Traditional antidepressants take weeks to reduce symptoms, may have considerable side effects and can be difficult to withdraw from if not managed properly. Importantly, a sizeable portion of individuals with depression are ‘treatment resistant’ – their symptoms are not improved by antidepressants or psychotherapy. In these individuals, Ketamine has been shown to quickly and significantly reduce depressive symptoms and suicidal thinking within hours of administration, which persists for up to at least a week, and may be extended through repeated administration. 

These results are promising and open new doors to understanding depression and how we treat it. Ketamine research is still in its infancy and there is a lot more to explore and fine-tune.  For example, research suggests that Ketamine may work better in ‘classic’ depression than in bipolar depression, a type of depression characterized by extreme changes in mood. Many new studies are exploring the effects of ketamine on other mental health conditions including post-traumatic stress disorder, obsessive-compulsive disorders, anxiety and substance use disorders.  While the evidence varies for each of these conditions, there appear to be positive signals overall. However, the studies to date are difficult to compare due to variations in study design, method of administration and how benefit is measured.  Studies also vary in their involvement of psychotherapeutic elements: if they are combined with psychotherapy sessions (and if so, which model) or if people are asked to debrief and integrate their experiences with therapists after following a session. 

The question of the extent to which the psychedelic properties of Ketamine contribute to its therapeutic effect and if and how it should be involved in treatment is an ongoing tension among clinicians and researchers. Since the dawn of Ketamine’s synthesis, researchers have tried and continue to try to separate the psychedelic effects from its antidepressant effects. While most clinicians and therapists interested in providing Ketamine therapy use Ketamine ‘off-label (i.e for a purpose other than a drug was originally approved for), pharmaceuticals have been working to develop new ketamine-based medications and treatment protocols. In 2019, a Ketamine nasal spray was approved by the American Food and Drug Agency. This insurance reimbursed treatment is not designed to induce psychedelic experiences and does not require the patient to engage with a psychotherapist. Instead, patients receive their low dose under supervision of medical doctors and nurses. 

There is sufficient evidence to suggest that at least in the short term, this approach still reduces depressive symptoms. However, many advocate that ketamine treatment will be most effective when it induces psychedelic experiences and is used within a psychotherapeutic or ‘meaning-making’ context.  Therapists may use ketamine in low dosages to facilitate discussions about deeply traumatic or difficult topics and to facilitate the therapist-patient relationship. Others advocate for the more established psychedelic therapy model (commonly used in psilocybin and LSD trials) where individuals are encouraged to go inward and explore their inner state of consciousness and to integrate with psychotherapists following the session. 

These approaches propone that viewing ketamine solely in neurobiological terms may be too reductive. Ketamine, like many other psychedelics, may use our chemistry against (or one might argue, for) us to facilitate mental paradigm shifts through its ability to create new neural connections. It may move one from habitual and entrenched states of being and thinking to new and more fluid states, disorganising our brain just enough to let us re-organise in new and more helpful ways. Ketamine as a new antidepressant drug with limited to no psychedelic experiences may seem more palatable to those fearful of or uncomfortable with psychedelic experiences. However, it pays to remember that the power of psychedelics often lies in the lesson they teach about letting go and acceptance. To embrace letting go of control and to let oneself be overwhelmed by the possibility of chaos and disorganisation. It is often in the eye of a storm that we find the peace and resilience needed to come out of the other side. 

If you are interested in exploring Ketamine Therapy, we advise you to think deeply about how effective ketamine may be for your specific difficulties and the extent of psychedelic effects you are willing to experience.  It is worth remembering that Ketamine is still an illegal and regulated drug in most countries, that very few Ketamine treatments are formally approved or embedded in public health systems and that the research is still in its infancy, with many questions still unanswered. This golden child may very well change the way we treat mental health difficulties in the future, but for now be safe and smart. Always work with trusted and reliable providers who will integrate the treatment into your overall care.