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Ketamine has been around since the 1960s and very quickly became an off-label therapy for mental health problems. However, in recent years, due to the renaissance in psychedelic therapies and the fact that ketamine is legal for licensed prescribers to administer, it has seen a huge rise in popularity. In this article, we will provide a summary of ketamine’s history, pharmacology, effects, therapeutic potential, and emphasize the model of ketamine-assisted therapy (KAT, or -psychotherapy, KAP).
Ketamine comes from a family of general anesthetic drugs called the arylcyclohexylamines discovered and developed by the Parke-Davis pharmaceutical company. Ketamine was invented by organic chemist Calvin Stevens in 1962. In 1964 Edward Domino, MD conducted the first human trials and noticed its anesthetic, analgesic, antidepressant, and hallucinogenic effects. To avoid the controversy around psychedelics and the term psychotomimetic, Domino’s wife came up with the term dissociative anesthetic which is still used to describe the drug.
Once it was FDA approved it became very popular in the Vietnam war and its use in hospitals in America and the world became widespread. Ketamine has also become popular in veterinary and pediatric medicine for its wide safety profile. In fact, it is on the World Health Organization’s List of Essential Medicines. In the late 1990s, the National Institute of Mental Health did a series of studies on its antidepressant effects.
They found that it had rapid-acting but short-lived antidepressant effects, but because it was off patent and had negative associations with psychedelic drugs, its use in psychiatry failed to flourish. However, it has seen a steady increase in recent years due to the success of other psychedelic treatments such as psilocybin therapy.
Ketamine is classified as a dissociative anesthetic, where “dissociation” means a sense of disconnection between mind and body, and from one’s ordinary reality and usual sense of self. Its mechanism of action is different from that of other psychiatric drugs such as the SSRIs, SNRIs, mood stabilizers, antipsychotics, benzodiazepines, etc. The primary mechanism of action of ketamine hydrochloride is the blockage of N-methyl-d-aspartate (NMDA) receptors.
Glutamate is the primary excitatory neurotransmitter in our nervous systems and when it binds with an NMDA receptor it depolarizes a brain cell causing an electrical signal to be conducted. By shutting down the NMDA excitatory pathway, pain and other sensory perceptions can be effectively turned off. Some studies suggest that decreased glutamate in the dorsolateral prefrontal cortex (dlPFC), dorsomedial PFC (dmPFC), and anterior cingulate cortex (ACC) is correlated with depression. By blocking NMDA receptors there is an upregulation of NMDA receptor synthesis and glutamate production resulting in a glutamate surge that accounts for the antidepressant effects of ketamine.
Ketamine also seems to either directly or indirectly lead to μ-opioid receptor inhibition, dopamine reuptake inhibition, serotonin reuptake inhibition, acetylcholine modulation, GABA stimulation, cannabinoid stimulation, and nitric oxide stimulation.
Electroencephalography under the influence of ketamine shows 3-4 fold increases in theta wave activity in all regions of the cerebral cortex. Theta waves are associated with meditation states and hypnosis which may account for some of its therapeutic effects. There is also a 1.5-2 fold increase in delta wave activity. Delta waves are increased during sleep and activate numerous neuroendocrine functions.
Imaging studies demonstrate a plethora of effects which is a testament to how widespread we find the glutamate pathway. Among the most notable regions affected are the subgenual ACC (sgACC), posterior cingulate cortex (PCC), prefrontal cortex (PFC), and the hippocampus. The sgACC is more active in depressed individuals and greatly reduced under the influence of ketamine.
Ketamine also interrupts hyperconnectivity of the default mode network (DMN) and reduces the connectivity of the pregenual ACC (pACC) and dorsal PCC (dPCC). These function to dampen the cognition of the self and strong negative biases which are increased in depression. There is also speculation that ketamine activates reward circuitry which is also dampened in depression. Ketamine therapy is commonly used for silo wellness to reduce neuropathic pain thus reducing anxiety and mental illness with just one infusion.
Ketamine is also anti-inflammatory and promotes brain-derived neurotrophic factor (BDNF) resulting in neurogenesis and spinogenesis. These neuroplastic effects may also account for improvements in depression symptoms though serotonergic psychedelics seem to have stronger effects.
Ketamine is usually given intravenously (IV) where it is completely absorbed. Intramuscular (IM) injections can also be used with a high rate of absorption. Other options include a nasal spray or sublingual troche (lozenge) but are less well absorbed thus requiring slightly higher doses for similar effects. It also means there is likely more variability from person to person in how well it is absorbed. Some people will be more sensitive than others. The dose is also adjusted for body weight.
The doses used for complete anesthesia, for surgeries and invasive procedures, are much higher than those used for mental health treatment. In the sub-anesthetic dose range, there can be different experiences based on the treatment goals. At higher doses, one is more likely to have a more mystical or psychedelic experience, while at lower doses it can be more empathogenic. In a psychedelic experience there usually isn’t much talking with a therapist and thus the integration sessions increase in their importance. At the more empathogenic level, a patient can engage in therapy with lowered defenses and inhibitions.
The purely pharmacological antidepressant effects can be short lived which is why that model of treatment requires frequent redosing (eg. once a week). While pairing this drug with therapy enhances treatment results, some repetition of the treatment may be warranted and any protocol is best to be tailored to the individual.
The ketamine experience is characterized by the relaxation of ordinary concerns and usual mindset, all while maintaining conscious awareness. This tends to lead to a disruption of negative feelings and preoccupations. Some ketamine providers feel that this interruption--and the exploration of other possible states of consciousness--can lead to significant shifts in overall well-being. At lower doses, you will most likely experience mild anesthetic, anxiolytic, antidepressant, and psychoactive effects.
You might experience increased sensitivity to light and sound, as well as an altered sense of time. Some people experience empathogenic (similar to MDMA) effects in this dose range. This state may also enhance participation in therapy, as defenses are relaxed, yet communication with others is still possible. Higher doses are more likely to produce psychedelic, dissociative states that are largely internal journeys away from the external world.
Body sensations are greatly diminished. Such journeys may provide a more robust treatment effect, often assisting in the resolution of existential concerns, accelerating psychological and (and possibly spiritual) growth, and promoting a positive change in outlook and character that we refer to as a transformative response. Sensory effects of ketamine may include distorted visualization of colors, feeling suspended in space or floating, experiencing out-of-body sensations, vivid dreaming, and changes in visual, tactile, and auditory processing. Synesthesia (a mingling of the senses) may occur. Familiar music may not be recognizable. You will likely experience time dilation.
These effects typically start 5 to 10 minutes after ketamine dosing. The peak effects typically last 30 to 40 minutes, and then slowly diminish for the next hour. Some alterations in sensory perception, speech, and motor ability may continue for approximately 5 hours. Two to three hours after ketamine administration, clients can return home with another driver. Driving an automobile or engaging in hazardous activities should not be undertaken on the day of the administration, and not until all effects have stopped.
The administration of ketamine may be most effective when paired with therapy. A therapy program will prepare you for your ketamine sessions, encourage you to explore your mind while within the ketamine space, and assist you in integrating your experiences afterward. This program emphasizes the potential for change, and such change is best facilitated within a structured, supportive psychotherapeutic environment with providers who are aware of your issues, hopes, desires, and struggles. Ketamine has the potential to create a non-ordinary state of consciousness, facilitating a profound transpersonal or mystical peak experience. These sorts of peak experiences have been shown to expand one’s sense of self and understanding of existence and may enable you to access your own healing wisdom. Your providers serve as guides and assist in processing the experience and its impact on your everyday life.
Ketamine’s altered state can create conditions of relational and psychological openness, and thus we believe that trust in your providers enables the deepest possible work to occur. Therapy sessions are meant to build that sense of connection and trust between you and your providers. Many have found it beneficial to set an intention for the experience. Intentions should be personal and focused, which could include alterations in habits (such as the use of alcohol or cannabis, exercising, etc.), shifts in self-defeating patterns of thought or social interactions, or exploration of spiritual/existential realms.
A treatment team will work with you to formulate your goals, and will also encourage you to hold those lightly, as resistance or attempts to control the experience can produce anxiety. Every experience is unique to the individual and each session. All such journeys are adventures that cannot be programmed. They evolve from your own being in relation to this medicine, and it is best to relax into the path that unfolds.
Many enjoy the journey, while others do not. Everyone comes through it, and often with greater insight into themselves and their lives. A good therapy program is designed to assist you in integrating these insights into your daily functioning. As a byproduct of your experience, you may feel improvement in your emotional state and reduction in symptoms such as depression, anxiety, and post-traumatic manifestations.
You may notice that you are a bit different after a ketamine experience, and that difference may feel liberating, allowing for new perspectives and behavior. For those who have used traditional antidepressants, ketamine in a lower dose at first can be used effectively for many psychiatric disorders. Suicidal ideation decreases in just a single dose.
These shifts may happen during treatment, in the aftermath, and/or in the days and weeks that follow. Some experiences may be temporarily disturbing, but your therapist will support you in learning to understand your experience in the context of your healing process.
Both therapy and medication (including psychedelic medicines) are effective, but the combination is much more powerful than either on their own, thus providing a unique opportunity for growth and change. Ketamine assisted psychotherapy helps patients who have treatment resistant depression and have exhausted all traditional medicine methods.
Actively engaging in the therapeutic process as well as the medication administration with the understanding that it is not the therapist or the medicine that does the healing, but rather the inner healer that lives within each of us, will produce the longest lasting and optimal results.
Based on research, Ketamine therapy is used for pain management for chronic pain, depressive symptoms, bipolar disorder, and mood disorders. Suicidal thoughts decrease and ketamine provides pain relief for severe depression and other mental health issues such as obsessive compulsive disorder and post traumatic stress disorder.
In places such as the Portland Ketamine Clinic patients use the ketamine infusion therapy to relieve serious mental disorders and connect to inner peace. Ketamine treatment has tremendous potential to heal, and this is only the beginning.
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