Ketamine is a dissociative anesthetic commonly used in Western medicine and has psychedelic-like effects. It is not considered a classic psychedelic. Ketamine acts primarily as an antagonist to the N-methyl-D-aspartate (NMDA) receptors1 in the brain, which are involved in the regulation of pain perception, memory, and learning. Its mechanism of action also involves the modulation of other neurotransmitter systems, such as glutamate, dopamine, and serotonin.
Ketamine Science and Research
Things to Know
- Esketamine, a more potent form of ketamine, is being studied to treat resistent depression and suicidal ideation
- Research shows that ketamine treatments can rapidly regulate mood states
- Ketamine is used off label for legal mental health treatments
Chemistry and Neuroscience
Researchers speculate that depression is a result of neuronal dysfunction or deficiency, largely brought about by chronic stress of various sorts. They find that ketamine infusions rapidly restore neural activity to regulated mood states2 , thereby producing a rapid-onset antidepressant effect3 .
In the simplest sense, depression destabilizes specific synaptic brain activity. Treatment with ketamine rapidly restores this brain activity, quickly and temporarily alleviating symptoms of depression for up to four weeks, depending on the treatment and the participant.
Ketamine has been shown to block and bind to NMDA receptors, stimulating a release of the neurotransmitter glutamate, which strengthens neuronal activity.
Ketamine increases the level of glutamate at synapses (the space where neurons meet). This spike in glutamate leads to the activation of other glutamate receptors, known as AMPA receptors, which are integral to synaptic plasticity. Plasticity refers to the process of strengthening the connection between neurons and is an integral part of the neurochemical foundations of learning and memory.
Thus, the initial ketamine-induced blockade of NMDA receptors coupled with increasing levels of glutamate and AMPA receptor activation leads to the release of other molecules which promote synaptogenesis—the formation of new synapses.
By creating new synapses and strengthening existing connections between neurons, ketamine has the ability to positively affect mood, thought patterns, and cognition4. Ultimately, this action increases brain function overall and may account, in-part, for ketamine’s ability to help alleviate the symptoms of refractory mental health issues such as Treatment-Resistant Depression and PTSD 5 .
Numerous clinical trials have investigated the efficacy of ketamine as a treatment for a wide range of conditions, including Treatment Resistant Depression, Major Depression, PTSD, Substance Use Disorder, anxiety disorders, OCD, and pain management.
Clinical trials are looking at ketamine as a treatment for Treatment Resistant Depression for people who are on an antidepressant6 . Another study investigated ketamine as a treatment for social anxiety disorder7 .
Researchers have also studied ketamine as a possible treatment for alcoholism8 and pain management9 . An open label trial investigated ketamine as a treatment for OCD, as well10 . This report details how ketamine helped manage a woman’s opioid withdrawal11
One recent clinical trial looked at how low dose esketamine could help women experiencing postpartum depression. Another clinical trial looked at how using ketamine may help women prevent postpartum depression[footnote]https://beta.clinicaltrials.gov/study/NCT03927378?cond=Depression%20Postpartum&term=ketamine&rank=2 after a C-section12 .
Studies are also investigating ketamine as a treatment for bipolar disorder. One study13 looked at the NMDA receptors in the brain (the receptors ketamine acts on) and their relation to bipolar disorder, while another14 looked into inhaled esketamine for treatment-resistant bipolar depression.
There are more ketamine studies underway than for all other psychedelic substances combined. However, esketamine (available as Spravato) is the only form of ketamine approved by the FDA as a mental health treatment, and that is only for treatment resistant depression and suicidal ideation. Nonetheless, off-label use is common, based on two decades of research into the antidepressant effects of ketamine.
Studies include a number of clinical trials looking at ketamine’s impact on postpartum depression15 and ketamine as a treatment for bipolar depression16 .