Ketamine is a Class B drug first synthesized in the 1960s and licensed for use in anaesthesia. It is considered a dissociative anaesthetic with activity characterised by catalepsy (muscular rigidity and a lack of response to external stimuli), amnesia and analgesia. In medicinal use, its sympathetic activity may stimulate the heart and increase breathing rates, but occasionally can cause respiratory depression.²⁵

Activity is attributed to being a non-competitive antagonist of glutamate N-methyl-D-aspartate (NMDA) receptors in the CNS. Increased glutamate release in the brain’s cortex and subcortex ultimately leads to 5-HT_2A receptor activation in the pre-frontal cortex. Ketamine activity may also derive from interactions with opiate receptors at central and spinal sites and interaction with norepinephrine, serotonin and muscarinic cholinergic receptors.^25,27

Esketamine is the S-enantiomer of ketamine, the isomer having more analgesic activity, although it can cause dissociative anaesthesia. It is licensed for analgesia and anaesthesia, but also to treat major depressive disorder if given in combination with an SSRI or SNRI.²⁵

Its mode of action in depression is attributed to NMDA antagonism with glutamate release increasing neurotrophic signalling which may help restore synapse function in brain regions associated with mood and emotional behaviour. In addition, it may help restore dopaminergic neurotransmission in the brain regions associated with reward and motivation and decrease stimulation of brain regions involved in anhedonia (the inability to experience joy or pleasure).²⁵

Recent research has found potential for ketamine for refractory chronic migraine. Inhaled intranasally, it reduced headache intensity and improved quality of life “with relatively tolerable adverse events”, although given its potential for overuse, the researchers proposed it should be reserved for those clearly in need of more effective rescue treatment with appropriate safety precautions.⁴

Ketamine may also be useful for suicidal patients. Giving two doses intravenously over two days in additional to standard treatment increased the proportion of patients reaching full remission of suicidal ideas at day 3, with effects potentially lasting six weeks.²⁸