220 ‒ Ketamine: Benefits, risks, and promising therapeutic potential | Celia Morgan, Ph.D.

KEYPOINTS

• 01

  Ketamine began as a safer replacement for PCP

  Celia Morgan, a psychopharmacologist who has studied ketamine for nearly 20 years, explains that Parke-Davis synthesized it in the 1960s as an anaesthetic to replace phencyclidine (PCP, 'angel dust'). Both act on the NMDA receptor, but ketamine is about 10 times less potent and lacks PCP's long-lasting psychosis-like effects. Edward Domino coined the term 'dissociative anaesthetic' for the class, which some also extend to nitrous oxide. Ketamine remains a valuable anaesthetic, especially where respiratory depression is a concern.

• 02

  Its effects change with dose

  At low doses, ketamine has stimulant properties. Higher doses bring perceptual distortions, a sense of floating or melting and dissociation. Morgan notes that people at higher doses are especially vulnerable to accidents because they are partly but not completely detached from reality. Like LSD, it has no practical lethal dose in the usual sense because it doesn't suppress breathing, but behaviour under its influence can be dangerous.

• 03

  Heavy recreational use causes serious bladder damage

  Ketamine is directly toxic to the lining of the bladder. Morgan has worked with heavy users, including 16-year-old girls, who needed their bladders removed (cystectomy). This harm appears mainly at very high, repeated doses. She has seen people functioning on several grams a day, doses that 'would floor an elephant'. It became a recreational epidemic in the UK in the 1990s and early 2000s, partly because it was cheap and gave strong escapism.

• 04

  Regulation came late

  Morgan says the US scheduled ketamine (now Schedule III) around 1997, and the UK followed in 2006. In 2003 Putin banned it in Russia even for human medical use. After Brigitte Bardot petitioned him on behalf of animals, the ban was lifted for veterinary use but kept for humans, which Morgan calls 'horrendous' given how good an anaesthetic it is.

• 05

  A single low-dose infusion can lift treatment-resistant depression within hours

  Robert Berman's group at Yale published an early study in 2000 using a single infusion of 0.5 mg/kg over 40 minutes in treatment-resistant depression. For an 80 kg person that is 40 mg, compared with perhaps 100–200 mg for a recreational 'blast off'. Early studies such as Carlos Zarate's at NIMH reported response rates around 75%. As with most new treatments, rates have fallen as more studies have come out. Morgan's rough estimate is that 50–60% of patients may not respond, and she says better real-world data are needed. Benefits often last about two days to a week.

• 06

  How it works is still debated

  One theory is that ketamine blocks NMDA receptors on glutamatergic neurons directly, triggering a downstream cascade. Another is that it blocks NMDA receptors on GABAergic interneurons, releasing the brakes on glutamate. It may be both. Either way, it increases synaptic plasticity in the prefrontal cortex, growing new synapses and dendrites, and this correlates with the antidepressant effect. In animals, the plasticity window starts about four hours after a dose and peaks around 24 hours.

• 07

  Time therapy for when the brain is most plastic

  As a psychologist, Morgan's interest is in pairing ketamine with psychological therapy delivered in that window, so people can learn new patterns while the brain is most able to change. Her group is using EEG to chart when that window occurs in humans. She worries about frequent low or daily 'maintenance' dosing given what she has seen in addicted users, and says an international registry of real-world patients would help define safe dosing.

• 08

  Ketamine plus therapy showed promise for alcohol dependence

  Morgan's trial gave three infusions of 0.8 mg/kg, one to two weeks apart. The dose was higher than for depression because of cross-tolerance with alcohol. The trial had four arms of 24 patients each (96 in total), and patients received about 11 hours of support over six months. In the group that got ketamine plus relapse-prevention therapy, the abstinence rate at six months was about 86%. The group that got placebo plus education still reached about 68%, which she partly credits to a supportive team and trial effects. A 280-patient phase 3 trial funded by the UK government is under way in NHS settings.