From Veterinary to humans
Ketamine, approved as dissociative general anaesthetic for human use by the Food and Drug Administration in the Seventies thanks to its good safety profile (retention of protective airway reflexes, hemodynamic stability and spontaneous ventilation) is a widely used anaesthetic, especially where there is limited availability of resuscitation equipment.1
In veterinary medicine, ketamine is the most widely used anaesthetic agent in all animal species and, since its large use in equine medicine, it is also commonly called "the horse tranquilliser".2
Its therapeutic relevance has increased considerably in respect to its first use as anaesthetic, and many medical sectors currently employ and study its properties. However, its remarkable psychoactive effects in the awakening phase after anaesthesia have also made ketamine attractive as recreational drug. In fact, these effects, characterised by delirium, visual and auditory hallucinations, near-death and out-of-body experiences are the reasons for the increasing abuse of this substance all over the world.1
Acute and chronic damages
Despite the last pharmacovigilance legislation introducing a new definition of adverse reaction, which allows reporting of adverse reactions due to abuse of a substance, no increase has been recorded for ketamine.3 In fact, among the over 14 million reports present in VigiBase (the adverse drug reaction database by WHO) by December 2016, of which around 3,000 related to ketamine, only 202 (about 6.7%) were linked to recreational abuse (https://www.who-umc.org/vigibase/vigibase/).
Nevertheless, adverse reactions and damages caused by the acute and chronic abuse of ketamine are widely described. In acute abuse, high doses can cause nausea and vomit, delirium, amnesia, memory and motor functionality impairment, hyperthermia and cardiac problems (increase of hearth rate and blood pressure), increase of blood flow in the brain and intracranial pressure. Death by overdose of ketamine is rare, whilst the risk of death or damages for accidental causes is high, due to the dissociative state of the subject.
Other types of damage are linked to the chronic use of ketamine. Many problems concern the urinary system and the symptoms described include increased frequency and urgency of urinating, dysuria, incontinence and haematuria. It can cause ulcerative cystitis and unilateral or bilateral hydronephrosis, especially in high-doses consumers. Other complications involve the gastrointestinal apparatus with intense abdominal pain (K-cramps), malfunctioning of the gallbladder (for example biliary dilatation) and hepatotoxicity. It is therefore important to investigate the potential use of ketamine in subjects presenting these ailments when other causes have been excluded.
Our research group has recently characterised the reinforcing effect of ketamine and the development of use disorder for this substance.4 The psychological effects include hallucinations, space-time distortion and cognitive impairment with impact on short and long-term memory. In some cases, we verified an increase of the depressive state, in contrast with studies that suggest the use of ketamine as antidepressant.5 In fact, among the potential clinical uses of ketamine currently undergoing research, the use as antidepressant is the most investigated. In 2000, Berman published the results of the first double blind randomised and controlled trial that evaluated the effects of a single intravenous administration of ketamine. Since then, the interest has increased and in the last few years many more studies have been carried out, showing that a single low-dose intravenous infusion of ketamine (0.5 mg/kg/40 minutes) produce a rapid antidepressant effect that can last up to 7-14 days in patients with bipolar disorder or major depression or resistant major depression.6
The effect induced by ketamine and the good results obtained are encouraging and the development and research process for the selection of ketamine-like drugs is in continuous evolution. Researchers and clinicians nevertheless agree on the fact that, despite the encouraging outcomes, the current evidences are affected by some biases (for example the reduced dimension of the sample in the study) and by limited data on important confounding factors.7 Besides, it is necessary to keep in consideration all the undesired effects that could derive, such as reinforcing, sedative, psychotomimetic or stimulant properties. We agree with some experts, whom underline that the off-label use of ketamine as antidepressant in absence of evidences of therapeutic benefits and safety on a long term should be monitored.8
In order to define the most appropriate composition for the clinical practice, it is therefore important the prompt identification, characterisation and description of the adverse reactions to ketamine and it is equally important to investigate its administration other than intravenous, that could potentially reduce its clinical feasibility.9 To conclude, if from one side it is important to investigate the potential abuse through preclinical and clinical studies as required by the regulatory agencies, on the other side the post marketing surveillance should be more substantial and specific.
Elena Arzenton, Cristiano Chiamulera
Pharmacology unit, Diagnostic and Public Healthcare Department, University of Verona.
- Peck T, Hill S, Williams M. Pharmacology for anaesthesia and intensive care 3rd Edition, 2008, Cambridge University Press.
- Morgan C, Curran H (2011) Ketamine use: a review. Addiction 107:27-38. CDI
- Directive 2010/84/EU of the European Parliament and of the Council. Official J Eur Union 2010;L348:74-99. Available at: http://eur-lex.europa.eu/legal-content/EN/TXT/?qid=1477301106512&uri=CEL...
- Tedesco V, Collo G, et al. Mechanisms of ketamine induced neuroplasticity: potential effects on brain and behaviour. In: Ketamine use and abuse, 2014, Ed. David T. Yew, Taylor & Francis, Boca Raton, pp. 301-324.
- Morgan C, Muetzelfeldt, et al. Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study. Addiction 2010;105:121-33. CDI
- Berman R, Cappiello A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000;47:351-54. CDI NS
- Caddy C, Amit B, et al. Ketamine and other glutamate receptor modulators for depression in adults. Cochrane Database Syst Rev 2015, Sep 23(9):CD011612. CDI
- Newport D, Schatzberg A, et al. Whiter ketamine as an antidepressant: panacea or toxin? Depression Anxiety 2016;33:685-8. CDI NS
- McCloud T, Caddy C, et al. Ketamine and other glutamate receptor modulators for depression in bipolar disorder in adults.