Harm related to recreational ketamine use and its relevance for the clinical use of ketamine. A systematic review and comparison study

ABSTRACT

Backgrounds

Ketamine is a dissociative anesthetic that is currently considered for several new indications.

Aim

To deduce the safety of long-term ketamine treatment using the harm of heavy recreational (non-medical) ketamine use as a proxy for maximal possible harm of ketamine treatment.

Methods

Systematic literature review according to PRISMA guidelines to identify controlled studies on ketamine-related harm in heavy recreational ketamine users. Results were compared with serious adverse events (SAEs) in patients treated with ketamine according to three systematic reviews considering dosing regimen and cumulative dose.

Results

The systematic search yielded 25 studies. Heavy recreational ketamine use can escalate to ketamine dependency and was often dose-dependently associated with other SAEs, including cognitive and mental disorders, and gastrointestinal and urinary tract symptoms, which disappeared upon marked reduction of ketamine use. Heavy ketamine users have a much higher cumulative exposure to ketamine than ketamine treated patients (>90 times), which may explain why SAEs in the clinical context are mostly mild and reversible and why ketamine dependence was not reported in these patients.

Conclusion

Treatment of patients with ketamine is not associated with ketamine dependency or SAEs. However, caution is needed since data on long-term clinical ketamine use with a long-term follow-up is lacking.

KEYWORDS:

• Ketamine
• adverse effects
• cognition
• recreational use
• non-medical use
• urinary complications

Article highlights

• Ketamine is an anesthetic that is currently also used for the treatment of depression and chronic pain.

• The safety of long-term ketamine treatment is largely unknown.

• Recreational (non-medical) ketamine use is dose-dependently associated with adverse events and dependence, but many of them seem reversible.

• Cumulative ketamine exposure (dose and duration) in the clinical setting is much lower than in most recreational users.

• Given the observed dose–response relationship in recreational users and the much lower exposure to prescribed ketamine, clinical use of ketamine seems relatively safe.

• New patented (es)ketamine applications are being developed.

• Long-term follow-up studies should confirm the safe clinical use of ketamine, including its newly patented applications.

This box summarizes key points contained in the article.

Author contributions

WvdB and JvA performed the systematic search and drafted the paper.

Declaration of interest

W van den Brink reports personal fees from Lundbeck, Novartis, D&A Pharma, Takeda, Mundipharma, Angelini, Opiant, Idivior, Kinnov Therapeutics, and Camurus for services outside the submitted work. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have a published patent on development of a controlled release ketamine tablet formulation of depression. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors received no financial support for the research, authorship and/or publication of this article.