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Influence of formulation and route of administration on ketamine’s safety and tolerability: systematic review

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Abstract

Purpose

Ketamine has rapid-onset antidepressant effects in patients with treatment-resistant depression. Common side effects include dissociation (a sense of detachment from reality) and increases in systolic and diastolic blood pressure. The objective of this structured review was to examine the effect of ketamine formulation and route of administration on its pharmacokinetics, safety and tolerability, to identify formulation characteristics and routes of administration that might minimise side effects.

Methods

This was a structured review of published ketamine pharmacokinetics, safety and tolerability data for any ketamine formulation. The ratio of ketamine:norketamine was calculated from reported Cmax values, as a measure of first pass metabolism. The effect of formulation and route of administration on safety was evaluated by measuring mean changes in systolic blood pressure and tolerability by changes in dissociation ratings. Data were correlated using Spearman’s method.

Results

A total of 41 treatment arms were identified from 21 publications, and included formulation development studies in healthy volunteers, and studies in clinical populations (patients undergoing anaesthesia, or being treated for pain or depression). Ketamine:norketamine ratios were strongly positively correlated with change in dissociation ratings (r = 0.89) and change in blood pressure (r = 0.96), and strongly negatively correlated with ketamine Tmax (r = − 0.87; p < 0.00001 for all). Ketamine Tmax strongly positively correlated with a change in dissociation ratings (r = − 0.96) and change in blood pressure (r = − 0.99; p < 0.00001 for all).

Conclusion

Ketamine formulations that maximize first pass metabolism and delay Tmax will be better tolerated and safer than formulations which lack those characteristics.

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Authors and Affiliations

  1. Psychological Medicine, School of Medical Sciences, University of Otago, PO Box 913, Dunedin, New Zealand

    Paul Glue

  2. School of Pharmacy, University of Otago, Dunedin, New Zealand

    Bruce Russell & Natalie J. Medlicott

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  1. Paul Glue
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  2. Bruce Russell
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Contributions

Paul Glue conceived of the study topic, searched for and collected study data, and performed initial analyses. Bruce Russell and Natalie Medlicott critically reviewed the manuscript and were substantially involved in data interpretation. All authors read and approved the final manuscript.

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Correspondence to Paul Glue.

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Conflict of interest

Drs Glue and Medlicott have a contract with Douglas Pharmaceuticals to develop novel ketamine formulations.

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Glue, P., Russell, B. & Medlicott, N.J. Influence of formulation and route of administration on ketamine’s safety and tolerability: systematic review. Eur J Clin Pharmacol 77, 671–676 (2021). https://doi.org/10.1007/s00228-020-03047-z

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