Drug interactions and pharmacogenetic reactions are the basis for chloroquine and mefloquine-induced psychosis

Med Hypotheses. 2006;67(5):1090-4. doi: 10.1016/j.mehy.2006.01.059. Epub 2006 Jul 14.


Background: Chloroquine and mefloquine used for prophylaxis and treatment of malaria sometimes causes severe mental status changes, through mechanisms that are poorly understood.

Presentation of the hypothesis: Psychosis is caused by interactions with other drugs or by pharmacogenetic vulnerabilities that cause heightened responses to chloroquine or mefloquine alone, mediated through dopamine, acetylcholine, serotonin, P-glycoprotein, inhibited cortical activity, deranged calcium homeostasis, and impaired synaptogenesis.

Testing the hypothesis: Retrospective studies can identify all other drugs taken coincident with chloroquine or mefloquine psychosis. Various genes from patients could be cloned and compared to those from individuals who tolerated chloroquine and mefloquine, culminating with transgenic animal studies. Identification of candidate genes may be aided by pharmacogenomic analysis of single nucleotide polymorphism maps. Finally, prospective studies with cerebrospinal fluid analysis and PET scanning could help verify the hypothesis.

Implications of the hypothesis: If this hypothesis is correct, the incidence of chloroquine and mefloquine psychosis can be greatly reduced by avoiding interacting medications and by conducting genetic screening prior to initiating chloroquine and mefloquine. Validation of the hypothesis would also provide a paradigm to follow for avoiding neuropsychiatric side effects if antidepressants and neuroleptics are used to overcome chloroquine resistance, if new antimalarial drugs chemically related to chloroquine and mefloquine are developed and if chloroquine and mefloquine are used for non-malarial applications such as HIV and cancer.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Antimalarials / adverse effects
  • Antimalarials / therapeutic use
  • Chloroquine / adverse effects*
  • Chloroquine / therapeutic use
  • Drug Interactions
  • Drug-Related Side Effects and Adverse Reactions / epidemiology
  • Humans
  • Loperamide / pharmacokinetics
  • Loperamide / therapeutic use
  • Mefloquine / adverse effects*
  • Mefloquine / therapeutic use
  • Mental Disorders / chemically induced
  • Mental Disorders / drug therapy
  • Psychotic Disorders / epidemiology*
  • Psychotic Disorders / genetics
  • Psychotic Disorders / physiopathology


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antimalarials
  • Loperamide
  • Chloroquine
  • Mefloquine