Conceptual foundations of the UCSD Statin Study: a randomized controlled trial assessing the impact of statins on cognition, behavior, and biochemistry

Arch Intern Med. 2004 Jan 26;164(2):153-62. doi: 10.1001/archinte.164.2.153.


Background: Statin cholesterol-lowering drugs are among the most prescribed drugs in the United States. Their cardiac benefits are substantial and well supported. However, there has been persistent controversy regarding possible favorable or adverse effects of statins or of cholesterol reduction on cognition, mood, and behavior (including aggressive or violent behavior).

Methods: The literature pertaining to the relationship of cholesterol or statins to several noncardiac domains was reviewed, including the link between statins (or cholesterol) and cognition, aggression, and serotonin.

Results: There are reasons to think both favorable and adverse effects of statins and low cholesterol on cognition may pertain; the balance of these factors requires further elucidation. A substantial body of literature links low cholesterol level to aggressive behavior; statin randomized trials have not supported a connection, but they have not been designed to address this issue. A limited number of reports suggest a connection between reduced cholesterol level and reduced serotonin level, but more information is needed with serotonin measures that are practical for clinical use. Whether lipophilic and hydrophilic statins differ in their impact should be assessed.

Conclusion: There is a strong need for randomized controlled trial data to more clearly establish the impact of hydrophilic and lipophilic statins on cognition, aggression, and serotonin, as well as on other measures relevant to risks and quality-of-life impact in noncardiac domains.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Aggression / drug effects
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
  • Cholesterol / blood
  • Cholesterol / physiology
  • Cognition / drug effects*
  • Humans
  • Hypercholesterolemia / drug therapy
  • Pravastatin / therapeutic use*
  • Randomized Controlled Trials as Topic*
  • Serotonin / blood
  • Serotonin / physiology
  • Simvastatin / therapeutic use*
  • United States


  • Angiotensin-Converting Enzyme Inhibitors
  • Serotonin
  • Cholesterol
  • Simvastatin
  • Pravastatin