Cognitive Impact of Paracetamol in Healthy Volunteers
Condition: Healthy
Study type: Interventional
Phase: Phase 1

Summary: 
      Randomized study, double-blind, crossover, controlled versus placebo.
    

Detailed description: 
      Paracetamol impact on cognitive processes has been until recently little studied in
      literature that presents conflicting results. Some authors do not describe any cognitive
      performance change (Bradley and Nicholson, 1987) but more recent studies (Ishida et al.,
      2007) report an interesting performance improvement in therapeutic doses of paracetamol.

      This improved performance would use the serotonergic pathway that is involved in the
      analgesic mechanism of paracetamol as the investigators demonstrated in our laboratory on
      previous work (Pickering et al. 2006, 2008). However, non-therapeutic dose, instead, showed a
      deterioration of memory processes in animals which may be link to implication of
      Cyclooxygenases COX-2. Indeed, several studies have demonstrated (Sharifzadeh et al. 2005;
      Teather et al., 2005) that anti COX-2 (such as Celebrex) cause in animal a deleterious effect
      on memory, while an anti COX1 and 2 (as indomethacin) or an anti COX1 (as piroxicam) lead to
      no change. A dose-effect relationship is therefore suggested on animals. Furthermore, a
      recent study in healthy volunteers showed that paracetamol acts not only on pain but also on
      pain / stress in society in everyday life (" social pain ") (deWall et al., 2010). By fMRI,
      these psychologists have shown that the reduction of "social" pain is associated with a
      decrease in neuronal activity in brain regions that are involved in social processes but also
      those who are involved in pain processes (anterior cingulate cortex , anterior insula etc..).
      They also showed that paracetamol known for its painkillers properties may reduce the painful
      feelings of rejection or shelved in everyday life. The cognitive-emotional impact of
      paracetamol is even more interesting that the investigators now know that its metabolism
      could involve cannabinoids receptors, particularly CB1 in hippocampus and association cortex
      involved themselves in cognitive phenomena.

      INSERM U766 team to which the investigators belong has proposed the following sequence from
      preclinical : 1) metabolism of acetaminophen in analgesic metabolite AM404 via FAAH enzyme,
      2) AM404 acts indirectly on CB1 receptors, 3) strengthening of bulbo spinal descending
      pathways by the endocannabinoid system, 4) involvement of serotonergic receptors pain
      suppressors.

      This protocol follows a pilot that the investigators completed (HOP clinicaltrial.gov
      NCT01053650, unpublished results yet) where the investigators studied the impact of 2g of
      paracetamol in healthy volunteers. The investigators showed a memory improvement, but with no
      placebo group, it has not been possible to conclude a significant impact of oral paracetamol.
      Thus, this protocol will allow us to better understand if paracetamol can affect some
      cognitive processes, particularly vigilance, memory and decision making.

      In addition, the investigators will build a biological collection to assess the
      pharmacogenetic profile of subjects and, in a secondary objective, correlate it to cognitive
      characteristics of subjects.
    

Intervention name(s): Cantab®
Intervention type(s): Drug
Intervention description(s): Randomized study, double-blind, crossover, controlled versus placebo.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Paracetamol; Cognitive impact