Neuroendocrine responses to intravenous infusion of physostigmine in patients with Alzheimer disease

Sanjay Asthana, Kathleen C. Raffaele, Nigel H. Greig, Mark B. Schapiro, Marc R. Blackman, Timothy T. Soncrant

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


We have reported that physostigmine, a reversible cholinesterase inhibitor, enhances verbal memory in patients with Alzheimer disease (AD). To elucidate the mechanism of cognition enhancement, plasma hormones were measured during high-dose acute and low-dose chronic steady-state intravenous infusions of physostigmine in nine subjects with AD. High-dose hormone responses were measured during and for 24 h after the infusion of physostigmine 1-1.5 mg over 45-60 min. Chronic responses were measured during continuous intravenous infusions of physostigmine at doses (0.5-25 mg/day) that escalated over 2 weeks, and then during 1 week infusion of the dose that optimized cognition (2-12 mg/day) or placebo administered in a randomized, double-blind, crossover design. A replicable improvement in verbal memory was found in five subjects. High-dose physostigmine infusion that produced noxious side effects resulted in significant elevation above baseline in plasma levels of adrenocorticotrophic hormone (ACTH) (p = 0.0001), cortisol (p = 0.0001), and β-endorphin (p = 0.0001). Chronic physostigmine administration, in the absence of adverse effects, produced no significant elevation in ACTH (p = 0.08), cortisol (p = 0.70), or β-endorphin (p = 0.82). These results indicate that high-dose physostigmine activates the hypothalamic-pituitary-adrenal (HPA) axis, likely representing a 'stress response.' In contrast, cognition-enhancing doses do not produce a peripheral corticosteroid response. Thus, physostigmine-induced memory improvement is independent of the activation of the HPA axis.

Original languageEnglish (US)
Pages (from-to)102-108
Number of pages7
JournalAlzheimer disease and associated disorders
Issue number2
StatePublished - 1999


  • Alzheimer disease
  • Cortisol
  • HPA-axis
  • Memory
  • Physostigmine

ASJC Scopus subject areas

  • Clinical Psychology
  • Gerontology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health


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