Histamine Release Timing at Night
In healthy adults, histamine levels reach their minimum around 11 PM (23:00 hours) and then rise to peak levels during the early morning hours between 4 AM and 11 AM, with the highest concentrations occurring around 11 AM. 1
Circadian Pattern of Histamine Release
The release and regulation of histamine follows a clear circadian rhythm that is opposite to what many might expect:
- Histamine levels are lowest during the sleep period (nighttime in humans), reaching their nadir around 11 PM 1
- Histamine levels are highest during the active/wake period (daytime in humans), with peak concentrations occurring at approximately 11 AM 1
- Histaminergic neuronal activity is maximal during wakefulness (2.3 spikes/second during active waking) and virtually silent during slow-wave sleep and REM sleep 2
Regulatory Mechanisms
The circadian control of histamine involves multiple enzymatic processes:
- Histidine decarboxylase (the biosynthetic enzyme) peaks at 4 AM in the hypothalamus, with a notable mid-day trough at 4 PM 1
- Histamine N-methyltransferase (the degradation enzyme) also peaks at 4 AM, with a secondary broad peak throughout the daytime hours 1
- The mast cell clock temporally regulates organic cation transporter 3 (OCT3), which controls histamine transport and contributes to circadian variations in plasma histamine levels 3
Clinical Implications
This circadian pattern has important clinical relevance:
- Plasma histamine exhibits nocturnal peaks at steady state in some contexts, which may contribute to nighttime exacerbation of allergic symptoms 3
- Histamine plays a critical role in maintaining wakefulness and arousal, explaining why antihistamines cause sedation when taken at bedtime 2, 4
- First-generation antihistamines taken only at bedtime can still cause significant daytime drowsiness due to prolonged plasma half-lives and persistent end-organ effects 5
Important Caveats
- The specific timing can vary based on the light-dark cycle and individual sleep-wake patterns 4
- Stress and aberrant light-dark conditions can desynchronize the mast cell clockwork, disrupting normal circadian variations in histamine levels 3
- The pattern described reflects endogenous histamine regulation in healthy individuals, not pathological histamine release from allergic reactions or mast cell disorders 5, 6