Awake at 3 a.m.: what cortisol, the HPA axis and blood sugar really have to do with it

There is a sober physiological explanation for this, not a mysterious one. In the second half of the night sleep naturally becomes lighter: the proportion of deep sleep decreases, REM phases and light sleep increase, and short waking moments at the end of a sleep cycle are normal. At the same time the HPA axis begins to release more cortisol in the early morning hours. This combination makes us more easily rousable between roughly 2 and 4 a.m. Those with little stress sleep through this phase. Those under tension, rumination or low sleep pressure wake up in exactly this phase and stay awake. The fact that it happens reproducibly around 3 a.m. for many people is due to a consistent sleep-wake rhythm, not to a particular organ. If the awakening is rare and you fall back asleep easily, it is harmless. With more than 3 nights per week over more than 3 months, this is called a sleep maintenance disorder, which should be assessed by a doctor.

Cortisol follows a pronounced daily rhythm. The lowest value (nadir) is around midnight, after which cortisol rises continuously in the second half of the night and reaches its peak shortly after waking. This morning rise is called the Cortisol Awakening Response (CAR). Elder and colleagues described in 2013 in Sleep Medicine Reviews that cortisol typically rises by 38 to 75 percent in the first 30 minutes after waking and reaches its peak about 30 minutes after waking. This rise begins before subjective awakening and is physiologically meaningful: it prepares the body for the day. Under increased stress this rhythm can be amplified. Roth and colleagues described in 2006 in Sleep Medicine Reviews an overactivity of the HPA axis with increased CRF and cortisol release in primary insomnia. Cortisol alone does not cause the awakening, but its natural rise in the early morning hours lowers the arousal threshold.

A relevant nocturnal drop in blood sugar can theoretically trigger a hormonal counterregulation with a rise in adrenaline and cortisol that leads to waking. This is robustly studied above all in people with diabetes on insulin therapy. Jauch-Chara and colleagues showed in 2007 in Diabetes, in a controlled study of 16 healthy subjects, that an experimentally induced drop in blood sugar to 2.2 mmol/l led to awakening, but that the hormonal counterregulation (adrenaline, noradrenaline, ACTH, cortisol, growth hormone) was markedly weaker in late sleep than in early sleep. In practice this means: a genuine nocturnal hypoglycemia is rarely the main cause of regular awakening in metabolically healthy people without diabetes. Those who eat very late in the evening with a lot of sugar or alcohol may sleep more restlessly due to blood sugar and insulin fluctuations or due to the sleep-fragmenting effect of alcohol. With night sweats, racing heart and trembling that improve after eating, this should be medically evaluated.

The Chinese organ clock assigns each time of day an organ with maximum activity, for example the liver between 1 and 3 a.m. and the lungs between 3 and 5 a.m. For the idea that waking at a particular time points to a disorder of exactly that organ, there is no robust scientific evidence. What can be said credibly: the body does indeed have an internal clock. Very many physiological processes follow a circadian rhythm controlled by the central clock in the suprachiasmatic nucleus, including cortisol, core body temperature, melatonin and blood pressure. In that sense the basic idea that bodily functions fluctuate over the day is correct. What is wrong is the specific assignment of clock time equals organ problem. If you wake reproducibly at a particular time, that is an indication of your stable sleep-wake rhythm and your sleep architecture, not of a diseased organ. The organ clock is useful as a rough mnemonic for daily rhythms, not as a diagnostic instrument.

Very early awakening, that is waking at 3 or 4 a.m. without being able to fall back asleep, is regarded as a classic symptom of a depressive episode, especially of the melancholic form. It often goes along with a morning low in mood. One background is an altered regulation of the HPA axis. Lu and colleagues described in 2016 in the Journal of Psychiatric Research that an HPA axis overactivity with an enhanced Cortisol Awakening Response and disturbed glucocorticoid feedback occurs in depression, particularly after adverse childhood experiences. Early morning awakening is therefore not proof of depression, but a serious indication, especially when it coincides with low mood, lack of drive, loss of interest, rumination or hopelessness. In that case a medical or psychotherapeutic evaluation is advisable. More on this in the spoke on sleep and depression.

In midlife, waking at night, night sweats and early awakening are among the most common complaints. Woods and colleagues reported in 2015 in Menopause that hot flashes, waking at night, night sweats and early morning awakening are among the most frequently mentioned symptoms of women in midlife, and that hot flashes are, from the women's perspective, frequently a contributor to the sleep disturbance. The hormonal transition with fluctuating and falling estrogen levels affects temperature regulation and sleep stability. So anyone who newly begins, in this phase of life, to regularly wake up drenched in sweat should not hastily attribute it to the organ clock but have it assessed gynecologically and in general medicine. Night sweats also have further possible causes, from infections through the thyroid to medications, which should be ruled out.

Occasional brief awakening with rapid return to sleep is normal and no cause for concern. A brief glance at the clock, a quiet change of sleep stage, all of that is part of a normal night. You should have it medically assessed if the awakening occurs more than 3 nights per week over more than 3 months and impairs you during the day (exhaustion, concentration problems, irritability), if it goes along with low mood, hopelessness or rumination, if night sweats, racing heart, shortness of breath or a feeling of suffocation occur, if you snore loudly and pauses in breathing are observed (suspicion of sleep apnea), or if unintended weight loss, fever or other general symptoms are added. This list does not replace a medical examination, it can only help you recognize the moment for a conversation.

First: do not stare at the clock and do not calculate how much sleep is left. That activates the stress system and makes falling back asleep harder. Second: if you have not fallen back asleep after about 20 minutes, get up briefly, do something calm in dim light and only return to bed when sleepy. This stimulus control is a core component of cognitive behavioral therapy for insomnia. Third: strengthen the basics during the day: a fixed wake-up time including weekends, daylight in the morning, caffeine only in the first half of the day, reducing alcohol in the evening, avoiding heavy and very late meals. Fourth: work on stress regulation, since the HPA axis and nocturnal rumination are closely linked. Breathing exercises, daytime movement and writing down worries in the early evening can lower nocturnal hyperarousal. If these measures do not take effect after a few weeks, cognitive behavioral therapy for insomnia is the most effective non-pharmacological option and should be arranged through a doctor.

The nocturnal lying awake with racing thoughts, often called the hour of the wolf in the media, is very common and usually the result of a simple chain: sleep is lighter in the second half of the night, the cortisol level rises physiologically, the brain is more easily rousable, and in the silence of the night without distraction worries seem larger and more threatening than during the day. This is a perceptual distortion, not a reliable reality check. The key is to put it in context: a one-off or rare bout of nocturnal rumination is harmless. If it becomes the rule and always circles the same dark themes, it can be a sign of an anxiety disorder or depression and should be evaluated. It helps not to take the nocturnal thoughts at face value, to briefly note them down if needed, and to consciously postpone the decision about the worry to the next day.