A lack of sleep puts a major dent in a lot of physiological systems, from insulin sensitivity to immune function, as well as psychological functioning like mood, willpower, and decision making. It’s looking like three days of ‘oversleeping’ constituting of ~9 hours of sleep is enough to reverse at least some of the effects of chronic sleep deprivation [1].
This can be problematic for a lot of people, insomniacs, sleep disorders, chronic anxiety, or simply those who when they wake up early in the morning—like myself—can’t fall back asleep. I’ve been using something called Cyproheptadine occasionally for a few months to top off my sleep tank, but only recently delved into the pharmacology of why exactly it works, and what to do about the downsides.
Often sold under the brand names Ciplactin or Periactin here in Europe, Cyproheptadine (above) is an first-generation, old school anti-histamine. Your parents have likely used it if you haven’t (it’s still sold OTC and prescribed) and works incredibly well for things like hay fever and itching. Right now, it’s not used often because although it works well as an anti-histamine, it also has a high binding affinity to other receptors and can cause drowsiness — making it less than ideal for daytime use.
A deal-breaker for regular anti-histamine use, Cyproheptadine has been shown to increase restorative slow-wave sleep [2], improve sleep outcome [3] and has been used successfully to treat nightmares, keeping sufferers of PTSD asleep throughout the night [4]. While it works impressively well at improving sleep architecture it has some drawbacks. Taken too close to bedtime I found any dose gave me a hangover leaving me extremely groggy; though I noticed a U shaped response curve, with 1mg being worse than 2mg, and almost as bad as 4mg. While the improvements in sleep outweighed the negative effects, losing half a day to the hangover and becoming ravenously hungry the entire day after taking a dose, made it useful only under very specific circumstances.
These drawbacks seem to occur because cyproheptadine binds to the 5HT2 receptor sites with a higher affinity than serotonin (5HT) itself, dramatically reducing serotonin uptake in the brain. It does this so well in fact that it’s been used to treat patients with Serotonin Syndrome (a potentially fatal overdose of serotonin) in under two hours [5].
Low serotonin levels are associated with hunger, low mood and energy, and supplementation of 5HTP causes significant appetite suppression and effortless weightless even in obese subjects [6] [7].
In addition, also it down-regulates dopamine D3 receptors and acetylcholine receptors fairly broadly which both contribute to sluggish thinking and flat moods.
Cyproheptadine also suppresses growth hormone and cortisol during sleep significantly [8], the latter may explain why sleep duration increases are so often noted since cortisol normally increases in the morning to the point it’s a contributing factor to ‘waking’ up. It may also contribute to the hangover symptoms the morning after, with cortisol too low to give any sense of purpose, leaving one too relaxed.
The downsides noted here have relatively easy fixes, first increasing low serotonin levels is as simple as supplementing with 5HTP, 100mg should be fine. Cortisol on the other hand is a little harder to spike as quickly. Caffeine works [9], as does exercise at 60+% of your VO2Max aka cardio or a weightlifting workout with little/no rest between sets and exercises [10]. Either or preferably both would spike cortisol far higher than normal baseline and I’ve found the combination to restore cognitive capacity fairly quickly.
With all that said, this is not a protocol that should be used too often. The effects on Growth Hormone alone are reason enough for most people to avoid taking it regularly, but when catching up on sleep is necessary or you need to guarantee a great night, this is the cocktail to try. It works better than anything else I’ve found, has the benefits of preventing vivid dreams, and keeps me asleep for 9+ hours no matter what. With that said, I couldn’t recommend anyone take it more than once a week and ideally only when the following day doesn’t require peak mental performance just in case the evening dose or morning antidote isn’t well calibrated for your particular body and mind.
The Protocol
-2:00h pre-bed:
0.5mg Cyproheptadine
Immediately upon waking:
50-100mg 5-HTP (5-HTP can make some people queasy, start with 50mg)
100mcg Huperzine-A
200mg caffeine
As soon as possible after that: Cardio or a Crossfit-style workout
At lunchtime:
50-100mg 5-HTP (only if mood is low, or abnormally hungry)
And that should do it. To repeat the warning, this sort of OTC sleep aid should only be used when necessary. You’re an adult (probably), please do your research before deciding if this is something you want to do — I’m not proposing this as a good idea, merely a practical solution backed up with some research.
You can find more about Cyproheptadine here:
NICE
DrugBank
References
1. Killick, R. et al., 2015. Metabolic and hormonal effects of “catch‐up” sleep in men with chronic, repetitive, lifestyle‐driven sleep restriction. Clinical Endocrinology, 83(4), pp.498–507. ↵
2. Idzikowski, C., Mills, F.J. & Glennard, R., 1986. 5-Hydroxytryptamine-2 antagonist increases human slow wave sleep. Brain research, 378(1), pp.164–168. ↵
3. Adam, K. & Oswald, I., 1989. Effects of repeated ritanserin on middle-aged poor sleepers. Psychopharmacology, 99(2), pp.219–221. ↵
4. Gupta, S. et al., 1998. Efficacy of cyproheptadine for nightmares associated with posttraumatic stress disorder. Comprehensive Psychiatry, 39(3), pp.160–164. ↵
5. Graudins, A. et al., 1998. Treatment of the serotonin syndrome with cyproheptadine. Journal of Emergency Medicine , Volume 16 , Issue 4 , 615 – 619 ↵
6. Ceci, F. et al., 1989. The effects of oral 5-hydroxytryptophan administration on feeding behavior in obese adult female subjects. Journal of Neural Transmission, 76(2), pp.109–117. ↵
7. Cangiano, C. et al., 1992. Eating behavior and adherence to dietary prescriptions in obese adult subjects treated with 5-hydroxytryptophan. The American Journal of Clinical Nutrition, 56(5), pp.863–867. ↵
8. Chihara, K. et al., 1976. Suppression by cyproheptadine of human growth hormone and cortisol secretion during sleep. Journal of Clinical Investigation, 57(6), pp.1393–1402. ↵
9. Lovallo, W.R. et al., 2005. Caffeine Stimulation of Cortisol Secretion Across the Waking Hours in Relation to Caffeine Intake Levels. Psychosomatic medicine, 67(5), pp.734–739. ↵
10. Exercise and circulating cortisol levels: the intensity threshold effect. ↵