REM sleep rebound

Radulovacki M., Walovitch R., Yanick G. (1980). Caffeine produces REM sleep rebound in rats. Brain Res. 201, 497-500. 

Sleep lab recordings reveal that in the first three days following alcohol withdrawal, the REM sleep rebound becomes so intense as to practically displace the NREM sleep that alcohol had initially enhanced at the expense of REM. This is REM debt payback with a vengeance. As the subject becomes more and more tremulous, more and more delirious, and more and more seizure prone, REM sleep levels go to 100 percent of sleep, indicating a marked shift in brain excitability that we assume is related to a desperate attempt of the system to restore neuromodulatory equilibrium. 

T Insomnia and REM sleep rebound occur after barbiturates or benzodiazepines are used to induce sleep. 

The toxic effects of an overdosage result from profound central depression and may include coma, respiratory and cardiovascular depression with hypertension, and shock leading to renal failure. Withdrawal of the drug is more frequently a problem with barbiturates than with benzodiazepines. Withdrawal of barbiturates leads to rapid eye movement (REM) sleep rebound and rebound insomnia. 

BZD effects on human sleep are well characterized (Mendelson 2001) (a) decreased sleep latency (b) decreased awakenings (c) increased stage II sleep (d) suppressed stage III and IV sleep (e) increased REM sleep latency (f) initial reduction and fragmentation of REM sleep. Discontinuation of BZD treatment after three to four weeks produces a rebound of REM sleep as well as slow-wave sleep (SWS). BZD and non-BZD compounds are pharmacological agents indicated in the management of anxiety, insomnia, and other conditions in which anxiety is the main symptom, and should be considered as symptomatic medications (Nishino et al. 2004). 

Like the barbiturates, the benzodiazepines make it easier to fall asleep and to stay asleep through the night. However, they also suppress REM sleep, which can lead to REM rebound when they are discontinued. Tolerance to their sleep-promoting effects often develops after chronic use. Some long-acting benzodiazepines, such as flurazepam (Dalmane), are associated with pronounced hangover effects in the morning and are therefore problematic as sedative-hypnotics. Others, with a short-to-intermediate dnration of action, are more desirable as hypnotics. 

Histamine Hi receptor antagonists which enter the brain (diphenhydramine, promethazine and others) have sedative actions and polysomnographic recordings have shown that they suppress REM sleep and modestly increase SWS. A rebound in REM sleep sometimes occurs on discontinuation. Stimulation of central Hi and H2 receptors markedly potentiates signals produced by excitatory amino acids and it has been suggested that histamine acts as a waking amine (Schwartz et al., 1986). The effects of centrally acting antihistamines on sleep may be due to inhibition of these effects. 

Many psychotropic drugs from various classes other than antidepressants have been shown over the years also to suppress REM sleep, but they do not have any antidepressant efficacy (Kales 1995). A review, however, indicated that, compared with other REM suppressant drugs, antidepressants produce a suppression of REM sleep that is larger, more persistent, and followed more frequently by REM rebound on drug discontinuation (G. W. Vogel et al. 1990). Thus, differences across drug classes indeed make antidepressants unique, with their REM suppressant effect paralleling only that of the arousal-induced REM sleep deprivation. 

Compared to barbiturates, benzodiazepines are relatively safe medications that produce little tolerance and suppression of REM sleep, and benzodiazepine overdoses are much less common. However, benzodiazepines are not without unwanted side effects. As mentioned above, longer-acting benzodiazepines can produce residual drowsiness, grogginess, and weakness the next day (benzodiazepines are also muscle relaxants). Benzodiazepines can produce rebound insomnia, in which the person experiences significant insomnia after he or she stops taking the medication. This is particularly true with benzodiazepines that have short half-lives. To avoid this, the patient should never stop cold turkey rather, the dosage should be slowly tapered off over several days to a week. 

Delta-9-tetrahydrocannabinol (THC), the main active ingredient in marijuana, reduces the amount of time spent in REM sleep, although tolerance to this effect can develop over time and the overall amount of time spent in REM sleep returns to normal levels. However, like people who constantly drink alcohol or take narcotic pain relievers, people who smoke marijuana daily can experience REM rebound after stopping the drug. 

Jimenez-Anguiano A, Baez-Saldana A, Drucker-Colin R. Cerebrospinal fluid (CSF) extracted immediately after REM sleep deprivation prevents REM rebound and contains vasoactive intestinal peptide (VIP). Brain Res 1993 63 345-348. 

---