Slow wave sleep (SWS) is strongly linked to IQ.
Pharmacologic augmentation of SWS likely enhances daytime memory consolidation.
These observations are best pursued by investigating potent and selective 5HT2A (serotonin receptor) antagonists and evaluating their effects on SWS architecture and cognition.
Increase Slow Wave Sleep (SWS)
A strong interrelationship exists between slow wave sleep (SWS) and growth hormone (GH) release.
There is a linear association between the time spent in SWS and the amount of concomitant GH secretion. Many of the neurorestorative properties of SWS are likely linked to GH.
GH secretion, along with SWS, declines exponentially during natural aging (see the adjacent figure) and with precisely the same chronology. However, ghrelin agonists like MK-677 robustly reverse this decline in growth hormone secretion.
Growth hormone has additionally been noted to regulate neural stem cells in animal models:
We have previously shown that the growth hormone (GH)/prolactin (PRL) axis has a significant role in regulating neuroprotective and/or neurorestorative mechanisms in the brain and that these effects are mediated, at least partly, via actions on neural stem cells (NSCs)
And also promote hippocampal cell survival:
Our findings indicate that GH strongly promotes cell proliferation in the adult brain and also protects the hippocampal neuronal precursors against the deleterious effect of prolonged sleep loss
I wrote previously about how SWS electroencephalographic (EEG) architecture (amplitude, spindle density, slope) is tightly associated with cortical thickness. This article represents a continuation of that line of thinking.
Part I. SWS is the pre-eminent correlate of IQ
Total time spent in slow wave sleep (SWS), along with SWS architecture, may in fact be one of the most significant correlates of intelligence (and overall efficiency of neural networks) identified to-date. Now, before being dismissed for hyperbole and sensationalism, please consider the following assertions from the literature.
Individuals with a swift reaction time spend more time in SWS1:
Previous research has shown that healthy young adults with relatively fast reaction times on daytime testing have significantly more nocturnal slow-wave sleep than do age-matched subjects with relatively slow reaction times on such testing.
Sleep spindle density is correlated with IQ2:
Recent evidence suggests the spindle is highly correlated with tests of intellectual ability (e.g.; IQ tests) and may serve as a physiological index of intelligence.
Daytime learning itself precedes an increase in SWS2:
Further, spindles increase in number and duration in sleep following new learning and are correlated with performance improvements.
Moreover, SWS likely underlies the benefits of a daytime nap on cognitive performance2:
Spindle density and sigma (14-16Hz) spectral power have been found to be positively correlated with performance following a daytime nap, and animal studies suggest the spindle is involved in a hippocampal-neocortical dialogue necessary for memory consolidation.
And differences in mental ability are related to SWS (aka non-REM) parameters 3:
Our aim is to reveal the relationship between non-rapid eye movement sleep-specific oscillations (the slow oscillation, delta activity, slowand fast sleep spindle density, the grouping of slow and fast sleep spindles) and general mental ability assessed by the Raven Progressive Matrices Test (RPMT). The grouping of fast sleep spindles by the cortical slow oscillation in the left frontopolar derivation (Fp1) as well as the density of fast sleep spindles over the right frontal area (Fp2, F4), correlated positively with general mental ability.
Moreover, delta power (the amplitude of slow waves) correlates with waking cerebral metabolic rate4:
Other research shows that delta power in sleep is positively linked to waking cerebral metabolic rate. Such findings suggest that < 1 Hz activity may reflect waking performance at neuropsychological tests specific to the PFC
Soberly recalling that correlation =! causation, it may be that the extremely precious simply sleep more efficiently as a kind of epiphenomenon of intellectual ability. This is tantamount to saying that increased slow wave sleep (SWS)
doesn’t make you smarter; being smarter simply results in pristine SWS architecture.
But this hasty conclusion ignores certain aspects of the evidence. Namely, it overlooks that SWS in itself enhances memory consolidation; being precluded from SWS also underlies the impairing effects of sleep deprivation. It has been recently reported in *Science *that the restorative function of sleep may be a consequence of enhanced removal of neurotoxic waste products (including amyloid beta) that accumulate during wakefulness in the central nervous system.
What about rapid eye movement (REM) sleep? REM is excluded from the discussion because almost all antidepressants markedly suppress REM sleep5 without any obvious cognitive side-effects, indicating that REM plays a limited role in daytime cognitive performance.
II. Increase Slow Wave Sleep (SWS) With Drugs
This brings us to part II. Can we increase slow wave sleep or in enhance it in some other way?
Consider the following list of drugs which have been reported to increase SWS.
|Drug||Mechanism of action||Reference|
|Tiagabine||GAT-1 inhibitor||Mathias et al., 200136|
|Gaboxadol||Selective extrasynaptic GABAA agonist||Deacon et al., 200721|
|[Gabapentin](http://www.brainprotips.com/gabapentin-recreational-use/)||α2-δ site on voltage-gated calcium ion channels||Bazil et al., 200537|
|Pregabalin||α2-δ site on voltage-gated calcium ion channels||Hindmarch et al., 200538|
|GHB||GABAB/GHB agonist||Pardi et al., 200639|
|Ritanserin||Partially selective 5HT2A receptor antagonist||Dahlitz et al., 199040|
|Eplivanserin||Antagonist of Serotonin Two A Receptors (ASTAR)||Hindmarch et al., 200822|
|[Mirtazapine](http://www.brainprotips.com/remeron-for-sleep/)||Multiple receptors, including 5HT2 antagonist||Shen et al., 200641|
|Olanzapine||Multiple receptors, including 5HT2 antagonist||Sharpley et al., 200542|
|Trazodone||Multiple receptors, including 5HT2 antagonist||Mendelson, 200543|
This laundry list of drugs indicate that both gamma-amino-buyric acid (GABA) receptors and the serotonin receptor 5HT2A likely play an important role in the regulation of slow wave sleep (SWS).
Indeed, it has previously been reported that 5HT2A antagonists “produced more consolidated sleep, increased non-rapid eye movement sleep (NREM) sleep, and increased electroencephalographic delta power during NREM sleep”  (for our purposes, NREM sleep = slow wave sleep).
Certainly, giving the above table a cursory glance, no one would advise taking the atypical antipsychotic Olanzapine for nootropic purposes. Looking for more selective 5HT2A antagonists, we discover the following:
|Drug||Mechanism of action||Reference|
|AMDA (9-Aminomethyl-9,10-dihydroanthracene)||Selective 5HT2A antagonist||Westkaemper RB et al |
|Volinanserin (MDL-100,907)||Selective 5HT2A antagonist||Schmidt CJ et al |
|Ketanserin||nonselective; high-affinity 5HT2A antagonist; antihypertensive agent||V. G. Bampalis et al |
|LY-367,265||potent and selective antagonist at 5HT2A, selective serotonin reuptake inhibitor (SSRI)||Pallar IA et al |
|Metergoline, mesulergine, mianserin and ritanserin||nonselective 5HT2A antagonists||Mazzola-Pomietto P et al |
Before definitive conclusions can be reached, more research needs to be conducted on the effects of pharmacologic augmentation of SWS on daytime cognitive performance.
For the time being, extreme carbohydrate restriction and vigorous exercise are the soundest ways to increase sleep efficiency and % time spent in SWS 11.
Slow-wave sleep and waking cognitive performance among older adults with and without insomnia complaints (1999). ↩
The function of the sleep spindle: a physiological index of intelligence and a mechanism forsleep-dependent memory consolidation (2011). ↩
Sleep spindling and fluid intelligence across adolescent development: sex matters (2014) ↩
Prefrontal cortex: links between low frequency delta EEG in sleep and neuropsychological performance in healthy, older people (2003) ↩
Selective 5HT2A and 5HT6 Receptor Antagonists Promote Sleep in Rats (2008) ↩
9-(Aminomethyl)-9,10-dihydroanthracene is a novel and unlikely 5-HT2A receptor antagonist (1999) ↩
5-HT2 receptors exert a state-dependent regulation of dopaminergic function: studies with MDL 100,907 and the amphetamine analogue, 3,4-methylenedioxymethamphetamine (1992) ↩
Effect of 5-HT2A receptor antagonists on human platelet activation in blood exposed to physiologic stimuli and atherosclerotic plaque (2011) ↩
LY367265, an inhibitor of the 5-hydroxytryptamine transporter and 5-hydroxytryptamine(2A) receptor antagonist: a comparison with the antidepressant, nefazodone (2000) ↩
Functional subsensitivity of 5-HT2A and 5-HT2C receptors mediating hyperthermia following acute and chronic treatment with 5-HT2A/2C receptor antagonists (1997) ↩
[^12]: Acute effects of the very low carbohydrate diet on sleep indices (2008)