glycine

Sleep quality naturally declines during aging. For example, sleep duration and sleep consolidation both deteriorate as we age. (Less consolidated sleep is more fragmented, with shorter mean sleep bout duration). Moreover, impaired sleep quality is a sensitive prodromal sign of future cognitive decline and Alzheimer’s disease (AD).

Improving sleep quality often translates to improved mood, enhanced cognitive function, and general well-being. We’ve cataloged ten of the most relevant ways to improve sleep quality. The first few tips apply more to healthy subjects; the latter suggestions are aimed at individuals struggling with clinically significant insomnia.

Circadian rhythm is coupled to light cues from the environment. Individuals who sleep in an environment that is not dark enough will have a blunted circadian rhythm (e.g., impaired expression of the proteins that regulate sleep/wake oscillations). To maximize sleep quality, use black electrical tape to cover all light sources (e.g., blinking electronics).

This tip is an extension of the previous one. Download the f.lux app, which calibrates the wavelength of the light emitted by your laptop screen (or monitor) according to the time of day.Screens normally emit high-energy/low wavelength blue light which interferes with the biological block. With flux activated, at night your laptop will emit warm, red/orange light (like a sunset), which is less likely to cause the “circadian rhythm phase delay” that impairs sleep onset.

Turn the thermostat down at night to slightly chilly temperatures. Internal body temperature drops to a trough at around 4 AM. Low temperatures at night are considered an environmental cue that entrains the biological clock and helps facilitate sleep initiation.

Vigorous exercise before bed has been consistently noted to improve sleep quality.

Practice good sleep hygiene by going to bed and waking up at the same time. Humans are creatures of habit, and following a regular schedule can help synchronize your body clock. Limit stimulating activities in the evening. For years, I played computer games until 2 am right before going to bed. Suffice it to say, I had vivid dreams and sleep quality was not ideal.

Nutraceuticals that show promise in alleviating (mild) insomnia
- Magnesium (bioavailable such as glycinate, aspartate or taurate are recommended)
- Melatonin (low doses, e.g. <1 mg are paradoxically more effective than higher doses)
- Glycine (an inhibitory neurotransmitter and co-agonist at NMDA receptors)
- L-Theanine
- Herbal tea with lemon balm, passionflower, and chamomile

If you have clinically significant insomnia, do not be deterred from using prescription drugs to manage your symptoms. Long-term sleep loss is extremely taxing on the body and mental health. Often primary insomnia will not respond to tips #1-6. It is tempting to dismiss patients with clinically significant insomnia with soft-core interventions like “get more exercise” but that just won’t cut it for this patient population.

Unfortunately, when it comes to sleep aids, there is an inverse relationship between long-term safety and efficacy. The most effective sleep aids are more likely to adversely affect brain health. This cost/benefits analysis and the trade-offs of different medications should be weighed by your clinician. When shopping for sleep aids, start with the safest, most suitable agents for long-term use:
- Ramelteon (Rozarem)
- Suvorexant (Belsomra)
- Trazodone (Desyrel)
- Mirtazapine (Remeron)
- Hydroxyzine (this antihistamine has a long half-life but has negligible anticholinergic activity)
- Other antihistamines and sedatives
Higher-risk options:
- Phenibut
- Z-drugs (e.g., Ambien)
- Benzodiazepines (e.g., Xanax)
- Ibutamoren (aka MK-677)

Resolve/treat contributory diseases. The most important disorders that can exacerbate sleep disorders are:
- Sleep apnea
- Hyperthyroidism/hypothyroidism
- Disorders of hyperarousal (Anxiety disorders, PTSD, depression)
- ADHD
- Restless leg syndrome
- Delayed sleep phase syndrome/other circadian rhythm disorder

Sometimes, chronic insomnia develops from a self-reinforcing psychological process. Let’s say a major life event disrupts your sleep and mood for a short period of time. Many people will recover the lost sleep quality, but some people will begin to obsess about their inability to get a proper night’s rest. This results in a positive feedback loop where as you become more worried about fixing your broken sleep, your sleep quality deteriorates further.Panic disorders often arise from a similar process, where the object of your anxiety is the anxiety itself. For example, you might be concerned that heightened anxiety will cause a heart attack (because your heart is palpitating), which adds more fuel to the fire, culminating in a full-blown panic. Harvard has devised some behavioral interventions that can be helpful for this kind of self-perpetuating neurotic sleep disorder. They suggest taking a sabbatical from work (if you can afford it), and instead of trying to go to bed, trying to stay up as long as possible. Chronically restricting the total amount of time in bed may be one of the most robust behavioral interventions for treating sleep-onset insomnia.

A promising sleep enhancement strategy worth mentioning is the pharmacologic augmentation of slow-wave-sleep (SWS) using selective 5-HT2A antagonists.

Sarcosine and D-Serine are two endogenous substances that are currently being researched for a number of conditions. Although these substances have many interesting properties and may be effective add-on treatments to disorders such as depression and schizophrenia, they are too nonspecific to work effectively as a standalone, and should never be used in place of a doctor’s recommendation. That being said, there is some promising evidence for a nootropic, antidepressant and antipsychotic effect.

D-serine vs L-serine

This article includes references from studies using both enantiomers of serine. The two may have somewhat similar effects since L-serine is converted to D-serine by serine racemase, an enzyme that requires vitamin B6 to function. It is thus important to supplement vitamin B6 when supplementing L-serine.

Studies involving both forms of serine clearly demonstrate its interesting scope of effect. That being said, L-serine may be less effective since it requires an extra step before it can be used by the body.

Mood and Depression

D-serine produces both acute^[1] and chronic^[2] antidepressant effects in animal models. Chronic use was also reported to lower markers of anxiety. Studies have also shown that it may prevent cognitive impairment in subjects exposed to stressful situations^[3] (like a job interview) but not in normal day-to-day situations. D-serine, therefore, does not strictly meet the definition of a nootropic. It is, however, ubiquitous in the body, and with many interesting effects in promoting cerebral health, certainly a worthy supplement.

Sarcosine was the star of a landmark 2013 study, which underpinned a role of the Glycine transporter 1 (GlyT1) in depression^[4]. The antidepressant effect of sarcosine and other GlyT1 inhibitors may be related to the increased levels of glycine, an inhibitory neurotransmitter that seems to have an anti-stress effect. The study found sarcosine monotherapy to be superior to the SSRI citalopram (Celexa) in remitting depression, with rapid onset of action and few side-effects.^[5] The role of glycine in mental disorder may be much larger than originally thought.

As expected, users have reported varying levels of effectiveness from sarcosine as an antidepressant, with some drawing a comparison between ketamine or citalopram, while others have not noticed a significant effect. The research has suggested a strong general effect, which may still nevertheless depend on the individual.

Schizophrenia and Psychosis

The glutamate system is the largest excitatory system in the brain and it commands functions across every region, so one would expect sarcosine to be useful in depression, memory loss, or interestingly, psychotic disorders. The glycine transporter’s influence over NMDA receptors (which are essential for memory and learning) may also explain why sarcosine makes a useful adjunctive therapy to antipsychotics. It’s all to do with the involvement of NMDA and glutamate in schizophrenia:

… the hypofunction hypothesis of glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors in the pathophysiology of schizophrenia suggests that increasing NMDA receptor function via pharmacological manipulation could provide a new therapeutic strategy for schizophrenia. The glycine modulatory site on NMDA receptor complex is the one of the most attractive therapeutic targets for schizophrenia. […] Some clinical studies have demonstrated that the GlyT-1 inhibitor sarcosine (N-methylglycine) shows antipsychotic activity in patients with schizophrenia. Currently, a number of pharmaceutical companies have been developing novel and selective GlyT-1 inhibitors for the treatment of schizophrenia..

Because of the diverse actions of the glycine transporter and its involvement in other neurotransmitter systems, sarcosine has also been found to modulate striatal dopamine release. This may help further explain its antipsychotic properties.

While it may not be terribly effective on its own, used in conjunction with pharmaceuticals, sarcosine can deliver a real knockout blow^[6], conveniently complimenting pharmaceuticals in treating both negative and positive symptoms. This is particularly remarkable because most pharmaceuticals were developed to address only positive symptoms; there has been a race to find more effective treatments for the negative symptoms, which have often come in the form of over-the-counter supplements, exercise programs, and specific diets.

Sarcosine and N-acetylcysteine were both found to restore glutamate activity in mGluR5 knockout mice^[7] Low activity of this receptor may be related to schizophrenia. Interestingly, positive allosteric modulators of mGluR5 may have nootropic properties. ^[8]

Sarcosine is known to have potential in Parkinson’s^[9] and other dopamine dysfunction disorders, such as ADHD.^[10] Sarcosine and its metabolite glycine modulate dopamine in the striatum^[11], which includes the hippocampus.

Another study^[12] has confirmed as helpful the addition of sarcosine to antipsychotic therapy, concluding it increases survival of neurons and glial cells in the dorsolateral prefrontal cortex (a key structure damaged by aging and drug abuse, it is involved in executive functions, such as working memory, cognitive flexibility, planning, inhibition, and abstract reasoning). Sarcosine may soon become a popular supplement in the psychiatric industry.

Summary

Even though they are far from being popular nootropic supplements, D-Serine and Sarcosine are two fascinating compounds.

If you are being medicated for schizophrenia or depression, you should definitely consider supplementing one of these two compounds to augment your psychiatric medication. Sarcosine, in particular, is very inexpensive and has a lot of evidence backing up its use. ^[13] ^[14]

Nootropic users who have tried Sarcosine report improvements in focus, motivation^[15] and visual acuity^[16], and there is some evidence that it may help those living with ADHD.^[17]

References [ + ]

1.	↑	Acute D-serine treatment produces antidepressant-like effects in rodents. (2012)
2.	↑	Effects of Chronic D-Serine Elevation on Animal Models of Depression and Anxiety-Related Behavior. (2013)
3.	↑	D-serine prevents cognitive deficits induced by acute stress. (2014)
4.	↑	Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression. (2013)
5.	↑	Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression. (2013)
6.	↑	Adding Sarcosine to Antipsychotic Treatment in Patients with Stable Schizophrenia Changes the Concentrations of Neuronal and Glial Metabolites in the Left Dorsolateral Prefrontal Cortex. (2015)
7.	↑	The glutamatergic compounds sarcosine and N-acetylcysteine ameliorate prepulse inhibition deficits in metabotropic glutamate 5 receptor knockout mice. (2010)
8.	↑	mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning (2009)
9.	↑	Activation of N-methyl-D-aspartate receptor glycine site temporally ameliorates neuropsychiatric symptoms of Parkinson’s disease with dementia. (2014)
10, 17.	↑	Sarcosine treatment for oppositional defiant disorder symptoms of attention deficit hyperactivity disorder children. (2016)
11.	↑	Modulation of striatal dopamine release by glycine transport inhibitors. (2005)
12.	↑	Glycine transporter inhibitor sarcosine changes neuronal and glial parameters in the left dorsolateral prefrontal cortex and glutamatergic parameters in the left hippocampus in stable schizophrenia (2016)
13.	↑	Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study. (2005)
14.	↑	A randomized, double-blind, placebo-controlled comparison study of sarcosine (N-methylglycine) and D-serine add-on treatment for schizophrenia. (2010)
15.	↑	Sarcosine – The Model NMDA-Receptor Co-Agonist – Brain Health – LONGECITY
16.	↑	Sarcosine – The Model NMDA-Receptor Co-Agonist – Brain Health – LONGECITY