The title is not mine. i found a interesting post by sirsadalot on Reddit and thought i'd share since there isn't that much info abou d-serine on the forum.
In summary, this is what I know about its use in humans:
D-Serine also stimulates adult neurogenesis[31] in regions vulnerable despite spatial constraints.[43]
Experience: One should expect mild anti-anhedonic effects, a reduction in anxiety, improved attention and better recall. There may also be anti-addictive effects.
Dose: For a healthy person, a reasonable dose of D-Serine is 2-5g. For a Schizophrenic person, 5-9g. It has a half life of 4 hours. More about where to buy it at the bottom of this post.
The basics: In the context of neurotransmission, D-Serine serves to prime the NMDAR for activation. It does this through the NMDA glycine site, which could ironically be renamed the "D-Serine site", as there it functions as the dominant endogenous agonist.[13] Glycine and D-Serine together are called "co-agonists", as NMDA requires either D-Serine or glycine to fire when glutamate binds.
Binding to NMDAR causes either long term potentiation (LTP) or long term depression (LTD) which is the strengthening or weakening, respectively, of a synaptic connection. This is a downstream event essential to learning and memory.
D-Serine is synthesized by an enzyme called Serine Racemase, which converts L-Serine to D-Serine. This enzyme and process is also stimulated by magnesium.[54] More on the importance of magnesium in relation to D-Serine later.
L-Serine has many important biological functions: it secretes insulin, it is a building block for mRNA in the brain, and it is a rate-limited precursor to both glycine and cysteine, thus glutathione.[55] L-Serine also interacts with glycine receptors (which are different from the NMDA glycine site).[56]
Evolutionary role of D-Serine: Early in life, glycine is used as the primary co-agonist, but it quickly transitions to D-Serine with age.[13] Crosstalk between glycine and D-Serine "fine-tunes" the NMDAR,[19] and glycine inhibits D-Serine synthesis and release. Unlike glycine, D-Serine causes internalization of NR2B, and this catalyzes an important developmental process called the "synaptic shift".[11] The result is a synaptic reliance on NR2A, inducting electrical currents that are shorter and with higher amplitudes than those of NR2B. Genetic removal of D-Serine prevents the synaptic shift[22] and this results in strange social behavior,[23] reminiscent of Schizophrenic phenotypes. It can be assumed that the synaptic shift happens to promote societal congruence and more directional learning.
Furthermore, Schizophrenics quite literally have less D-Serine[24][25] and more glycine.[26] Schizophrenia is characterized by NMDA hypofunction, so it provides a lot of insight. A model of prenatal maternal infection presents cognitive deficits resembling Schizophrenia and this is reversed by D-Serine supplementation in young mice.[27] Thus, improper D-Serine remains a compelling theory in the pathogenesis of Schizophrenia. More on this later.
D-Serine has identical mechanisms at Ketamine in treating depression,[21] logically through releasing glutamate by preferentially internalizing NR2B[11] which then binds to AMPA to stimulate BDNF. This triggers adult neurogenesis.[31] D-Serine in other contexts, normally released by AMPA activation,[28] also appears to inhibit AMPA currents,[29] probably as negative feedback. So there appears to be a complicated relationship, with exogenous D-Serine administration leaning towards a positive feedback loop with AMPARs, but naturally co-existing with bioregulatory responses.
As for Social Anxiety, the role of D-Serine in promoting social memorization could have a similar effect. PQQ was shown to improve this in combination with D-Serine by enhancing its binding.[33] D-Serine also protects from chronic social defeat stress, which is known to induce depression and anxiety in rat models.[34] Since exposure therapy is a tactic in resolving Social Anxiety, it makes sense that D-Serine could help in practice.
D-Serine's efficiacy as an antidepressant is shown both acutely and chronically when supplied exogenously. It is still undergoing trials for depression, but was shown to reduce sadness in one human study.[1]
Modern-day exposure to addiction is a huge problem: social media, drugs, porn and the like. So ideally D-Serine could help reduce addictive tendencies while promoting mental health.
D-Serine also promoted spatial reversal learning in a rat model where the authors concluded it may help cognitive flexibility and regulate sanity.[53]
If Sarcosine increases glycine, and glycine inhibits D-Serine, then perhaps that could have some unforeseen consequences.
It would be particularly interesting alongside Piracetam, an AMPA positive allosteric modulator that was also shown to improve ADHD.[52]
Glutamate stereotypes: A public misconception is that glutamatergic drugs result in the enhancement of addiction, depression, anxiety, seizures, etc. although this is largely untrue and depends on the circumstance. The antidepressant effects of ketamine for instance are dependent on NR2B[44] and the positives of many NMDA antagonists can be attributed to just shifting the flow of glutamate. As proven above, D-Serine is anxiolytic and antidepressant. Synaptic NMDARs are neuroprotective and neuroplasticity-inducing, whereas extrasynaptic NMDARs are the opposite.[42]
Excitotoxicity: D-Serine is primes all NMDAR for activation, making it necessary for excitotoxicity, via extrasynaptic NMDARs.[14] This is a greater concern during endogenous processes than supplementation, as it may be released locally in toxic amounts by beta amyloids.[45] NMDAR hypofunction is equally as toxic, and D-Serine in reasonable amounts is actually neuroprotective meaning there is a threshold.[57] However it is my personal opinion that D-Serine should be consumed alongside Magnesium L-Threonate (Magtein), as L-Threonate reliably enhances magnesium influx through the blood brain barrier[36] which primarily inhibits extrasynaptic NMDA receptors through increased extracellular magnesium, and would target the problem at its source to offer protection as well enhance learning further.[37] Furthermore it appears the antidepressant mechanisms of magnesium are blocked by exogenous D-Serine administration[38], bolstering the argument that they are in direct competition at that site, thus supporting a need for supraphysiological levels of magnesium in the brain.
Seizures and epilepsy: There appears to be conflicting evidence about D-Serine's role in epilepsy, one source stating it contributes to the pathogenesis of the condition[47] while others claim it can delay the condition, prevent seizures and mitigate cell damage[48] as well as improving cognition in epilepsy.[49] Neither stance is supported with hard human evidence, and so it may be best to avoid D-Serine if you have epilepsy. Although it shows promise.
Insulin resistance and oxidative stress: D-Serine has a controversial role in the secretion of insulin. The main study demonstrating insulin resistance used high, and clinically irrelevant doses, and some studies show opposite effects.[10] It was also shown to have a negative effect on oxidative stress and mRNA formation.[35][40] These concerns are warranted as something similar was found in D-Phenylalanine, but completely reversed by an equal dose of L-Phenylalanine.[39] There was not a conclusion explaining this outcome, but it is logical that D- isomers biologically compete with L- isomers. As described earlier, L-Serine is an insulin secretagogue, important for mRNA formation, and reduces oxidative stress. Therefore it makes complete sense that a high dose of D-Serine would induce opposite results. For long term users of D-Serine, it is advisable to take it alongside L-Serine and Magtein. L-Serine is also a precursor to D-Serine in the brain, however this effect is mainly seen with long-term chronic use.[50]
Note: L-Serine may be sedating. A 2:1 ratio of D/L-Serine may be more desirable for daytime users.
Kidney toxicity: The biggest concern expressed in literature, is the possibility of neprotoxicity. But more recent work suggests it is well tolerated even up to over 8 grams per day, with room to spare.[10] So with that being said, I agree with authors suggesting it was a miscalculation pertaining to more sensitive rat species, that projected less dose lenience. The mechanism is suspected to be due to D-Amino Acid Oxidase (DAAO), which oxidizes D-amino acids to corresponding α-keto acids, generating oxidative stress in the process. Inhibiting this enzyme has therefore been a promising avenue for many drugs, given that it should also increase circulatory D-Serine by inhibiting its breakdown and has been suggested to be used in concert with D-Serine. Sodium Benzoate, DAAO inhibitor, has also been a surprisingly successful treatment for Schizophrenia despite its extreme inefficiency due to its short half life.[41]
References:
D-Serine: The holy grail of cognitive enhancers?
Introduction to D-Serine
How can one drug help everyone? We constantly hear about people's different experiences, but at the end of the day we all learn in the same way. And this is why I've been fascinated by D-Serine for the past few months. In this post I hope to explore D-Serine in its entirety, from the human trials down to the mechanistic workings in the brain, as I believe this is something that could truly help a wide variety of people.In summary, this is what I know about its use in humans:
- Nootropic effect of D-Serine in young, healthy people: Reduces sadness and anxiety. Improves attention, learning performance and information retention.[1]
- Nootropic effect of D-Serine in old, healthy people: Improves spatial memory, learning and problem solving. Didn't change mood.[17]
- Outlier to the two studies above: Surprisingly, D-Serine failed to improve cognition in different tests that were emotionally charged, suggesting its nootropic effect may not be universally applicable.[18]
- D-Serine benefits in PTSD: Improves anxiety, depression and general PTSD symptoms.[15]
- D-Serine benefits in Parkinson's: Significantly improves symptoms in parkinson's patients.[16]
- D-Serine benefits in Schizophrenia: Significantly improves Positive, Negative and cognitive symptoms of Schizophrenia. Meta analysis.[8]
D-Serine as a supplement
When taken orally, D-Serine can be used to enhance learning. It seems widely applicable, capable of not only enhancing cognition in healthy people, but those with serious disorders as well. D-Serine has the stereotypical benefits of both NMDA antagonists and glutamatergic drugs.D-Serine also stimulates adult neurogenesis[31] in regions vulnerable despite spatial constraints.[43]
Experience: One should expect mild anti-anhedonic effects, a reduction in anxiety, improved attention and better recall. There may also be anti-addictive effects.
Dose: For a healthy person, a reasonable dose of D-Serine is 2-5g. For a Schizophrenic person, 5-9g. It has a half life of 4 hours. More about where to buy it at the bottom of this post.
D-Serine as a neurotransmitter
Note: I tried my best to separate the information by topic, as I know it's a lot. Sorry if it's hard to maneuver.The basics: In the context of neurotransmission, D-Serine serves to prime the NMDAR for activation. It does this through the NMDA glycine site, which could ironically be renamed the "D-Serine site", as there it functions as the dominant endogenous agonist.[13] Glycine and D-Serine together are called "co-agonists", as NMDA requires either D-Serine or glycine to fire when glutamate binds.
Binding to NMDAR causes either long term potentiation (LTP) or long term depression (LTD) which is the strengthening or weakening, respectively, of a synaptic connection. This is a downstream event essential to learning and memory.
D-Serine is synthesized by an enzyme called Serine Racemase, which converts L-Serine to D-Serine. This enzyme and process is also stimulated by magnesium.[54] More on the importance of magnesium in relation to D-Serine later.
L-Serine has many important biological functions: it secretes insulin, it is a building block for mRNA in the brain, and it is a rate-limited precursor to both glycine and cysteine, thus glutathione.[55] L-Serine also interacts with glycine receptors (which are different from the NMDA glycine site).[56]
Evolutionary role of D-Serine: Early in life, glycine is used as the primary co-agonist, but it quickly transitions to D-Serine with age.[13] Crosstalk between glycine and D-Serine "fine-tunes" the NMDAR,[19] and glycine inhibits D-Serine synthesis and release. Unlike glycine, D-Serine causes internalization of NR2B, and this catalyzes an important developmental process called the "synaptic shift".[11] The result is a synaptic reliance on NR2A, inducting electrical currents that are shorter and with higher amplitudes than those of NR2B. Genetic removal of D-Serine prevents the synaptic shift[22] and this results in strange social behavior,[23] reminiscent of Schizophrenic phenotypes. It can be assumed that the synaptic shift happens to promote societal congruence and more directional learning.
Furthermore, Schizophrenics quite literally have less D-Serine[24][25] and more glycine.[26] Schizophrenia is characterized by NMDA hypofunction, so it provides a lot of insight. A model of prenatal maternal infection presents cognitive deficits resembling Schizophrenia and this is reversed by D-Serine supplementation in young mice.[27] Thus, improper D-Serine remains a compelling theory in the pathogenesis of Schizophrenia. More on this later.
D-Serine has identical mechanisms at Ketamine in treating depression,[21] logically through releasing glutamate by preferentially internalizing NR2B[11] which then binds to AMPA to stimulate BDNF. This triggers adult neurogenesis.[31] D-Serine in other contexts, normally released by AMPA activation,[28] also appears to inhibit AMPA currents,[29] probably as negative feedback. So there appears to be a complicated relationship, with exogenous D-Serine administration leaning towards a positive feedback loop with AMPARs, but naturally co-existing with bioregulatory responses.
Generalized Anxiety, Social Anxiety and PTSD
Since D-Serine is so capable of enhancing learning, it can facilitate a phenomena called "fear extinction".[32] Basically, anxiety can be looked at as a learning disorder, in where the victim is unable to draw a non-threatening association to new circumstances. By extension, PTSD would be a severe example of this. That is why D-Serine was trialed for PTSD, where it was shown to help, albeit a pilot study.[15] In healthy individuals, reduced anxiety was also noted,[1] so this adds to the large body of evidence that D-Serine is an anxiolytic drug, both chronically and acutely.As for Social Anxiety, the role of D-Serine in promoting social memorization could have a similar effect. PQQ was shown to improve this in combination with D-Serine by enhancing its binding.[33] D-Serine also protects from chronic social defeat stress, which is known to induce depression and anxiety in rat models.[34] Since exposure therapy is a tactic in resolving Social Anxiety, it makes sense that D-Serine could help in practice.
Depression
Like other disorders, depression can be looked at as a learning impairment. And ironically, this is how NMDA antagonists help. D-Serine has identical mechanisms to ketamine in this regard,[21] and this can be summarized by synaptic changes and increased BDNF in the hippocampus, decreased BDNF in the nucleus accumbens.[34] Increased dendritic growth in the nucleus accumbens is a well known complication in depression[46] as well as addiction.D-Serine's efficiacy as an antidepressant is shown both acutely and chronically when supplied exogenously. It is still undergoing trials for depression, but was shown to reduce sadness in one human study.[1]
Self control and behavioral effects
D-Serine has anti-addictive effects demonstrated in rat models with cocaine[2], alcohol[3] and morphine.[4] Further promise is shown in the context of obesity, where it ameliorated preference towards unbalanced diets[5] and FUST where it prevented anhedonia-driven sex seeking.[20] Perhaps it does this by triggering learning where it would normally be dampened or absent due to bias.Modern-day exposure to addiction is a huge problem: social media, drugs, porn and the like. So ideally D-Serine could help reduce addictive tendencies while promoting mental health.
D-Serine also promoted spatial reversal learning in a rat model where the authors concluded it may help cognitive flexibility and regulate sanity.[53]
Schizophrenia and the Sarcosine debate
There have been doubts about its efficiacy in comparison to Sarcosine by one Taiwanese researchers[6][7], but the strongest form of evidence, a meta-analysis, does not reciprocate this,[8] and Sarcosine sometimes fails when used alone.[12] And strangely, Sarcosine is incorrectly given credit for D-Serine's success on the Serine wikipedia.[9] There is, however, something greatly overlooked here, and that is dose. More recent evidence suggests that D-Serine is both safe and more effective at higher doses (~8g vs. common 2g).[10] D-Serine is anything but a failed drug, which is why there are so many on-going strategies to increase this neurotransmitter and a few trials underway still. The rumors claiming Sarcosine to be a superior drug are false.If Sarcosine increases glycine, and glycine inhibits D-Serine, then perhaps that could have some unforeseen consequences.
D-Serine... Useful for ADHD?
In my research I was extremely surprised to see no trials for ADHD, even in rodents. NMDA dysfunction has been proposed for ADHD, even with the glycine site being named as a potential target.[51] Attention was shown to be improved in healthy people as well.[1]It would be particularly interesting alongside Piracetam, an AMPA positive allosteric modulator that was also shown to improve ADHD.[52]
Side effects, toxicity and safety
Safety: Human trials indicate that D-Serine is not only very safe, but well tolerated at high doses. Read. But a large portion of this post will be dedicated to exploring the safety of D-Serine consumption long-term, as it is a necessary measure to ensure health.Glutamate stereotypes: A public misconception is that glutamatergic drugs result in the enhancement of addiction, depression, anxiety, seizures, etc. although this is largely untrue and depends on the circumstance. The antidepressant effects of ketamine for instance are dependent on NR2B[44] and the positives of many NMDA antagonists can be attributed to just shifting the flow of glutamate. As proven above, D-Serine is anxiolytic and antidepressant. Synaptic NMDARs are neuroprotective and neuroplasticity-inducing, whereas extrasynaptic NMDARs are the opposite.[42]
Excitotoxicity: D-Serine is primes all NMDAR for activation, making it necessary for excitotoxicity, via extrasynaptic NMDARs.[14] This is a greater concern during endogenous processes than supplementation, as it may be released locally in toxic amounts by beta amyloids.[45] NMDAR hypofunction is equally as toxic, and D-Serine in reasonable amounts is actually neuroprotective meaning there is a threshold.[57] However it is my personal opinion that D-Serine should be consumed alongside Magnesium L-Threonate (Magtein), as L-Threonate reliably enhances magnesium influx through the blood brain barrier[36] which primarily inhibits extrasynaptic NMDA receptors through increased extracellular magnesium, and would target the problem at its source to offer protection as well enhance learning further.[37] Furthermore it appears the antidepressant mechanisms of magnesium are blocked by exogenous D-Serine administration[38], bolstering the argument that they are in direct competition at that site, thus supporting a need for supraphysiological levels of magnesium in the brain.
Seizures and epilepsy: There appears to be conflicting evidence about D-Serine's role in epilepsy, one source stating it contributes to the pathogenesis of the condition[47] while others claim it can delay the condition, prevent seizures and mitigate cell damage[48] as well as improving cognition in epilepsy.[49] Neither stance is supported with hard human evidence, and so it may be best to avoid D-Serine if you have epilepsy. Although it shows promise.
Insulin resistance and oxidative stress: D-Serine has a controversial role in the secretion of insulin. The main study demonstrating insulin resistance used high, and clinically irrelevant doses, and some studies show opposite effects.[10] It was also shown to have a negative effect on oxidative stress and mRNA formation.[35][40] These concerns are warranted as something similar was found in D-Phenylalanine, but completely reversed by an equal dose of L-Phenylalanine.[39] There was not a conclusion explaining this outcome, but it is logical that D- isomers biologically compete with L- isomers. As described earlier, L-Serine is an insulin secretagogue, important for mRNA formation, and reduces oxidative stress. Therefore it makes complete sense that a high dose of D-Serine would induce opposite results. For long term users of D-Serine, it is advisable to take it alongside L-Serine and Magtein. L-Serine is also a precursor to D-Serine in the brain, however this effect is mainly seen with long-term chronic use.[50]
Note: L-Serine may be sedating. A 2:1 ratio of D/L-Serine may be more desirable for daytime users.
Kidney toxicity: The biggest concern expressed in literature, is the possibility of neprotoxicity. But more recent work suggests it is well tolerated even up to over 8 grams per day, with room to spare.[10] So with that being said, I agree with authors suggesting it was a miscalculation pertaining to more sensitive rat species, that projected less dose lenience. The mechanism is suspected to be due to D-Amino Acid Oxidase (DAAO), which oxidizes D-amino acids to corresponding α-keto acids, generating oxidative stress in the process. Inhibiting this enzyme has therefore been a promising avenue for many drugs, given that it should also increase circulatory D-Serine by inhibiting its breakdown and has been suggested to be used in concert with D-Serine. Sodium Benzoate, DAAO inhibitor, has also been a surprisingly successful treatment for Schizophrenia despite its extreme inefficiency due to its short half life.[41]
Conclusion
D-Serine is a safe, broadly applicable over the counter supplement that can be used concurrently with Magtein, L-Serine and/ or Piracetam to improve cognition in the general populace as well as treat various disorders.References:
- D-Serine enhances cognition, mood and reduces anxiety in young, healthy people
- D-Serine facilitates the effects of extinction to reduce cocaine-primed reinstatement of drug-seeking behavior in rats
- D-Serine and D-Cycloserine reduce compulsive alcohol intake in rats
- Administration of exogenous D-Serine in rats has an anti-addictive effect in rats given morphine
- D-Serine ameliorates preference for a high-fat, high-carb and high-protein diet, but not for normal chow in mice
- Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia
- Comparison study of sarcosine and D-serine add-on treatment for schizophrenia
- Meta-analysis among NMDAR modulators for Schizophrenia
- Serine Wikipedia
- D-Serine: A Cross Species Review of Safety
- Co-agonists differentially tune GluN2B-NMDA receptor trafficking at hippocampal synapses
- Adjunctive sarcosine plus benzoate improved cognitive function in chronic schizophrenia patients with constant clinical symptoms
- Postsynaptic Serine Racemase Regulates NMDA Receptor Function
- D-Serine Is the Dominant Endogenous Coagonist for NMDA Receptor Neurotoxicity in Organotypic Hippocampal Slices
- Pilot controlled trial of D-serine for the treatment of post-traumatic stress disorder
- D-Serine in Neuropsychiatric Disorders: New Advances
- The effect of D-serine administration on cognition and mood in older adults
- A single administration of ‘microbial’ D-alanine to healthy volunteers augments reaction to negative emotions: A comparison with D-serine
- Glycine and D-Serine crosstalk
- Acute D-serine treatment produces antidepressant-like effects in rodents
- Acute Amino Acid d-Serine Administration, Similar to Ketamine, Produces Antidepressant-like Effects through Identical Mechanisms
- Genetic removal of D-Serine, different from enzyme removal
- Social deficits in SR KO mice
- Decreased blood D-Serine in Schizophrenia
- Schizophrenia D-Serine parameters
- Increased blood Glycine in Schizophrenia
- Prenatal maternal infection cognitive deficits reversed by D-Serine
- The Gliotransmitter d-Serine Promotes Synapse Maturation and Axonal Stabilization In Vivo
- D-Serine inhibits AMPA currents
- Potential and Challenges for the Clinical Use of D-Serine As a Cognitive Enhancer
- D-Serine enhances adult neurogenesis
- D-Serine and fear extinction
- PQQ enhances D-Serine binding
- D-Serine produces antidepressant-like effects in mice through suppression of BDNF signaling pathway and regulation of synaptic adaptations in the nucleus accumbens
- D-Serine induces oxidative stress
- L-Threonate enhances BBB transport of Magnesium
- Neuroprotective mechanism of Magnesium
- D-serine, a selective glycine/NMDA receptor agonist, antagonizes the antidepressant-like effects of magnesium and zinc in mice
- Competition between D- and L- isomers
- Genetic evidence of D-Serine toxicity
- Add-on Treatment of Benzoate for Schizophrenia
- Extrasynaptic vs. synaptic NMDARs CREB/ cell death
- The adult neurogenesis debate
- NR2B required for ketamine antidepressant effect
- Beta amyloids release D-Serine
- Dendritic growth in the nucleus accumbens
- D-Serine contributing to the pathogenesis of epilepsy
- D-Serine neuroprotective role in epilepsy
- D-Serine pro-cognitive role in epilepsy
- Chronic L-Serine increases brain D-Serine
- Glycine site potentially useful for ADHD
- Piracetam and ADHD
- D-serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning
- Magnesium and calcium stimulates the activity of Serine Racemase
- L-Serine as an antioxidant and precursor
- L-Serine as a glycine receptor agonist
- D-Serine toxic in excess, neuroprotective in reasonable amount.
