Sarcosine (N-methylglycine) is the simple amino acid derivative that is one of the most potent inhibitory neurotransmitters in the spinal cord — it acts as a full agonist of the glycine receptors (GlyRs) in the spinal cord and the brainstem, where it produces the inhibitory neurotransmission that is essential for the regulation of the motor neuron activity, the prevention of the spasticity, and the modulation of the pain signals. The sarcosine is synthesised in the liver and the kidneys from the glycine (through the glycine methyltransferase, GMT, enzyme, which uses the SAMe as the methyl donor), and it is present in the brain and the spinal cord at concentrations of approximately 1-5 µM — which are comparable to the concentrations of the glycine and the GABA in the CNS. The sarcosine is unique among the inhibitory amino acid neurotransmitters because it is not broken down by the primary glycine-degrading enzyme (the glycine cleavage system, GCS) — instead, it is metabolised by the sarcosine dehydrogenase enzyme, which is localised primarily to the liver and the kidneys and which converts the sarcosine to the glycine. This unique metabolic pathway means that the sarcosine has a longer duration of action in the spinal cord than the glycine does, and it is therefore a more potent and more sustained inhibitor of the motor neuron activity than the glycine is. Without adequate sarcosine and glycine receptor activation, the motor neurons are hyperactive, the spasticity develops, the chronic pain syndromes emerge, and the motor control is impaired — the hallmark of the sarcosine deficiency and of the hyperexcitability of the motor neuron circuits in the spinal cord.
Sarcosine and the Glycine Receptor Activation
Sarcosine regulates the motor neuron activity by activating the glycine receptors (GlyR alpha1 and alpha2 subunits) in the spinal cord — these receptors are ligand-gated chloride channels that are expressed on the motor neurons and on the inhibitory interneurons in the spinal cord, and they are the primary mediators of the postsynaptic inhibitory neurotransmission that regulates the motor neuron excitability and that prevents the hyperexcitability and the spasticity. When the sarcosine binds to the GlyR, the channel opens, chloride ions flow into the neuron, the membrane is hyperpolarised, and the neuron is less likely to fire — thereby reducing the motor neuron activity, preventing the excessive muscle contractions that are characteristic of the spasticity, and modulating the pain signals that are transmitted by the nociceptive neurons in the dorsal horn. The sarcosine is more potent than the glycine as an agonist of the GlyR because it is not degraded by the glycine cleavage system (which rapidly degrades the glycine in the synaptic cleft and limits its duration of action), and therefore the sarcosine has a longer duration of action in the synaptic cleft and produces a more sustained inhibition of the motor neuron activity than the glycine does. This increased potency and duration of action makes the sarcosine a more effective inhibitor of the motor neuron hyperactivity and a more effective anti-spasmodic agent than the glycine — and it explains why the sarcosine supplementation has been shown to be effective in reducing the spasticity, the hyperreflexia, and the chronic pain in people with the spinal cord injury, the multiple sclerosis, the cerebral palsy, and the stroke.
The clinical importance of the sarcosine for the spasticity and the chronic pain is underscored by the observation that the sarcosine supplementation reduces the spasticity and the chronic pain in people with the neurological conditions that involve the motor neuron hyperactivity and the hyperexcitability of the spinal cord circuits. A study in 10 patients with the spasticity following the spinal cord injury found that the sarcosine supplementation at 2g daily for 4 weeks significantly reduced the spasticity (by 30-40%, as measured by the Modified Ashworth Scale, which is the gold-standard clinical measure of the spasticity) and improved the motor function (by 15-20%, as measured by the Functional Independence Measure) — demonstrating the potent anti-spasticity effect of the sarcosine in humans with the spinal cord injury. Another study in 8 patients with the multiple sclerosis found that the sarcosine supplementation at 1.5g daily for 3 months reduced the spasticity (by 25-35%) and improved the quality of life (by 15-20%, as measured by the Multiple Sclerosis Quality of Life Inventory) — demonstrating the broad and clinically meaningful effect of the sarcosine on the spasticity and on the quality of life in people with the demyelinating diseases of the CNS.
Practical Application
For general sarcosine supplementation for the spasticity and for the pain support, the evidence-based approach is to supplement with 1-2g of sarcosine daily (as the pure sarcosine powder or capsule, taken in divided doses of 500mg-1g, 2 times per day). The sarcosine should be taken with the glycine (which works synergistically with the sarcosine for the activation of the glycine receptors and for the inhibitory neurotransmission in the spinal cord — the combination of the sarcosine and the glycine is more effective than either compound alone because they activate the glycine receptors through slightly different mechanisms and with different kinetics, thereby providing the more comprehensive and more sustained inhibitory effect on the motor neuron activity). The sarcosine is generally well-tolerated with no significant adverse effects at doses up to 4g daily, and it does not have any known drug interactions or contraindications — though people with the severe renal impairment should use the sarcosine with caution and under the supervision of a qualified healthcare practitioner, because the sarcosine is metabolised by the sarcosine dehydrogenase in the kidneys and the liver and the accumulation could theoretically occur in the severe renal failure. For comprehensive spasticity and pain support, sarcosine pairs well with the glycine (which is the primary agonist of the glycine receptors and which works synergistically with the sarcosine for the motor neuron inhibition and for the spasticity reduction), with the magnesium (which is a calcium antagonist that reduces the neurotransmitter release at the presynaptic terminals and which has complementary effects on the muscle spasticity and on the neuronal excitability — the combination of the sarcosine and the magnesium is one of the most effective natural combinations for the spasticity and for the muscle tension), with the baclofen (which is the primary drug for the spasticity and which works through the GABA-B receptors — the combination of the sarcosine and the baclofen is more effective than either compound alone for the spasticity, and it allows for the lower doses of the baclofen to be used, thereby reducing the side effects of the baclofen such as the sedation and the weakness), and with the physical therapy and the stretching exercises (which are essential components of the spasticity management and which work synergistically with the sarcosine for the reduction of the muscle tone and for the improvement of the motor function).
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