GABA, beta-alanine, carnosine, homocarnosine and gabapentin

In researching the previous blog post Changing the threshold for neuromuscular fatigue in the young and old, carnosine or beta-alanine supplementation, I discovered a fascinating set of relationships among the substances mentioned in the title of this post and promised to report further on them.  I do that here, requiring a review of some of the basic biochemistry involved.  Although I am not clear of all the implications involved, I flag a few of these in the areas of pain management, synapse development and learning, maintaining mental balance, sleep and mental acuity.   


GABA (gamma-Aminobutyric acid) “is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system. In humans, GABA is also directly responsible for the regulation of muscle tone.[1] (ref)”  The operation of GABA is complex.  In vertebrates, GABA acts at inhibitory synapses in the brain by binding to specific transmembrane receptors in the plasma membrane of both pre- and postsynaptic neuronal processes. This binding causes the opening of ion channels to allow the flow of either negatively charged chloride ions into the cell or positively charged potassium ions out of the cell. This action results in a negative change in the transmembrane potential, usually causing hyperpolarization. Two general classes of GABA receptor are known: GABAA in which the receptor is part of a ligand-gated ion channel complex, and GABAB metabotropic receptors, which are G protein-coupled receptors that open or close ion channels via intermediaries (G proteins).  GABAA receptors are chloride channels, that is, when activated by GABA, they allow the flow of chloride ions across the membrane of the cell (ref).” “GABAB receptors (GABABR) are metabotropic transmembrane receptors for gamma-aminobutyric acid (GABA) that are linked via G-proteins to potassium channels.[1] These receptors are found in the central and peripheral autonomic nervous system[2](ref). 

Carnosine, homocarnosine, anserine and beta-alanine

Carnosine and homocarnosine are closely related dipeptide substances, both found in substantial quantities in the mammalian brain and muscles, and they are similar also to anserine found in bird muscles and brains as well as humans.  L-Carnosine is a dipeptide composed of the two amino acids L-histidine and beta-alanine.  And Homocarnosine is a dipeptide composed of the amino acids L-histidine and GABA.  The chemical structures of the two substances are remarkably similar; you can see them diagrammed here.  (Unfortunately, the way this blog software is set up it is hard for me to include diagrams here).  This little article L-Carnosine and Related Histamine-Derived Molecules comments further on the three substances. “Carnosine and homocarnosine are both produced by the same ATP-driven enzyme, carnosine synthetase, and both molecules exhibit very similar properties. The concentration of homocarnosine in the human brain, however, is about 100 times that of carnosine. It is manufactured by glial cells (oligodendrocytes) except in the olfactory bulb, where it is synthesized by neurons. The highest brain homocarnosine concentrations are found in the substantia nigra, dentate gyrus and olfactory bulb as well as in the cerebrospinal fluid.”

So, going back to the discussion of the previous blog entry, Changing the threshold for neuromuscular fatigue in the young and old, carnosine or beta-alanine supplementation, chemically, beta-alanine is one of the dipeptide components of l-carnosine, the wonderful stuff discussed in the blog entry The curious case of l-carnosine.  Homocarnosine, on the other hand, molecularly substitutes GABA for beta-alanine. 

The three dipeptides Carnosine, homocarnosine, and anserine, have a number of biological properties in common.  All appear to be antioxidants(ref).  All three are protective against peroxyl radical-mediated Cu,Zn-superoxide dismutase modification(ref).  Both carnosine and homocarnosine can detoxify the highly reactive aldehyde acrolein(ref).  Of particular note, all three are inhibitors of GABA metabolism.  That is, they lead to higher levels of GABA in the brain.  This was pointed out in a 1978 publication Homocarnosine, carnosine and anserine on uptake and metabolism of GABA in different subcellular fractions of rat brain.  “L-Carnosine, L-homocarnosine and L-anserine are inhibitors of GABA metabolism. They show differential action on GABA-transaminase from synaptosomes compared to the extrasynaptosomal enzyme.” A 2004 publication also identifies beta-alanine as a GABA uptake inhibitor. 

Much of the research literature on these substances was published prior to 2000. The more-recent literature has since been scanty and scattered as indicated in the 2005 title Carnosine and homocarnosine, the forgotten, enigmatic peptides of the brain 

Carnosine and homocarnosine are degraded in the body by carnosinase, “An enzyme that hydrolyzes carnosine (amino-acyl-l-histidine) and other dipeptides containing l-histidine into their constituent amino acids(ref).”  Activity of carnosinase tends to increase with age, leading to lower levels of carnosine in older people, however a very recent publication suggests that the presence of homocarnosine tends to inhibit the degradation of carnosine by carnosinase.  Activity of carnosinase (CN1), the only dipeptidase with substrate specificity for carnosine or homocarnosine, varies greatly between individuals but increases clearly and significantly with age. — Further, CN1 activity was dose dependently inhibited by homocarnosine. — Homocarnosine inhibits carnosine degradation and high homocarnosine concentrations in cerebrospinal fluid (CSF) may explain the lower carnosine degradation in CSF compared to serum. Because CN1 is implicated in the susceptibility for diabetic nephropathy (DN), our findings may have clinical implications for the treatment of diabetic patients with a high risk to develop DN. Homocarnosine treatment can be expected to reduce CN1 activity toward carnosine, resulting in higher carnosine levels.”

Further background information on carnosine, homocarnosine, anserine and other related nerve and muscle histidine can be found in the online monograph Carnosine and Oxidative Stress in Cells and Tissues. This monograph also describes several pathways through which these substances can be created as metabolic products of each other.

A few of the key points for the purpose of this discussion are:

·        While carnosine can play key health and longevity-supporting roles, it or beta-alanine are far from the only games in town.  Carnosine acts in synergy with homocarnosine and its levels are controlled by carnosinase. 

·        Although exogenous supplementation is possible with one or several of these dipeptides, they are created and broken down in the body in complex ways.  Homocarnosine can be formed when GABA replaces the beta-alanine component in carnosine.  It appears that carnosine and beta-alanine release is stimulated by glutamatergic receptors, at least in cultured rat oligodendrocytes(ref).  

·        Supplementation with carnosine and/or beta-alanine may be valuable for athletes and older people as described in the blog entry Changing the threshold for neuromuscular fatigue in the young and old, carnosine or beta-alanine supplementation.

·        Carnosine, beta-alanine and homocarnosine increase levels of GABA. 


I have discussed the drug gabapentin in the blog entry Spinal cord injury pain – a personal story and a new paradigm. As pointed out there it has been both a very popular as well as controversial drug used as an antic-convulsant, for control of neuropathic pain and, off-label, for a number of other psychiatric and medical conditions.  Gabapentin, like carnosine, beta-alanine and homocarnosine, is a GABA agonist that increases GABA levels in the brain(ref)(ref).  Further, gabapentin increases brain levels of homocarnosine(ref)(ref).  The studies cited were on patients or on tissues from patients prone to seizures, but I would wager that at least some increases in GABA and homocarnosine levels due to taking gabapentin would apply in general.

In my blog entry on neuropathic pain, I highlighted the possible role of gabapentin in quieting pathological pain due to over-excited microglia.  A July 2009 e-publication suggests that carnosine and N-acetyl carnosine might possibly be able to accomplish a similar result.  “Chronic inflammation and oxidative stress have been implicated in the pathogenesis of neurodegenerative diseases. A growing body of research focuses on the role of microglia, the primary immune cells in the brain, in modulating brain inflammation and oxidative stress. One of the most abundant antioxidants in the brain, particularly in glia, is the dipeptide carnosine, beta-alanyl-L-histidine. — The aim of the present study was to examine the role of carnosine and N-acetyl carnosine in the regulation of lipopolysaccharide (LPS)-induced microglial inflammation and oxidative damage. –. The data shows that both carnosine and N-acetyl carnosine significantly attenuated the LPS-induced nitric oxide synthesis and the expression of inducible nitric oxide synthase by 60% and 70%, respectively.  — we demonstrated a direct interaction of N-acetyl carnosine with nitric oxide. LPS-induced TNFalpha secretion and carbonyl formation were also significantly attenuated by both compounds. N-acetyl carnosine was more potent than carnosine in inhibiting the release of the inflammatory and oxidative stress mediators. These observations suggest the presence of a novel regulatory pathway through which carnosine and N-acetyl carnosine inhibit the synthesis of microglial inflammatory and oxidative stress mediators, and thus may prove to play a role in brain inflammation.”

Having been on gabapentin for three months now has contributed to vanishing my neuropathic pain due to a spinal injury and keeps me sleeping soundly.  See my blog entry Spinal cord injury pain – a personal story and a new paradigm. 

However, there are a few things I don’t like about gabapentin, one being that it often leaves me sleepy in the mornings making it difficult to concentrate. More seriously, I recently discovered something that bothers me a lot: gabapentin inhibits neuron synapse formation and therefore probably impairs new learning.  This was reported in an October 2009 study Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. “We have previously identified thrombospondin as an astrocyte-secreted protein that promotes central nervous system (CNS) synaptogenesis. Here, we identify the neuronal thrombospondin receptor involved in CNS synapse formation as alpha2delta-1, the receptor for the anti-epileptic and analgesic drug gabapentin.“  As explained in the LA Times Booster Shots: “Stanford University researchers examined the interaction between neurons and brain cells called astrocytes. Previous studies showed that a protein that astrocytes secrete, thrombospondin, is critical to the formation of the brain’s circuitry. In the study, researchers found that thrombospondin binds to a receptor, called alpha2delta-1, on the outer membrane of neurons. In a study in mice, they showed that the neurons that lacked alpha2delta-1 could not form synapses in response to the presence of thrombospondin. — Alpha2delta-1 is the receptor for gabapentin. That has been known, although scientists did not understand how gabapentin worked. But the new research revealed that when gabapentin was given to mice, it prevented thrombospondin from binding to the receptor, thus stopping the synapse formation.  While gabapentin, which is sold under the trade name Neurontin, does not dissolve pre-existing synapses, it prevents the formation of new ones. That’s why the medication may be dangerous if given to pregnant women or young children, the authors said. The majority of the brain’s synapses are formed in uteri and early childhood.”  We now know that synapse formation goes on throughout life, and I don’t like the idea of it being stopped in me. 

Some of the questions I am left with are:

·        Is seizure control associated with taking gabapentin due to higher levels of brain homocarnosine or GABA, or due to some other effect of the drug?

·        Can l-carnosine or N-acetyl carnosine achieve some of the pain control and other benefits attributed to gabapentin?

·        What if any of the general health benefits of supplementation by l-carnosine are also achieved by supplementation with beta-alanine, by taking gabapentin?  Is gabapentin a “longevity drug?”

·        What are the actual implications on adult learning of gabapentin inhibiting new synapse formation?

·        What are the differential effects of supplementation with l-carnosine, supplementation with beta-alanine, supplementation with GABA or taking the drug gabapentin on brain neurons, in CNS glial cells and in muscle tissues? 

My current personal plans are 1. to stay on 500mg of l-carnosine twice daily, 2.   To phase off of gabapentin as soon as possible consistent with my neuropathic pain not returning; pursuant to this,I have just phased down from 900mg a day to 600mg, and 3. Of course to keep alert to any new research developments that might affect these decisions.

About Vince Giuliano

Being a follower, connoisseur, and interpreter of longevity research is my latest career. I have been at this part-time for well over a decade, and in 2007 this became my mainline activity. In earlier reincarnations of my career. I was founding dean of a graduate school and a university professor at the State University of New York, a senior consultant working in a variety of fields at Arthur D. Little, Inc., Chief Scientist and C00 of Mirror Systems, a software company, and an international Internet consultant. I got off the ground with one of the earliest PhD's from Harvard in a field later to become known as computer science. Because there was no academic field of computer science at the time, to get through I had to qualify myself in hard sciences, so my studies focused heavily on quantum physics. In various ways I contributed to the Computer Revolution starting in the 1950s and the Internet Revolution starting in the late 1980s. I am now engaged in doing the same for The Longevity Revolution. I have published something like 200 books and papers as well as over 430 substantive.entries in this blog, and have enjoyed various periods of notoriety. If you do a Google search on Vincent E. Giuliano, most if not all of the entries on the first few pages that come up will be ones relating to me. I have a general writings site at and an extensive site of my art at Please note that I have recently changed my mailbox to
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8 Responses to GABA, beta-alanine, carnosine, homocarnosine and gabapentin

  1. res says:

    This disorder results in an excess of carnosine in the urine

    This will lead to too much carnosine in body and blood and in urine etc.

    We do not know fully..

  2. admin says:



    You are right we do not know fully. We don’t even know the half or third of it in many areas. The main thing is to keep learning and seeing how things can possibly fit in. When we get findings that don’t very well fit in, then there is a possibility for a breakthrough. Ever do a 1,000 piece jigsaw puzzle? Longevity is like a 700,000,000 piece one where a bunch of new pieces come by the Internet every day.

  3. jeg3 says:

    The Wiki article says this is a recessive genetic disorder, and likely does not apply to most people. But it is interesting that a compound with a lot of positives, can also be a negative without the enzyme to break it down (and where else does this apply?).

    “Carnosinemia is an autosomal recessive disorder,[3] which means the defective gene is located on an autosome, and two copies of the defective gene – one from each parent – are required to inherit the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.”

    Hi Vince,

    I have also been taking carnosine for about 8 years (off and on), but may take less and also take the BA because it seems to be effective for the skeletal muscle over a wide age range which is impressive (and the cost is less also).

  4. admin says:

    Right about the Wiki article. There are a lot of areas out there where absence or inhibition of a breakdown enzyme makes an innocent substance dangerous. Check out the area of drug cytochrome interactions

    Even a glass of grapefruit juice can be deadly if you are taking certain drugs because the juice inhibits the enzymes that break the drugs down.

    Re. your other point, I am considering taking BA too.


  5. Gaba B says:

    Gaba B:

    GABA (gamma aminobutyric acid) is a non-essential amino acid found mainly in the human brain and eyes. It is considered an inhibitory neurotransmitter, which means it regulates brain and nerve cell activity by inhibiting the number of neurons firing in the brain. GABA is referred to as the “brain’s natural calming agent”. By inhibiting over-stimulation of the brain, GABA may promote enhanced relaxation and ease nervous tension. Gaba B on discount at

    For more details please visit:

  6. Graeyewalker says:

    I have also used the gaba agonist gabapentin for treating a painful peripheral neuropathy. Now I use a purely dietary approach, which I have outlined in a brief and preliminary form on my webbsite. I am seeking a longevity diet.

    Asparagus and white mushroom caps in the diet are recommended, as they contain lots of beta-alanine, which is one of the substances that leads to diminished gaba metabolism and diminished central nervous system excitation.

  7. Graeyewalker says:

    Here is the correct link to my website.

  8. patku says:

    Did your experiment work? is L-carnosine effective for you as a replacement, at least partially, for gabapentin?

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