5.Neuroactive Steroids and More Drugs that Increase GABA
6.Cannabis Based Drugs (ie Sativex)
Increasing GABA Without Drugs : ECT and rTMS
Some Thoughts
In theory, things look pretty simple: a supplement that raises GABA levels would correct GABA deficiency and improve the anxiety, insomnia, seizures, muscle stiffness and other symptoms of low GABA.
The precursors of GABA are glucose (the predominant precursor) [3] , as well as pyruvate and the amino acid glutamine.
Glutamine → Glutamate → GABA
↑↓
Citric Acid Cycle ← Succinate semialdehyde (SA)
But in real life, things aren’t that easy. When supplementing with GABA is really important to understand the tight connection between GABA with the excitatory neurotransmitter glutamate -these two work together. You may boost GABA levels but imbalance/increase the levels of glutamate (which are too high in MS and many other diseases). The enzyme that converts glutamine to glutamate or GAD (that enzyme that converts glutamate to GABA) can also be a problem in some people. If you don t have enough vitamin B6 you many not convert properly glutamate to GABA (vitamin B6 is a cofactor in this reaction).. To make things even more complicated, glutamate is the precursor of GABA,and GABA can also convert back to glutamate. Below you can read about drugs that increase GABA. In this article I cover GABA natural supplements.
Drugs that increase GABA
Benzodiazepines (BZs): the most known drugs that increase GABA levels.
Examples of BZs: diazepam (Valium), alprazolam (Xanax), clonazepam, lorazepam (Ativan), chlordiazepozide. Some BZs are long acting, some are short acting.
How they work: they attach to post-synaptic receptors adjacent to the GABA receptors. As a result, they will increase GABA (which is an inhibitory neurotransmitter), leading to a decrease of neuron activity and sedation. There are 3 GABA receptors- A, B and C. Benzodiazepines work on GABA-A receptors [1].
Used for: anxiety, panic attacks, insomnia, muscle relaxation, relief from spasticity (associated with diseases affecting the brain/spinal cord- like MS), and epilepsy. Can be combined with antidepressant SSRIs for treating OCD or with antipsychotics for the management of mania [2]
BZs and MS: commonly used for anxiety associated with MS, but also prescribed to manage other symptoms. For example, diazepam helps decrease muscle spasticity and cramps in people with MS [3] , but causes more sedation than baclofen (described below)[4]. Diazepam appears to reduce inflammation, autoimmunity and excess release of glutamate- at least in animal models of MS [5]. Clonazepam can also be effective for MS spasticity [6] .Alprazolam helped improve symptoms of MS in animal models [7].
The biggest problems (side effects): tolerance, dependence and withdrawal symptoms (can be life threatening) and increased risk of Alzheimer’s disease are all more common with long term use.
Other side effects: drowsiness, lethargy, fatigue and amnesia; at higher doses they cause impaired coordination, dizziness, vertigo, slurred speech, blurry vision, mood swings, hostile or erratic behavior. Elderly should be closely monitored, as they are more sensitive to BZs [8], [ 9].
Another problem with BZs: they have a negative impact on glutamate /glutamate pathway (I would interpret cautiously the benefits of diazepam and alprazolam in animal models of MS). The tolerance and withdrawal symptoms can be partially explained by the fact that BZs make glutamate producing neurons more sensitive. The risk of anxiety and seizure is also increased after stopping these drugs [10].
How they work: barbiturates prolong and boost the action of GABA on GABAA receptors(at higher concentrations activate directly the receptors) [11].
Used for: insomnia (the most prescribed in the past); to induce anesthesia/sedation and treatment of seizure- phenobarbital is currently the most widely-prescribed anti epileptic drug in the world) [12]. In neurology, they can help manage essential tremors (especially primidone), other movement problems, and acute traumatic brain injuries [12], [13].Other uses: psychotic disorders, migraines, alcohol and benzodiazepine poisoning.
Did you know?
From a chemical point of view, barbiturates are ureic compounds, whose nucleus is malonylurea (a combination of urea- from urine, and malonic acid, an acid derivative taken from apples) [14] ?
Barbiturates for MS: they had been researched for treatment of seizures associated with MS [15]. (note: treatment with interferon-ß1b and copaxone may increase risk of seizures, — a rare, but serious side effect of these drugs [15]).
Barbiturates — common side effects: nausea, vomiting, confusion, headaches, lack of coordination.
The biggest problem: can be lethal even in low doses, as the therapeutic margins are narrow [16],[17]. In fact, vet doctors sometimes use barbiturates to put the animals to sleep.
Tolerance, dependence and withdrawal symptoms (sometimes fatal) are also seen with barbiturate use. Like Bzs, barbiturates can also affect glutamate system.
3.Baclofen
Baclofen also drug that increases GABA, is a muscle relaxant structurally similar to GABA.
How it works: acts on the presynaptic GABA-A site, decreasing synaptic transmission on the spinal cord.
It has been approved by FDA for muscle spasms and spasticity related to brain/spinal cord lesions, mostly used in MS. Can also be used for trigeminal neuralgia associated with MS as well.
Side effects include: include weakness, confusion, dizziness, drowsiness, vertigo, insomnia, constipation, urinary frequency. Baclofen carries a boxed warning: if discontinuation is abrupt it can cause confusion, hallucinations, seizures, and aggravation of spasticity [18]. Overdose of oral baclofen had also been associated with increased risk of seizures [19].
A systematic review of drugs used for spasticity associated with MS reveals the following: baclofen, tizanidine and gabapentin are the first-line therapy. Diazepam or dantrolene are considered as second line therapy. Nabiximols (Cannabis based drugs) appear effective as add-on therapy [20].
4.Other drugs that increase brain GABA
Other drugs that increase brain GABA and therefore can treat GABA deficiency : acamprosate, pregabalin, gabapentin, tiagabine, lamotrigine, topiramate
Acamprosate (the synthetic derivative of the amino acid taurine) acts either directly at GABA receptors and/or decreases glutamate activity, helps reduce symptoms, inflammation and autoimmunity in animal model of MS [21]. It could also help improve neuropathic pain (numbness and tingling), when combined with baclofen (animal studies) [22]
Pregabalin — mostly used for epileptic seizures, neuropathic pain, fibromyalgia, and sometimes for sleep disorders(restless leg syndrome), anxiety or mood disorders and hot flashes [23].
Gabapentin is used to treat some symptoms of MS- particularly muscle spasticity, neuropathic pain (tingling and numbness), insomnia and seizures. Both pregabalin and gabapentin help relieve symptoms of MS, but don’t prevent MS progression [24]. As a GABA analogue, gabapentin can increased brain GABA levels by 55.7%, according to a study [25].
Tiagabine — anti seizure drug, may correct GABA deficiency. How it works: blocks GABA uptake into the synaptic neurons permitting more GABA available for post synaptic cells. May help with muscle spasms and pain associated with MS [26]
Lamotrigine is commonly used for seizures and bipolar disorder. Some placebo controlled randomized studies suggest neuroprotection against axon degeneration, although other studies did not show neuroprotection [27]
Both lamotrigine and baclofen may help treat trigeminal neuralgia (which is 20 times more common in people with MS compared with those without MS) [28], [29]
Lamotrigine may help treat speech problems associated with MS [30], as well as tingling and numbness [31]
Topiramate is commonly used for seizure and migraines. Besides managing these two conditions, topiramate can help manage tremors and problems with movement and coordination associated with MS [32], as well as numbness and tingling [33] and trigeminal neuralgia in those with MS [34]
Side effects associated with these drugs are similar: tremors, dizziness, fatigue, insomnia, blurred vision or double vision;loss of coordination, memory loss, nausea, stomach pain, back pain.
Be aware of the risk of cancer with many of these drugs. Preclinical trials requested by FDA reveal the following in a 2015 study:
-70% of benzodiazepines were associated with carcinogenicity, specifically: clonazepam, zolpidem, zaleplon, diazepam, eszopiclone, oxazepam and midazolam
-85.7% of anti-convulsants were associated with carcinogenicity, specifically: valproate, carbamazepine, gabapentin, pregabalin, oxcarbazepine and topiramate. Lamotrgine was the only one on the list that didn’t show increased risk of cancer [35].
5. Neuroactive steroids and more drugs that increase GABA
Neuroactive steroids- just a quick note here, I will write a separate article about them. In my opinion, the best drugs that raise GABA for managing not just the symptoms of MS, but also deal with inflammation, neurodegeneration and autoimmune response.
For example, allopregnanolone (a progesterone derivative) and ganaxolone can help decrease inflammation and autoimmunity in MS (deficiency of neuroactive steroids had been linked with MS). Allopregnanolone and progesterone can help repair the myelin [36],[37],[38].
6. Cannabis based drugs
Cannabis medicines can also be considered as drugs that increase GABA, although their health benefits go well beyond improving GABA levels. For example, Sativex shows many benefits- ranging from improved anxiety and depression to muscle spasticity, pain (including neuropathic pain). Sativex (spray) is approved in several countries for spasticity associated with MS. Cannabis based drugs and supplements can also improve GABA levels. These drugs have very low risk of getting “high” as Sativex has almost 1-1 ratio THC to CBD [39].
Non-drug Options To Increase GABA: ECT and rTMS used for the treatment of depression and GABA
ECT (electroconvulsive therapy)seems to increase brain GABA levels as well as GABAB activity in cases of GABA deficiency [40]
rTMS (transcranial magnetic stimulation) also appear to raise GABA levels, and its mechanism of action involves improvement of glutamate-GABA pathways [41],[42].
Why rTMS helps treat spasticity: Technical : rTMS strengthened descending projections between the motor cortex and inhibitory spinal interneuronal circuits. This reversed a defect in reciprocal inhibition after spinal cord injury, and reduced leg spasticity [43]. It is used for treating depressions, and could also be helpful to manage insomnia, muscle spasticity, anxiety [44], [45], [46], [47],[48],[49],[50] .
rTMS for MS : can be quite effective for spasticity [51]. Another study (rTMS) and stimulation with the theta bursts (iTBS) can be and effective treatment for spasticity associated with secondary MS [52]. A review of 21 studies that evaluated rTMS tDCS(transcranial direct current stimulation)specifically for MS found evidence to have benefits for improvement of motor function (ie hand dexterity), improved cognition and pain treatment [53]
rTMS side effects : Unlike ECT, rTMS does not require anesthesia and sedation. rTMS therapy had not been linked with the common symptoms of antidepressants or anti anxiety drugs (sedation, digestive problems, sexual dysfunction, dry mouth, etc). Some may experience a mild headache or mild pain scalp sensations. The most serious, but very rare side effect would be seizures (and this happens more often in those who already had seizure) [54] .
Although seizures can be a rare side effect of rTMS, researchers evaluated the benefits of rTMS (low frequencies) for treating seizures/epilepsy and some studies found it beneficial [55],[56], [57].
Some thoughts
I explored different drugs that increase GABA in this article. The most common drugs like benzodiazepines, barbiturates, baclofen are clearly not my choice simply because of the risk of serious side effects. They may be needed in some cases (short term), but I think are overused and the majority of people may not need them.
I see a lot of value in rTMS (especially the low frequency rTMS) and other forms of magnetic or electric stimulation (ie PEMF, TENS) for muscle spasticity, improve mood and sleep. I wouldn’t use rTMS if there is history of seizures. Allopregnanolone and other neurosteroids can also be helpful.
If you are looking at specific symptoms of GABA deficiency know that there are natural effective (as effective as the drugs, but much safer) supplements to help you manage sleeping problems, anxiety and muscle spasticity.
For seizures, I reviewed in depth different drugs . In my opinion. levetiracetam (Keppra) may be a much safer alternative than the drugs mentioned above (levetiracetam works through a different mechanism, not by raising GABA). Diet and some supplement can be very helpful for seizures as well.
If you want to explore natural ways to increase GABA, read this article.
