Hello Everyone,
I was invited here by GallaxyShock, and I am glad that he brought this thread to my attention.
I personally am a severe Panic Disorder sufferer, and my team and I have synthesized a number of novel compounds including other phenylated GABA derivatives, Phenibut derivatives, and Phenibut pro-drugs (meaning drugs that produce Phenibut as an active metabolite) such our compound Phenigabine. I am intimately familiar with the various mechanism(s)-of action of these compounds, as well as their regular (daily) use in clinical settings to treat anxiety disorders, including Generalized Anxiety Disorder, Social Anxiety Disorder (Agoraphobia), and Panic Disorder (most notably), as well as the depressive disorders that often accompany such disorders, and their inherent symptoms, such as anhedonia and chronic apathy. My team and I have also identified specific mechanism by which Phenibut exerts antidepressant activity, by inducing pre-synaptic release of Dopamine - mediated by Phenibut's action on specific Cav1.4 and Cav2.1 binding sites along α2δ Subunit-Containing Voltage-Gated Ca2+ (Calcium) Channels, which are not dramatically noticed by some individuals, but which cause dramatic mood improvement and pro-social behavior in some subjects. As a biochemist, neurobiologist, and pharmacologist by trade, it is no surprise that, as a Panic Disorder sufferer, I have investigated the development of a myriad of GABA Receptor agonists, Reuptake Inhibitors, biosynthesis catalysts, Positive Allosteric Modulators, and combination action compounds - so I am certainly happy to lend my experience with Phenibut and related GABA-derivative agonist drugs here, both personally and in overseeing patients using such drugs regularly in clinical trial settings.
I do not mean to "talk down" to anybody in this thread, as there are some knowledgeable posters here; I will simply explain the basic biochemistry, biosynthesis, and the pharmacology and pharmacokinetics of GABA and GABA derivatives, such as Phenibut and Baclofen, and their practical therapeutic uses, the way that I would to a novice, just so that there are no miscommunications. I have briefly read over the posts in this thread so far, and there is some good information posted thus far, but I am short on time at the moment, and will post a more in-depth and comprehensive reply once I have some more free time.
As most of you know, GABA (chemically designated as Gamma-Aminobutyric Acid or y-Aminobutyric Acid) is the primary inhibitory neurotransmitter of the Central-Nervous-System which helps to calm neuronal channels, and balance-out the activity of the other, primarily excitatory (stimulatory) monoamine, catecholamine, and independent (such as Glutamate) neurotransmitters, to keep neuronal systems in the brain from being excited to the point of convulsion and seizure. GABA supplements exist, however, GABA must be produced in the brain and orally-administered GABA supplements do not cross the Blood-Brain-Barrier and are simply destroyed via first-pass metabolism in the stomach and gastro-intestinal tract.
Phenibut (or β-Phenyl-y-Aminobutyric Acid) is the GABA molecule with the simple addition of a cyclic phenyl ring on the GABA chain, which makes the molecule lipophillic (fat-soluble) enough to permeate the Blood-Brain-Barrier. The addition of the phenyl ring also significantly affects the compound's receptor selectivity, making it highly selective for the metabotropic GABA -B Receptors over the ionotropic GABA -A Receptors, and also inherently giving it some biochemical affinity for α2δ Subunit-Containing Voltage-Gated Ca2+ (Calcium) Channels (where it has an inhibitory action, as a "gabapentinoid"), and also an affinity for the TAAR1 (Trace-Amine-Associated Receptor 1) Receptors (where it acts as an antagonist, and blocks the binding of the brain's endogenous β-Phenethylamine and other Trace Amines). All three of these actions contribute to Phenibut's anxiolytic (anti-anxiety action), and this is why Phenibut tends to be more anxiolytic than Baclofen, which functions solely as a selective and competitive agonist of the GABA -B Receptor, and lacks Phenibut's TAAR1 and Ca2+ Channel activity.
So, the anxiolytic action of Phenibut is threefold. 1. It functions as a GABA -B Receptor agonist. 2. It binds to selective binding sites along α2δ Subunit-Containing Voltage-Gated Ca2+ (Calcium) Channels (where it has an inhibitory action, and acts as a "gabapentinoid") and calms neuronal ion channels in various neuronal pathways, and 3. It functions as a TAAR1 Receptor antagonist, where it blocks the binding of the brain's endogenous β-Phenethylamine and other Trace Amines, such as Octopamine, Synephrine, Phenylalanine, etc. (Phenethylamine is the prototypical chemical backbone for a class of compounds collectively referred to as "the Phenethylamines", which includes compounds like the Amphetamines and the Cathinones, which are often anxiety-provoking).
Baclofen (chemically β-(4-chlorophenyl)-γ-aminobutyric acid) is the same molecule as Phenibut (GABA with the addition of a cyclic phenyl ring), the only difference being the addition of a halogen group (in this case, a choride group) on the para-position of the phenyl ring. - This simple addition affects the pharmacology and pharmacokinetics of the molecule rather significantly. First, the addition of the chloride atom significantly shields the phenyl ring of Baclofen during first-pass metabolism and subsequently greatly increases its oral bioavailability compared to Phenibut. (An example being that typical oral Baclofen doses are 20mg, while common oral doses of Phenibut can be as large as 2000mg+)! Additionally, the addition of the chloride atom on the para-position of the phenyl ring of Baclofen, also negates any affinity for the α2δ Subunit-Containing Calcium Channels, and affinity for the TAAR1 Receptors, that Phenibut possesses. So, although Baclofen does possess some of Phenibut's anti-anxiety activity because of its GABA -B Receptor agonism, and for this reason can cause mild physical dependence (like Phenibut), it is not associated with any of the mild psychological "addiction" that some people develop for Phenibut, since it lacks activity at the Cav1.4 and Cav2.1 binding sites along the α2δ Subunit-Containing Ca2+ Channels that are responsible for the pre-synaptic dopamine release in the Frontal Lobe and Parietal Lobes. (Which is what causes the antidepressant and euphoric mood-lifting effects of Phenibut, as well as its pro-social effects).
Chemically, Phenibut is classified as a phenyl-substituted amino acid; as far as classifying Phenibut according to its pharmacological action - it is a selective and competitive agonist of the GABA -B Receptor. It also classifies as a "gabapentinoid" alongside drugs like Gabapentin (which consists of the GABA molecule with the addition of a cyclic cyclohexyl ring, in place of Phenibut's phenyl ring), and Pregabalin (which consists of the GABA molecule with the addition of a isobutyl group, in place of Phenibut's phenyl ring). Also, because of its mild antagonist action at TAAR1 (Trace Amine-Associated Receptor 1) Receptors, it can be classified as a weak TAAR1 Antagonist.
Phenibut is used by most people as an anxiolytic, to relieve anxiety caused by Generalized Anxiety Disorder, Agoraphobia (Social Anxiety Disorder), or Panic Disorder with or without Agoraphobia. However, since you seem to belong in the percentage of patients that receive significant antidepressant and pro-social effects from Phenibut, and because of Phenibut's rather unique pharmacology, suggesting any sort of alternative that will match the exact beneficial effects that you seem to receive from Phenibut, is actually very difficult, because of Phenibut's unique antidepressant mechanism(s)-of-action.As far as chemically related drugs that may address the anxiety you experience, Baclofen is a comparable GABA -B agonist in terms of affinity and agonistic strength, but it lacks the α2δ Subunit-Containing Calcium Channel feedback mechanism that is responsible for the pre-synaptic dopamine release in the Parietal Lobe that is responsible for providing the antidepressant, anti-anhedonia, and pro-social effects that you are experiencing from Phenibut. Likewise, other "gabapentinoid" drugs such as Gabapentin and Pregabalin, which also bind at α2δ Subunit-Containing Calcium Channels, are sometimes used to treat anxiety disorders because of their Ca2+ Channel inhibition, and because although they do not directly bind at GABA Receptors - they do enhance the action of GABA by increasing extracellular concentrations of GABA in various regions of the brain by producing a dose-dependent increase in L-Glutamic Acid Decarboxylase - an enzyme that bio-synthesizes GABA from the neurotransmitter Glutamate. These drugs also increase the synaptic density of the GABA Transporter Proteins, thereby enhancing the functional transport of GABA. In fact, Pregabalin does this so effectively, that it is a controlled drug under Schedule 4 in the US (the same category that benzodiazepine drugs are categorized under). Gabapentin is unregulated, rather weak milligram for milligram compared to Pregabalin, and is mostly used to treat neuropathic pain. However, these other "gabapentinoid" drugs are really just rather sedating in their overall effects, and bind at different sites along the α2δ Subunit-Containing Calcium Channels than the binding sites that Phenibut binds to to elicit its pre-synaptic dopamine release that is responsible for the euphoric, antidepressant, and pro-social effects that you are experiencing from Phenibut.
Of course, there are other classes of drugs that are available for the treatment of the various symptoms of the conditions that you mnetioned in your original post, that would could probably start 5+ more threads on. However, since you asked about Phenibut specifically, and specifically asked about its regular use as a first-line, regular therapeutic treatment option for your anxiety and depression symptoms, I will lend my thoughts. I personally take around 6000mg (6 grams) of Phenibut hydrochloride daily (though lately I have cut this dose down, as I have also been using Phenigabine - a Phenibut pro-drug developed by my team and I) and I have taken this dose for years. Now, I will admit that 6000mgs is past the maximum dose that even I would recommend for 95% of people. Some users dose twice daily, but I have always found that I only have to dose once in the morning to get a full day's worth of anxiety coverage. (Except for the rare occasion that I may have to take an additional 2g later in the evening). Many users who casually order Phenibut online, in an uncontrolled, reckless, and pseudo-medical manner, rapidly escalate their daily doses, chasing the euphoric and pro-social effects (which I will be honest, are the first effects to fade with regular use), as they chase some sort of a perceived "high". - (For anybody doing or thinking of doing this, please do not. Phenibut has absolutely no abuse potential, and does cause physical dependence with regular use). These are usually the same people who do not need to be taking Phenibut in the first place, and are usually the same idiots who wind up running out and discontinuing Phenibut abruptly, and are the very same individuals who post the horrific Phenibut withdrawal stories online. Now, I will be the first to admit that Phenibut, as a GABA agonist, can indeed cause a very unpleasant withdrawal syndrome if discontinued too abruptly. I tell people who make the jump to using Phenibut regularly that they have to be "all in" and committed to taking controlled and structured, regular daily doses - only as much as is needed to achieve its therapeutic effect, and only to dose as often as needed (for me, this is once daily).
Many posters fight me on this statement, but I believe (and in fact, I know) that Phenibut can be used regularly, even daily, if it is used in a structured and controlled setting (preferably under the supervision of somebody qualified, who can periodically judge your response to treatment. (Many people message me regularly, for this very purpose, and if you wish, you may also)) and is not discontinued abruptly - and discontinued on a slow and gradual taper if/when the time comes to stop Phenibut use. In the clinical trial settings that I oversaw patients taking Phenibut, related drugs, or Phenibut pro-drugs (meaning drugs that produce Phenibut as an active metabolite), upon the end of the studies, we gradually withdrew the Phenibut dose (or equivalent) by 10% every week, for ten weeks. (Note, that these were patients with diagnoses anxiety disorders, so our goal was to avoid any discontinuation syndrome at all; many patients could probably even withdraw a bit more rapidly than this). - Aside from two patients that I can recall during our pre-clinical trial for our Phenibut pro-drug Phenigabine (who simply experienced minor trouble falling asleep for a few nights), I have never encountered a patient with a (medically or emotionally) significantly hard time withdrawing, following this structured taper plan.
Now, some posters advise using a benzodiazepine drug while tapering, as the action of the ionotropic GABA -A Receptor agonist will mask all of the withdrawal symptoms, plus the rebound anxiety that some experience, while not prolonging the withdrawal (as the metabotropic GABA -B Receptor that Phenibut acts on, will still be in a state of withdrawal, and will rapidly be re-up-regulating in the absense of Phenibut. - As the metabotropic GABA -B Receptors are indeed very different receptors, morphologically and bio-mechanically, than the ionotropic GABA -A Receptors that benzodiazepines act on). Now, in some instances, involving patients who experience some degree of significant rebound anxiety during Phenibut withdrawal (which one shouldn't if they tapered correctly, anyway), then the temporary use of a low to moderate dose of a benzodiazepine with a long metabolic half-life, such as Diazepam, Clonazepam, (and even weaker benzos like Oxazepam, Tempazepam, and Flurazepam, etc) can be beneficial. (I am partial to Clonazepam, if available, because of its strength and about perfect metabolic half-life and duration-of-action for withdrawal purposes). However, I am always hesitant to recommend the benzodiazepine withdrawal method to casual posters on forums like this, since many have addictive personalities, and if using higher doses of benzodiazepines than required or for longer periods of time than required, then they are substituting a rather benign phenyl-substituted, metabotropic GABA -B Receptor agonist, for a MUCH more potent ionotropic GABA -A Receptor agonist - which produces a much more medically-significant withdrawal syndrome upon abrupt cessation of regular, long-term use. What I don't like to hear, is patients getting into trouble with Phenibut, and then trying to withdrawal with a benzodiazepine, only to find out that they "like" the effects of the benzodiazepine drug more than the Phenibut, and substitute Phenibut dependence for a much more medically-significant physical dependency and potential psychological addiction.
So, I suppose my defining words on the topic of using Phenibut regularly, and using a benzodiazepine drug to ease withdrawals if/when it comes time to discontinue regular Phenibut use, is that it all comes down to self-control. Only you truly know if you have the will-power to keep your daily Phenibut doses structured, and if you are able to use a benzodiazepine drug in the lowest effective dose, for the shortest necessary amount of time, to use it to ease Phenibut withdrawal if/when it comes time to discontinue Phenibut. (Personally, I have seen Phenibut and related drugs used in clinical settings by rather large numbers of patients for up to eight-month periods, and no benzodiazepine drugs were needed during the cessation of Phenibut (or equivalent drug) treatment following our 10% dose reduction / every seven days taper regimen). - However, some patients do experience what is known as "rebound anxiety" during withdrawal, that sometimes surpasses the original anxiety that they started using Phenibut for in the first place. In cases such as these, the short-term use of a low-moderate dose of a benzodiazepine with a long-duration of action and long metabolic-half-life (again, I am partial to Clonazepam if avail, but Diazepam (although weaker mg for mg) is another readily available benzo (in most places) with a long half-life), as long as it is taken in the smallest effective dose, for the shortest necessary amount of time. (Again, I stand by the fact that no noteworthy rebound anxiety should occur following our taper regimen, but some people have trouble following the regimen, or simply refuse to try, in which cases the use of a benzodiazepine drug to keep the patient comfortable during Phenibut withdrawal may be necessary, in some cases).
So, in answer to your question(s), yes, Phenibut can be used regularly, and even daily if it is used in a consistent and controlled manner. However, one thing that I should bring up to you is that, although Phenibut seems to retain its anxiolytic (anti-anxiety) action in most patients, long-term, the dopamine-mediated euphoric mood-lifting effects, and the pro-social effects are the first effects that begin to wane slightly with regular use. For this reason, if you do decide to start a daily Phenibut dosing regimen, be sure to start with the smallest effective dose, and to dose only as frequently as needed (for me this is once daily, but some users dose twice daily). Also, since it seems that you are using Phenibut primarily for it dopamine-influx-mediated antidepressant effects, I recommend that you occasionally keep in contact with somebody qualified and experienced, who can occasionally review your continued response to treatment - to determine when increases in dosage may be needed, and to evaluate whether or not continued use of Phenibut is really being all that beneficial or not. (If you wish, you can contact me if you wish, either here via private message (everybody does) or via our email at OracleLaboratories@gmail.com).
It really is baffling how often I am contacted specifically for this very topic - so much that I have decided to soon work on publishing a comprehensive guide to the use of Phenibut and other GABAergic drugs (including GABA -A agonists, like benzodiazepines), for the layman, that would answer a lot of the questions that I commonly repeat myself continually, to answer.
Although it may be a bit of a read, to sort through all of the posts, we addressed a lot of the very same questions regarding Phenibut and related drugs in the following thread, and some posters contributed some good information. The thread is entitled "Baclofen: alternative for Phenibut ???".
http://www.longecity...e-for-phenibut/
(Also, there is a link in that thread to a sumarry publication on our novel GABA and Phenibut pro-drug, Phenigabine (the full publication is to be release within the next two months), which is no longer active. It can now be found at: http://oraclelaborat...-Submission.pdf ).
-John Gona
Neurobiologist,
Psychopharmacologist,
Psychotropic Treatment Specialist
Oracle Laboratories
NeuroPsych Institute
Edited by Oracle Laboratories, 22 February 2017 - 07:16 PM.
I did abuse kratom for a few months when I first discovered it and I was almost an alcoholic around 5 years ago. But I did become better with time to keep myself in check.
