A recent set of in-vitro and in-vivo human analyses regarding the pharmacology and pharmacokinetics of Fluorophenibut (“F-Phenibut”) reveals the similarities and differences of the compounds’ pharmacology when compared to its existing structural relatives (ie Phenibut, Baclofen, Gabapentin, Pregabalin, etc). Since VERY little actually exists regarding Fluorophenibut’s pharmacology compared to Phenibut and Baclofen, despite the compound becoming increasingly more popular and more common on nootropic and research chemical supplier’s websites, I thought that it would be pertinent to share our initial findings with anybody who may be using this compound, or considering using it.
Many of you who keep track of new ‘nootropic’ and psychotropic research compounds may have noticed that recently, several fairly well-known nootropic and research chemical suppliers have been selling a new compound labeled as Fluorophenibut or “F-Phenibut”. Since it’s initial appearance on the scene about a year ago when it first started to be widely talked about, there has been thread after thread online, on sites like Reddit and others, trying to determine it’s effect(s), mechanism(s)-of-action, and its similarity to related compounds (ie. Phenibut, Baclofen, etc).
Over the course of the last several months, my team and I have investigated the in-vitro and in-vivo pharmacology of Fluorophenibut in a variety of rodent models, as well as preliminary human models, and can now definitively answer many of the questions that have been posed by many would-be psychonauts across the web, who are considering trying Fluorophenibut. In addition to this, some of the past compounds developed by Oracle Laboratories integrate Fluorophenibut (as well as other halogen-substituted phenyl GABA derivatives) in their chemical structure, or have produced Fluorophenibut as active metabolites. (As many of you know, I personally suffer from Panic Disorder and so I have always held a special place for anxiolytic drug development, and our team has extensive experience in developing experimental drugs based upon the GABA backbone structure (although also based on novel structure as well, of course). However, one of our newer, junior neurobiologists requested the project of examining the pharmacology and pharmacokinetics of Fluorophenibut specifically, as dosed by the users who are ordering it and using it. Personally, I have been very surprised that such work has not been done yet - if only because the fluorinated Phenibut molecule is so simple to analyze as far as its absorption, target receptor selectivity, metabolism, etc. (While not a priority at the moment, this work will be published, if only to put SOME kind of reference out there regarding the actual pharmacology of Flurophenibut, and its similarities to drugs like Phenibut, Baclofen, and Pregabalin.
One well-known nootropic research chemical supplier listed this in regard to Fluorophenibut’s activity and relative properties:
"F-Phenibut (Fluorophenibut) is a several-fold more potent derivative of Phenibut. Phenibut is an atypical anxiolytic and nootropic compound structurally similar to the well known inhibitory neurotransmitter GABA, as well as to baclofen (β-(4-chlorophenyl)-GABA) and pregabalin (β-isobutyl-GABA)1. Phenibut was originally thought to act solely as a selective GABAB receptor agonist, similar to its much more potent relative baclofen, but has more recently been found to additionally act with somewhat higher affinity as an inhibitor of α2δ subunit-containing voltage-gated calcium channels, a mechanism of action shared with gabapentin and pregabalin.2 Phenibut is known to have a wider spectrum of effects than baclofen; for example Phenibut has been found to be more effective as a nootropic and neuroprotective compound than baclofen2,3, while baclofen has a more narrowly focused spectrum of effects and anecdotally shows a reduced tendency to induce habituation or tolerance to its effects upon chronic daily administration4. Preliminary (unpublished) research tentatively suggests that F-Phenibut (Fluorophenibut) has a behavioral potency of approximately five to tenfold higher than Phenibut in vivo, and may have proportionally severalfold higher affinity as a GABAB agonist than Phenibut, but may also retain comparable affinity and inhibitory efficacy at α2δ subunit-containing voltage-gated calcium channels, making F-Phenibut unique as an evenly balanced ligand for these two receptors. As an intermediary between Phenibut and baclofen, these findings hint at the potential promise that this p-fluoro relative of Phenibut might retain the broader nootropic, anxiolytic, and mood elevating characteristics of Phenibut, while simultaneously partially sharing the relatively reduced tolerance inducing properties of its p-chloro relative baclofen."
First, this information states that Phenibut and Fluorophenibut are much more potent agonists than Phenibut itself, and while in one way that is somewhat true, the actual strength of the Baclofen and Fluorophenibut molecules are not much greater than Phenibut as agonists of the GABA -B Receptor, at all..
As far as binding affinity for the GABA -B Receptor, and agonist strength at the orthostatic (GABA) binding-site of the GABA -B Receptor, Phenibut, Baclofen, and Fluorophenibut are all pretty close, with the order of weakest to strongest (as far as binding affinity) going:
Phenibut (Ki: 112.02 nm) > Fluorophenibut (Ki: 99.04 nm) > Baclofen (Ki: 86.08 nm)
Phenibut (Ki: 112.02 nm) > Fluorophenibut (Ki: 99.04 nm) > Baclofen (Ki: 86.08 nm)
And, their strength as agonists at the GABA -B Receptor from weakest to strongest goes:
Phenibut (w 82.11) > Fluorophenibut (w 161.12) > Baclofen (w 166.04)
Phenibut (w 82.11) > Fluorophenibut (w 161.12) > Baclofen (w 166.04)
So, why are smaller doses of Baclofen and Fluorophenibut so much stronger than equal weight doses of Phenibut? (After all, typical doses of Baclofen are 20mg, while typical Phenibut doses are 2000mg)! - This has everything to do with absorption, and very little to do with actual binding affinity for GABA Receptors or the compounds’ strength as agonists at GABA -B Receptor binding sites. Phenibut is the endogenous GABA (Gamma-Aminobutyric Acid) molecule, with the addition of a cyclic phenyl ring - which makes the molecule lipophillic (fate-soluble) enough to pass across the Blood-Brain-Barrier (which GABA itself does not). However, the phenyl ring that is bound to the GABA molecule to form Phenibut is highly susceptible to metabolic cleavage via first-pass metabolism in the stomach and the gastrointestinal tract. This cleaving of the phenyl ring off of the Phenibut molecule (yielding again plain GABA, which doesn’t cross the Blood-Brain-Barrier, and is simply excreted) ensures that only a small percentage or an oral dose of Phenibut is actually absorbed - where it possesses three major pharmacological mechanisms-of-action.
1). Phenibut acts as a highly selective agonist of the orthostatic (GABA) Binding Site of the GABA -B Receptor. (While GABA itself has a plural-potentiality to bind at both GABA -A and GABA -B Receptors, the addition of the phenyl ring on the Phenibut molecule make the entire compound highly selective for the metabotropic GABA -B Receptor subtype over the ionotropic GABA -A Receptors). 2). Phenibut binds to binding sites along a2o-suntype Voltage-Gated Ca+ Calcium Channels (like “gabapnetinoid” drugs, such as Gabapentin (“Neurontin”) and Pregnable (“Lyrica”) ) where it has an inhibitory action and calms the neurotransmission along these channels. 3). Phenibut acts as an antagonist as TAAR1 (Trace Amine-Associated Receptors 1), where it blocks the binding of the endogenous, intermediate neurotransmitter B-Phenethylamine. Phenethylamine is an intermediate neurotransmitter in mammals that is metabolized into the neurotransmitters L-DOPA, Dopamine, Epinephrine, Norepinephrine, Synephrine, and p-Octopamine. It also serves as a chemical backbone for a class of synthetic chemicals known collectively as “the phenethylamines”, which includes amphetamines, substituted amphetamines, some cathinones, and some psychedelic, functional amphetamine substitutions - all drugs which agonize the TAAR1 Receptor, and induce anxiety.
In the case of Baclofen, we are dealing with the exact same molecule as Phenibut (the GABA molecule, with the addition of a cyclic phenyl ring), with only one tiny difference - the addition of a single halogen (in this case, a chloride) group on the para-position of the phenyl ring of the Phenibut molecule. This simple addition of a single chloride atom significantly protects the Baclofen molecule from first-pass metabolism in the stomach and gastrointestinal tract, and allows much more of the compound to be absorbed intact. Furthermore, the addition of the chloride atom on the compound’s phenyl ring negates almost all of the compound’s binding affinity for a2o-subunit-containing Voltage-Gated Calcium Channels, and the addition of the chloride atom also negates the compound’s affinity for the TAAR1 Receptor. This means that Baclofen functions almost solely as a selective and competitive agonist of the Orthosteric Binding-Site of the metabotropic GABA -B Receptor.
Now we have the emergence of another Phenibut derivative with the addition of a halogen group on the para-position of the phenyl ring (like Baclofen). However, rather than a chloride group, Fluorophenibut possesses a fluorine group on the para-position (^4) on the cyclic phenyl ring of the compound.
Now, theoretically, this should produce a compound that is much more similar to Baclofen than to Phenibut, and that is indeed the case. Just like the chlorine group on the phenyl ring of Baclofen protects the compound against extensive first-pass metabolism in the gut, the fluorine atom of Fluorophenibut does exactly the same thing. However, despite chlorine and fluorine groups both being halogens, a fluorine atom is slightly smaller (in terms of molecular weight, based on molarity) than a chlorine group (fluorine‘s atomic mass being 18.99 and chlorine‘s being 35.45), and possesses a slightly different polarity (fluorine groups possessing greater polarity than chlorine groups), which slightly changes the target selectivity of Fluorophenibut compared to Baclofen.
Like with all three (Phenibut, Baclofen, and Fluorophenibut) compounds, the addition of the cyclic phenyl ring allows the compounds to be lipophillic enough to permeate the Blood-Brain-Barrier (and thus be centrally active). The addition of the phenyl ring also makes all three compounds much more selective for the metabotropic GABA -B Receptor subtype of the ionotropic GABA -A Receptors. In the case of Baclofen and Fluorophenibut (which both possess halogen groups on the para-positions on the compounds’ phenyl rings), the addition of the halogen groups negates the compounds’ affinity for a2o-subunit-containing Voltage-Gated Ca+ (Calcium) Channels to a large extent, and also negates the compounds’ binding affinity for the TAAR1 Receptors. However, in the case of Fluorophenibut, which possesses a fluorine group in place of the chlorine group that Baclofen possesses, this compound retains some affinity for the TAAR1 Receptors (where it also acts as an antagonist, like Phenibut), and it also alters the overall polarity of the molecule enough that Fluorophenibut is the only one out of the bunch that possesses some degree of measurable affinity for the ionotropic GABA -A Receptors, in addition to its primarily action at metabotropic GABA -B Receptors.
The substitution of the chlorine group of Baclofen for the fluorine group of Fluorophenibut alters the overall polarity of the molecule because of the lessened molecular weight of the fluorine group (which in this case, functions as a hydrogen atom replacement) based on molarity, just enough to negate some of the GABA -B selectivity of the compound that is caused by the addition of its cyclic phenyl ring. Although Fluorophenibut does absolutely function primarily as a selective GABA -B Receptor agonist, the drug also possesses some of the TAAR1 (Trace Amine-Associated Receptor 1) that Phenibut possesses (where it acts as an antagonist, blocking the binding of endogenous phenethylamine). In addition to this, the addition of the fluorine group on the Fluorophenibut molecule, which is lighter and has a higher polarity than Baclofen’s chlorine group, balances out some of the GABA -B Receptor selectivity that the presence of the compound’s cyclic phenyl ring affects the compound’s overall binding affinity - enabling the molecule to bind with some degree of weak affinity at the orthosteric binding site of the ionotropic GABA -A Receptor, which typical, much stronger GABA -A agonist drugs such as barbituates, methaqualone, meprobamate, and benzodiazepines, etc., bind to.
According to our projections as the result of our recent study, approximately 94.03% of orally-administered doses will be absorbed into blood plasma and make its way to the brain, and approximately 12.02% of the total oral dosage that is absorbed in humans will bind at the Orthosteric (GABA) Binding Site of the ionotropic GABA -A Receptor. (Meaning that out of a 20mg oral dose, approximately 18.80mg will be absorbed into blood plasma and will cross the Blood-Brain-Barrier, and out of that 18.80mg that reaches the brain, approximately 2.25mg will bind at ionotropic GABA -A Receptors.
Because of these minor differences in Fluorophenibut’s target receptor selectivity over Phenibut and Baclofen, some degree of caution should be expressed towards anybody who is using or is considering using Fluorophenibut for any extended period of time, or alongside other GABAergic drugs which may produce a cumulative effect, or when used with other sedatives, regardless of action.
I have posted here several times regarding the use of Phenibut, and have designed and developed drugs that produce Phenibut as an active metabolite, are based on Phenibut’s chemical structure, or that function like Phenibut pharmacologically, and as I have said, although I do fully believe that Phenibut is a beneficial compound if used in a structured and controlled manner, and that it can absolutely be used responsibly, many users here have interjected their own experiences (either with what that have heard from others, or experienced themselves, regarding Phenibut withdrawal). Although I know from experience that Phenibut withdrawal can be minimized and even all-together eliminated, based on my experience using Phenibut and similar compounds in clinical trial settings, if used excessively and/or stopped too abruptly, Phenibut (being a GABA agonist) can indeed cause a very unpleasant withdrawal syndrome, which can include rebound anxiety, depression, aches and pains, headache, insomnia, Restless Leg Syndrome, and a host of other symptoms. - However, Phenibut, being a metabotropic GABA -B Receptor agonist, is not a drug that induces the severe tremors, convulsions, and even Grand Mal and Clonic seizures that many ionotropic GABA -A agonist drugs (such as barbituates, methaqualone, meprobamate, benzodiazepines, etc) can induce upon sudden withdrawal.
However, in the case of Fluorophenibut, since some degree of ionotropic GABA -A Receptor activity is observed in in-vitro analyses, it should at least be speculated that some symptoms associated with ionotropic GABA -A Receptor agonist symptoms may be associated with the rapid withdrawal of Fluorophenibut, following regular, prolonged or excessive use.
While we do not believe that Fluorophenibut possesses a physical dependency liability, or an abuse potential anywhere near the degree of the usual ionotropic, GABA -A Receptor agonists, and have concluded that like Phenibut and Baclofen - the main pharmacological action of Fluorophenibut responsible for its anxiolytic effect, is due to its selective and competitive affinity for the metabotropic GABA -B Receptors, where it acts as an agonist. (As well as possibly due to some degree of antagonism of that TAAR1 Receptors, where Fluorophenibut, like Phenibut, blocks the binding of the brain’s endogenous B-phenethylamine. Although, because some degree of ionotropic GABA -A Receptor affinity (12.02% of the oral dose absorbed) has been observed in in-vitro and in-vivo human models, it is worth mentioning that this activity may contribute to some increased degree of difficulty when withdrawing the drug following a regular dosage regimen, as well as potentially, an increased degree of risk when withdrawing Fluorophenibut following a regular, long-term dosage regimen.
The following figures are the average binding affinity values and agonist-strength values for Fluorophenibut, compared to Phenibut and Baclofen, based on the recent set of analyses completed by Oracle Laboratories junior neurobiologist Adam Leustman (publication of these findings will follow, if only because almost nothing published exists regarding the pharmacology and pharmacokinetics of Fluorophenibut), as well as previous studies conducted by Oracle Laboratories, regarding the pharmacology and pharmacokinetics of related compounds and derivative compounds, that have previously been analyzed for prior projects.
Binding Affinity for metabotropic GABA -B Receptors :
Baclofen (Ki: 86.08 nm)
Fluorophenibut (Ki: 99.04 nm)
Phenibut (Ki: 112.02 nm)
Agonistic Strength at Orthostatic Binding Sites on metabotropic GABA -B Receptors :
Baclofen (w 166.04)
Fluorophenibut (w161.12)
Phenibut (w 82.11)
A2o-Subunit-Containing Voltage-Gated Ca+ Channel Affinity :
Phenibut ( Ki: 18.03 nm )
Baclofen (Ki: 1496.28 nm)
Fluorophenibut (Ki: 2351.98)
TAAR1 (Trace Amine-Associated Receptor 1) Receptor Affinity :
Phenibut (Kd: 62.13 nm)
Fluorophenibut (Kd: 09.92 nm)
Baclofen (Kd: 01.02 nm)
Ionotropic GABA -A Receptor Binding Affinity :
Fluorophenibut (Ki: 93.72 nm)
Phenibut (Ki: 621.19 nm)
Baclofen (Ki: 1671.28 nm)
Also, although the final version of this study has not been published yet, here is the cover-page for the Oracle Laboratories publication regarding the pharmacology of Xyloridium - a structural derivative of Phenigabine (a previous Oracle Labs compound). Xyloridium is a novel anxiolytic medication, which acts as a pro-drug to (is metabolized into) two active metabolites - Baclofen and Fluorophenibut. (While the metabolite Baclofen selectively targets GABA -B Receptors, the compound’s metabolite Fluorophenibut possesses a plural-potentiality to bind at either metabotropic GABA -B Receptors as well as ionotropic GABA -A Receptors. Xyloridium (as well as Phenigabine) is an example of a novel Oracle Laboratories anxiolytic compound, based upon the structures of Phenibut and related phenyl-substituted GABA derivatives.
-John Gona
Psychopharmacologist
Psychotropic Treatment Specialist
Oracle Laboratories
NeuroPsych Institute
