Oops.. I somehow made a double-post. I though the original post didn't go through, and so I re-typed my reply, and now cannot delete the original post. Sorry for the confusion.
I’m not entirely sure what you’re asking. Are you asking if cross-tolerance develops to the effects of Phenibut and Baclofen, or if they substitute for each other during withdrawal syndrome? The answer is yes for both, to some extent..
Phenibut, like Baclofen, functions as a highly selective and competitive agonist of the GABA -B Receptor, although Phenibut also possesses the additional action of being a “gabapentinoid” - meaning that it acts at a2o-subunit-containing Voltage-Gated Ca+ (calcium) channels, where it exerts an inhibitory action. Although Baclofen does display some affinity for these a2o Ca+ Channel sites, it’s overall action at these sites is so minute that it is a medically irrelevant action - making Baclofen a pure, selective, and competitive GABA -B Receptor agonist, whereas Phenibut exerts this action, yet also acts at the a2o-subunit Voltage-Gated Ca+ channel sites.
As PeopleProgrammer mentioned, the classical “gabapentinoid” compounds are all based on the GABA carbon backbone, simply with various functional group substitutions that either make them lipophillic enough to permeate the Blood-Brain-Barrier, or give them an inherent affinity for a particular target binding site. GABA is produced in the brain and does not cross the Blood-Brain-Barrier on it’s own, so orally-administered GABA is completely destroyed via first-pass metabolism in the stomach. In the case of Phenibut and Baclofen, it is the addition of the cyclic aromatic phenyl ring that makes the overall molecule lipophillic (fat soluble) enough, and carries the GABA molecule across the Blood-Brain-Barrier where it is actually active, centrally. It is also the addition of this cyclic phenyl ring that makes Phenibut and Baclofen highly selective for the GABA -B Receptor over the GABA -A subtype. However, there is one slight addition of a halogen group (in this case, a chlorine atom) on the para position of the phenyl ring of Baclofen, that Phenibut lacks. This group alters the pharmacology and pharmacokinetic metabolism of Baclofen in two ways. Firstly, the addition of that single chlorine significantly protects the Baclofen molecule from the extreme first-pass metabolism that Phenibut is subjected to in the gut and the gastrointestinal tract (destroying the vast majority of the orally-administered dose) - which is why typical oral doses of Phenibut are around 1000mg to 2000mg, and typical oral doses of Baclofen are 10mg to 20mg. It is also the addition of this chlorine atom that nullifies almost all of Baclofen’s affinity for Voltage-Gated Ca+ (calcium) Channels that other gabapentinoids (including Phenibut, Gabapentin, and Pregabalin possess). - This makes Phenibut both a GABA -B agonist as well as a “gabapnetinoid”, whereas Baclofen is more appropriately categorized as a purely selective GABA -B agonist. So yes, Phenibut and Baclofen possess cross-tolerance as GABA -B Receptor agonists, and will substitute for each other in this regard, but not in Phenibut’s gabapentinoid action at Voltage-Gated Ca+ Channels, which Baclofen lacks.
(There is another research compound currently circulating known as F-Phenibut or Fluorophenibut, which functions along the same lines as Baclofen - and consists of the GABA molecule with a cyclic phenyl ring (Phenibut), with the addition of a halogen group at the para-position of the phenyl ring (in this case a fluorine group in the place of Baclofen’s chlorine group)).
Now, in the case of the other “gabapentinoid” compounds (such as Gabapentin (Neurontin) and Pregnable (Lyrica)) that exert action against neuropathic pain via their inhibitory action at a2o-subunit-containing Voltage-Gated Ca+ Channel sites, that do not have any direct affinity for GABA Receptors, most of them still have some GABAergic effect in enhancing the action of GABA, by increasing the metabolic pathways of glutamate decarboxylase and aminotransferase (two enzymes responsible for the biosynthesis of GABA from Glutamate), as well as increasing the neuronal density of GABA transporter molecules, which can affect pre-synaptic reuptake of GABA that is released into the synaptic cleft.
So, in short, yes - Phenibut will fully substitute for Baclofen withdrawal syndrome plus some (with it’s additional effect as a Voltage-Gated Ca+ Channel site inhibtor), however Baclofen will only partially substitute for Phenibut during withdrawal syndrome (at least the GABA -B Receptor agonism, but lacking the Ca+ Channel inhibition of Phenibut). Also, yes, to some degree over time, the GABA -B agonism will develop some cross-tolerance, as repeated use of either GABA -B Receptor agonist will eventually cause some down-regulation of GABA -B Receptors. However, if the drugs are alternated in cycles like you describe, this will probably slow the development of this cross-tolerance for a while.
We had poster ask me to provide some general information, comparing and contrasting several of the more well-known gabapentinoid compounds in a thread asking about Baclofen vs. Phenibut for anxiety, and that information is probably pertinent here, also:
Gabapentin (common brand name Neurontin) - Of course, this is the prototype of this class of compounds, that was first identified as having an inhibitory effect on a2o-subunit-containing Voltage-Dependent Ca+ channel neuro-transmission in certain neurons in the brain. This inhibitory action on Voltage-Gated Calcium Channels calms the action of certain neuronal channels, and although Gabapentin has no direct binding affinity for GABA -A or GABA -B Receptors directly, in some ways it can be characterizes as a GABA modulator and/or GABA-productionn catalyst. Chemically, Gabapentin is the neurotransmitter GABA (Gamma-Aminobutyric Acid) with the addition of a cyclic cyclohexyl ring to the GABA backbone. Pharmacologically, this appears to nullify any affinity for either the ionotropic GABA -A Receptors or the metabotropic GABA -B Receptors. Instead, it possesses a novel mechanism-of-action that defines the gabapentinoid class of compounds - that is that it acts selectively as an inhibitor of a2o-subunit-containing Voltage-Gated Ca+ Channels in various types of neurons throughout various brain structures. (As well as within a2o Ca+ channels within nerve fibers in the spinal cord and Peripheral-Nervous-System, as well). It is this action that makes Gabapentin suitable for the treatment of certain types of neuropathic pain disorders.
Although in some circles, Gabapentin is used for the treatment of some anxiety disorders, its only real prevalent use in psychiatry (in my personal experience, using it alongside psychiatrists) is its use off-label as a mood-stabilizer (similar to the way that Lithium is used) even though its precise mechanism-of-action is distinct from that of traditional mood-stabilizing drugs. The action by which Gabapentin exerts its mild mood-stabilizing effects is likely via the same mechanism that it effects anxiety disorders - in that Gabapentin modulates the action of glutamate decarboxylase and aminotransferase (two enzymes that are responsible for the biosynthesis of GABA).
Pregabalin (common brand name Lyrica) - A close structural analogue of Gabapentin, and another structural derivative of the endogenous neurotransmitter GABA (Gamma-Aminobutyric Acid). Chemically, Pregabalin is also composed of the chemical backbone of GABA, with the addition of an isobutyl group (in place of the cyclohexyl group on the Gabapentin molecule), making it roughly 2.5x as potent at a2o-subunit Voltage-Gated Calcium Channel sites than Gabapentin itself. Because of it's stronger inhibitory action at these sites, as well as its more prominent action on increasing GABA biosynthesis (via glutamate decarboxylase and aminotransferase) as well as increasing the synaptic density of the GABA transporter molecules and increasing the functional rate of GABA transport from synaptic space to pre-synaptic neurons (and vise-versa), it has been declared as a drug of potential abuse and federally scheduled as a Schedule V Drug by the US Drug Enforcement Administration. Because of its more pronounced action on GABA biosythesis, GABA reuptake (via affecting the GABA transporter), and its increased inhibitory action on a2o-subunit Ca+ Channels, it has been proven to be considerably more effective than Gabapentin in several clinical trials evaluating its effectiveness for the treatment of anxiety disorders such as Generalized Anxiety Disorder. (Although this use is generally accompanied by the use of a Tricyclic Antidepressant or Selective-Serotonin Reuptake Inhibitor (SSRI)). A recent clinical evaluation by Bandelow et al. (2007) comparing the long-term effectiveness of Pregabalin against traditional anxiolytic agents such as various benzodiazepines and drugs such as venlafaxine, concluded that Pregabalin may be as effective at treating Generalized Anxiety Disorder as these drugs are, while remaining more effective long-term compared to several benzodiazepine drugs, due to the rapid development of tolerance to benzodiazepine drugs in many subjects. Now, these findings are encouraging at first glance, but have yet to be replicated (or displayed on a large-scale study population), and in my professional opinion - although potentially beneficial for the treatment of Generalized Anxiety Disorder with the co-administration of a serotonergic agent such as a Tricyclic Antidepressant or Selective-Serotonin Reuptake Inhibitor (SSRI), I do not feel that Pregabalin provides enough GABAergic activity to truly be effective at treating severe anxiety disorders, or psychophysical anxiety disorders, such as Panic Attack Disorder.
Phenibut - Although originally believed to function solely as a selective and competitive metabotropic GABA -B Receptor agonist, recent studies have revealed that in addition to Phenibut's affinity for GABA -B Receptors, it too, like Gabapentin and Pregabalin, acts as a selective a2o-subunit Voltage-Gated-Calcium Channel site inhibitor. Now, as stated in this thread, I do feel that Phenibut is over-used by many in the nootropic/"research chemical" sector online, but I do absolutely feel that it has therapeutic value as an anxiolytic drug, and I have even developed structural relatives and novel compounds based upon its structure for the treatment of anxiety disorders. Phenibut exerts its anxioltyic action via three primary mechanisms-of-action - Firstly, because of its selective and competitive agonism of metabotropic GABA -B Receptors - Second, because of its gabapentinoid inhibitory action at a2o-subunit-containing Voltage-Gated Ca+ Channel neuro-transmission - And third, because of its action as a TAAR1 (Trace Amine-Associated Receptor 1) antagonist, which effectively antagonizes the endogenous substance B-phenethylamine. (Which is the prototype backbone structure for drugs such as amphetamine, some substituted cathinones, and some other substituted phenthylamines, which can induce anxiety). Chemically, Phenibut is also a derivative of GABA (Gamma-Aminobutyric Acid) and consists of the GABA backbone, with the addition of a cyclic phenyl ring, which allows the GABA molecule to be lipophillic (fat-soluble) enough to permeate the Blood-Brain-Barrier - and also makes it competitively selective for the GABA -B Receptor over the GABA -A subtype, also providing the molecule with a binding affinity for the TAAR1 Receptor. (Which GABA itself does not).
Gabapentin, Pregabalin, and Phenibut are all close structural relatives, and are all chemical derivatives of GABA (Gama-Aminobutyric Acid), the differences being the addition of a cyclohexyl group on the GABA chain in the case of Gabapentin, the substitution of that cyclohexyl group for an isobutyl group in the case of Pregabalin, and the substitution of that isobutyl group with a cyclic phenyl ring in the case of Phenibut.
Baclofen - Despite having some measurable affinity for the same a2o-subunit Voltage-Gated Calcium Channel sites that the other gabapentinoid compounds listed here do, the actual affinity of Baclofen for these sites is so minute, that I consider it medically insignificant in regards to Baclofen's overall pharmacological mechanism-of-action. Chemically, Baclofen is the exact same molecule as Phenibut (the GABA molecule with the addition of the cyclic phenyl ring) - with the only difference being the addition of a single chloride atom on the para position of the phenyl ring of Phenibut. This very slight chemical difference has a surprisingly dramatic effect on Baclofen's overall pharmacological mechanism-of-action. The addition of the chloride atom on Baclofen's phenyl ring dramatically shields it from the extensive first-pass metabolism in the stomach the Phenibut is subject to. (Typical doses of Phenibut are around 1000mg, whereas typical Baclofen doses are around 20mg). The addition of the chloride atom on Baclofen's phenyl ring does not affect its selectivity for the metabotropic GABA -B Receptor, as Baclofen retains similar binding affinity and action as an agonist at GABA -B Receptor subtypes. However, the addition of the chloride atom on Baclofen's phenyl ring does appear to significantly diminish its affinity for the a2o-subunit Voltage-Gated Ca+ Channel sites that the other gabapentinoid compounds mentioned here possess. Additionally, the addition of the chloride atom on the phenyl ring of Baclofen appears to block all affinity for the TAAR1 (Trace Amine-Associated Receptor 1), for which Phenibut displays noteworthy affinity for, and for which Baclofen does not. So, despite having some measurable affinity for a20-subunit Voltage-Gated Calcium Channel sites like the other gabapentinoids mentioned above, its actual action at these sites is so minute that Baclofen's only real medically noteworthy mechanism-of-action is as a highly selective and competitive metabotropic GABA -B Receptor agonist.
If you are using two or more of these drugs at once and are still not experiencing relief, you may be exhausting the therapeutic potential of this drug class, and may need to look into a ce ntrally-acting pain medication, such as an opioid painkiller. (Starting with something mild, such as Tramadol or hydroquinone, perhaps). As mentioned previously, Baclofen will work to relax skeletal smooth muscle tissue (like Phenibut, also), but has almost no medically-significant action on Voltage-Gated Calcium Channel sites like Phenibut does. With herniated disks, it can sometimes be difficult to determine if the pain you are experiencing is nerve pain, skeletal pain, or muscle pain. Whereas the gabapentinoid drugs that were covered in this thread will help to address nerve pain, and a centrally-acting opioid painkiller will address skeletal and muscle pain, one GABA -A Receptor agonist muscle-relaxant drug comes to mind.. namely, Carisoprodol (Soma), which was only recently scheduled in a lot of countries, but experienced fairly widespread use for years without being a controlled substance. It is a MUCH more effective skeletal muscle relaxant than Baclofen, and may offer you some relief. However, just as always, consult with your physician before combining multiple sedative drugs that affect overall cognition.
-John Gona
Psychopharmacologist
Psychotropic Treatment Specialist
Oracle Laboratories
NeuroPsych Institute
Edited by Oracle Laboratories, 12 July 2016 - 02:42 PM.
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