Saturday, November 2, 2013

Phenibut, Addictive Sleep Aid With Unhealthy Hangover? Dosages, Effects, Side Effects and Safety Concerns

Some say phenibut has addictive potential, others say it stops working after only a week and a third group of people will tell you that it's highly toxic and should not be used anyway... What's true? What's bogus? And how likely is it that phenibut helps / hurts you?
In a way today's SuppVersity article is part of the reverberations of the last installment of the Science Round Up, where Carl and I have been talking about the non-existent or surprisingly excitatory effects of GABA in certain individuals. I also presented a list of GABA alternatives that ranged from valerian to melatonin - a list of natural alternatives which did for that very reason not include phenibut (also "phenybut"; I will refer to it as "PB" for convenience reasons), a γ-aminobutyric acid (GABA) molecule with an additional phenyl group in the β-position.

It is this small, but important structural difference that allows the phenibut molecules to pass through the blood brain barrier (Shulgina. 1989) and allows them to do everything GABA should, but oftentimes cannot do, because it does not reach its destination in the brain.

What effects are we talking about here? 

According to Lapin phenibut can relieve tension, anxiety, and fear, and improve the sleep quality - specifically in psychosomatic or neurotic patients (Lapin. 2001). It is however important to remember that the effects are dose- and in some cases also patient-specific. Systemically administered phenibut produces a great variety of central effects:
  • At doses that do not affect motor activity (e.g., 20 mg /kg; HED 1.6mg/kg) PB inhibits food conditioned reflexes in mice. 
  • At doses higher than 70 mg kg i.p. (HED 5.7mg/kg) PB reduces motor and exploratory activities, rearings, muscle tone, coordination and body temperature.
Moroever, PB has been shown to potentiates the central effects of the anesthetics ether, chloral hydrate, and barbiturates - so you better be careful with PB supplements if you are scheduled to be exposed to any of those.

PB does not take much for the nootropic effects

In contrast to its anxiolytic and narcotic effects, PB's nootropic effects have been observed in rodent models at dosages as low as 5 to 10 mg/kg. In human beings this would equal ~0.4-0.8mg/kg and thus less than 75mg for the vast majority of us. Interestingly, ...
Table 1: Pharmacological effect of phenibut, diazepam, and piracetam based (Lapin. 2001)
"[t]he anxiolytic effect of PB appears to be dependent on the emotional reactivity of the animals. In anxious and passive cats, PB abolished or suppressed fear and brought about an aggressive reaction to provocation. In aggressive cats PB had no effect on aggression. In non-aggressive cats without obvious fear, PB expanded the scope of positive emotional symptoms." (Lapin. 2001)
In view of the fact that similar observations have been made in rabbits by Zyablitseva et al. in 2008, we may - not without the necessary healthy skepticism, though - assume that a similar influence of the baseline mental state can be observed in human beings, as well. This would imply that the often described calming effects will be most pronounced in those of us who are already chillin'. To effectively blunt aggression, on the other hand, dosages in the 2g+ range would be necessary (estimate based on rodent studies) and I hope I don't have to warn you that this amount of PB will leave you paralyzed if not worse!

GABA & dopamine, the phenibut double-whammy

Despite the fact that the majority of its effects are probably mediated by the interaction between the PB molecules and the GABA receptors, the existing research, the majority of which happens to be in Russian, suggests that PB may also stimulate dopaminergic processes and that this effect may be important for the sedative and tranquilizing effects of the drug (Goldblat. 1986; Mehilane. 1990).
Warning: Compounding phenibut with succinate, malate, nicotinate or glutamic acid can modify not just the potency, but also the expressiveness of some particular effects (Tiurenkov. 2011). These PB + organic acid combinations are thus not necessarily save and their effects are difficult to predict - you better stay away!
The antagonistim between PB and PEA (β-phenethylamine), on the other hand, could explain the anxiolytic (=anti-anxiety) effects of this compound, of which you should by now have realized that it PB is somewhat of a diva.

If the timing and dosing are right, it does however have some pretty interesting effect that do in fact reach far beyond the psychological effects that come with the changes in neurotransmitter levels.
  • This is what WebMD will tell you about the current usage (of phenibut) - "Used for: Anxiety. Alcoholism. Irregular heartbeat. Fear. Insomnia. Tension. Stress. Fatigue. Post-traumatic stress disorder (PTSD). Depression. Improving memory, learning, and thinking. Other conditions."
    Researchers from the Volgograd State Medical Academy, for example, report that the use of PB can help ameliorate stress induced overload of the heart (Perfilova. 2007), protect the heart against the damaging effects of alcoholism (Perfilova. 2006).
  • In a similar vein phenibut has been shown to protect against the phsychological side effects of chronic stress. In rodent models, it reduced the intensity of emotional disorders in the open-field test and elevated plus maze test, ameliorated cognitive disorders in the tests for conditioned avoidance response and extrapolatory deliverance and limited stress reaction due to a decrease in the intensity of adrenal hypertrophy, thymus involution, and stomach mucous membrane ulceration (Tiurenkov. 2012).
Moroever, data from 2011 suggests that phenibut (at a relatively high HED of 325mg) and other GABA-ergic agents can protect against lipopolysacharide(LPS)-induced immune stress as it would be produced by a leaky gut (Samotrueva. 2011) 
There is still one problem: Rumors have it phenibut is not save!

Let's be honest, what would the best nootropic, tranquilizing, sleep booster be worth, if using it would pose a serious health risk? How serious? Well about as serious as this:
  • In case I am not around, when you read the results of study, it may come handy to be able to calculate the human equivalent doses for mice, rats, rabbits, pigs and other animals, wouldn't it? If you'd agree I'd suggest you head over and read my previous article on "Human Equivalent Dosages" | read more
    PB has relatively a low lethal dose 50 of 900mg/kg in mice (HED: 73mg/kg) and 700mg/kg in rats (HED: 113mg/kg; the LD50 is the amount of a substance that has to be administered so that 50% of the lab animals die). It should be said, though, that I do have a case report here informing me that a former drug addict went up to 20g per day (Högberg. 2013), when he noticed that his new "dope" lost its efficiacy after only one week and survived - not without a serious psychosis, though!
  • PB has some addictive potential. The previously case report of the drug addict makes it quite clear: For susceptible individuals the tranquilizing effect of PB will definitely have addictive potential (Samokhvalov. 2013). Plus, the fact that it loses its effect pretty rapidly is not going to help to stay within the "no danger zone", either
Ok, I know what you are thinking now: "Where is the rest of the side effects, the addictions and the psychoses?" And yes, that's basically what I have been asking myself as well, when I started searching for studies to confirm the horror stories you hear about phenibut on the Internet. A single ex-substance-abuser who overdoses on 20g(!) of phenibut is not exactly what I was thinking of, when I started researching the often-touted health hazards of an OTC supplement, of which the next best user report on reddit will tell you that "after 7 days on 4 grams/day" the corresponding user became "addicted" and "decided to go cold turkey" (google it up, if you want the source). The purported results of not following any of the Three Simple Rules of Sensible Supplementation were:
"[L]iterally no sleep, not being able to eat anything, severe depression/serious contemplation of suicide, loud tinnitus, pissing/shitting(barely anything) every 30 minutes and overall mild body pain" (I will leave it with "Anonymous")
If we look at the results of the rodent studies 2,000g/d would equal a rodent dosage of ~300mg/kg which is, as you probably realize, already 1/3 of the dosage that will kill (!) more than 50 in 100 mice who received a 300mg/kg dose of phenibut via intraperitoneal injection (~orally; the injection is used to avoid that the animals regurgitate the drugs, the pharmacology is however similar to regular oral consumption).
So if 20g is insane and 2g already too much how much would be sane? As much as I would like to provide you with a scientifically verified dosing recommendation, I can't. The necessary evidence from human studies is simply non-existent and even if it was, it would probably be suspect to high inter-individual variability and vary from one desired outcome to another. What I can tell you, though is this:
  • Listen to the Science Round-Up and read the corresponding article to learn more about GABA and potential PB alternatives | go ahead!
    Based on rodent studies, you should feel nootropic effects with dosages as low as 75mg.
  • Based on what I read on "the boards", dosages in the 125-500mg range appear to produce relaxation effects that help you sleep.
  • Moreover, common sense tells you that the (allegedly) inevitable "phenibut resistance" will occur faster with higher dosages, therefore it appears reasonable to soft-paddle and cycle β-Phenyl-GABA (PB).
In view of the non-existent scientific evidence with regards to its long-term safety, I would strongly caution against taking it each and every night. The mere fact that there is an accommodation effect and that PB holds the potential for dose-depended withdrawal symptoms should tell you that it messes with the neurotransmitter levels in your brain and that's nothing you would want to risk, if practicing sleep hygiene, stress reduction and - if all that does not help - the use of safer alternatives should actually suffice to alleviate your sleep problems. Used irregularly and as a "quick fix", it is however unlikely to be "worse" than the average FDA regulated sleeping pill.
References:
  • Danilin VP, Krylov EN, Magalif AIu, Rait ML. [Effect of fenibut on the nocturnal sleep of patients with the alcoholic abstinence syndrome]. Zh Nevropatol Psikhiatr Im S S Korsakova. 1986;86(2):251-4. 
  • Goldblat YuV, Lapin IP. Potentiation of the therapeutic effect of antiparkinsonian drugs by phenibut.Zh Nevropatol Psikhiatrii1986;86:1146–1148 (in Russian with English summary).
  • Högberg L, Szabó I, Ruusa J. [Phenibut yielded withdrawal symptoms and psychosis. Drugs for cosmonauts--now marketed as dietary supplements online]. Lakartidningen. 2013 Apr 17-23;110(16):825-7. 
  • Tiurenkov IN, Bagmetova VV, Krivitskaia AN, Berestovitskaia VM, Vasil'eva OS. [Psychotropic effect of phenibut salts and their compositions with organic acids]. Eksp Klin Farmakol. 2011;74(2):3-7.
  • Lapin I. Phenibut (beta-phenyl-GABA): a tranquilizer and nootropic drug. CNS Drug Rev. 2001 Winter;7(4):471-81.
  • Samotrueva MA, Magomedov MM, Khlebtsova EB, Tiurenkov IN. [Influence of GABA derivatives on some indices of lipid peroxidation in immunocompetent organs under experimental immunopathology conditions]. Eksp Klin Farmakol. 2011;74(8):32-6.
  • Mehilane LS, Rago LK, Allikmets LH.Pharmacology and clinic of phenibut.Tartu: Izd. TGU, 1990 (in Russian with English summary). 
  • Perfilova VN, Tiurenkov IN, Berestovitskaia VM, Vasil'eva OS. [Cardioprotective effect of GABA derivatives in acute alcohol intoxication]. Eksp Klin Farmakol. 2006 Jul-Aug;69(4):23-7.
  • Perfilova VN, Tyurenkov IN, Lebedeva SA, Volotova EV, Berestovitskaya VM, Vasil'eva OS. Effect of citrocard on functional reserves of the heart under conditions of chronic stress. Bull Exp Biol Med. 2007 Jul;144(1):21-5.
  • Shulgina GI. On neurotransmitter mechanisms of reinforcement and internal inhibition. Pavlov J Biol Sci. 1986 Oct-Dec;21(4):129-40.
  • Tiurenkov IN, Bagmetova VV, Borodkina LE, Berestovitskaia VM, Vasil'eva OS. [Fenibut and its citrate prevent psychoneurological disorders caused by chronic stress (paradoxical sleep deprivation)]. Eksp Klin Farmakol. 2012;75(6):8-13.
  • Zyablitseva EA, Pavlova IV. Effects of the GABA receptor agonist phenibut on behavior and respiration in rabbits in emotionally negative situations. Neurosci Behav Physiol. 2008 Jul;38(6):555-62.