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Phenibut, the Gas Station Gabapentinoid and GABA(B) Agonist

Phenibut (β-phenyl-GABA)

phenibut structure, mechanism, mnemonics, ballicules, mascot

Nickname / Mnemonic phrase: “bacloFEN-a-butt is a GABApentinoid”

Pronunciation: Fin i but

Street nicknames: pbut, party powder

  • Voltage-gated calcium channel blocker (like gabapentin and pregabalin)

  • GABA-B agonist (like baclofen)

  • Rx drug in Russia, used for treatment of anxiety and alcohol withdrawal

  • Available at US gas stations, marketed as a nootropic

  • Illegal in some US states

Mechanism of action of phenibut in context of baclofen and gabapentin by Jason Cafer MD

Phenibut was first synthesized in Russia in the 1960s. It has become a popular drug of abuse in the US, available at gas stations as a nootropic ("smart drug") although it is more of a sedative.

Phenibut can cause physiological dependence. Although treatment guidelines have not been established, withdrawal could reasonably be managed with baclofen (Weleff et al, 2023) +/- gabapentin. Baclofen, which has no known abuse potential, could be continued for maintenance. Since gabapentin is abusable, it should probably not be used for maintenance in individuals who struggled with phenibut addiction.

Here is a phenibut-containing product from a Missouri gas station. No patients have brought this to me seeking approval.

ADDALL XR contains phenibut

To understand the mechanism of phenibut in context, let's look at baclofen and gabapentin, neither of which are FDA-controlled substances.

Baclofen (LIORESAL)

 ❖ Antispasmodic (muscle relaxer)

 ❖ GABA(B) agonist

Baclofen (Lioresal) mascot, mechanism of action, structure, mascot, ballicule by Jason Cafer MD

FDA-approved for:

 ❖ Spasticity

 ❖ Cerebral palsy

Used off label for:

 ❖ Alcohol use disorder

 ❖ Alcohol withdrawal

 ❖ Phenibut withdrawal

 ❖ Fibromyalgia

 ❖ Intractable hiccups

 ❖ Multiple sclerosis pain

 ❖ Interstitial cystitis pain

Mechanism of Baclofen

ballicules of GABA-B receptor ligands including GABA, baclofen, GHB (Xyrem), alcohol and phenibut with mnemonics by Jason Cafer MD

Baclofen mechanism at Gaba-B receptor by Jason Cafer MD

The muscle relaxant baclofen is generally referred to by its generic name, which is cooler than the trade name (Lioresal).  Baclofen activates GABA(B) receptors (“B” for baclofen), relieving spasticity without producing euphoria or pleasant effects. Although non-addictive, baclofen is associated with a withdrawal syndrome similar to GABA(A) receptor agonists like benzodiazepines.

Baclofen is not a controlled substance.

For cerebral palsy, baclofen may be administered intrathecally (into cerebrospinal fluid) through an implanted pump. There are only two other drugs FDA-approved for intrathecal administration—morphine (opioid) and ziconotide (atypical analgesic that reduces release of Substance P).

There is a black box warning that abrupt discontinuation of intrathecal baclofen may result in high fever, altered mental status and exaggerated rebound spasticity, which in rare cases has advanced to rhabdomyolysis and multiple organ-system failure. Caregivers must understand the importance of keeping refill visits and heeding pump alarms.

Baclofen may elevate blood glucose, a side effect not seen with GABA(A) receptor agonists such as benzodiazepines.

Baclofen is used off-label for alcohol use disorder (AUD) to reduce anxiety and cravings. It may be more effective for AUD than the FDA-approved medications for this indication (acamprosate, naltrexone, disulfiram).

For unknown reason baclofen appears to increase risk for opioid overdose relative to other muscle relaxants (Khan et al 2022).

Dosing of Baclofen

For spasticity, start 5 mg PO TID, may increase by 15 mg/day increments in 3-day intervals. Target dose is 20–80 mg divided TID–QID; Max is 80 mg/day. For alcohol use disorder there is no established dose, but most trials used fixed dosing of 30–80 mg/day in divided doses; Consider prescribing 5 mg TID x 3 days, then 10 mg TID, may increase dose to 20 mg TID; Taper gradually to stop.

Gabapentin (NEURONTIN)

 ❖ Antiepileptic drug

 ❖ Voltage-gated calcium channel blocker (decreases glutamatergic neurotransmission)

Mnemonics for gabapentin (Neurontin) with mascot and ballicule from CaferMed

FDA-approved for:

 ❖ Focal seizures

 ❖ Post-herpetic neuralgia

 ❖ Restless legs syndrome (as Horizant ER)

Used off label for:

 ❖ Neuropathic pain

 ❖ Fibromyalgia

 ❖ Migraine prophylaxis

 ❖ Anxiety (generalized, social, panic) 

 ❖ Alcohol use disorder (sobriety maintenance)

 ❖ Alcohol withdrawal

 ❖ Cannabis use disorder

 ❖ Nightmares

 ❖ Improved quality of sleep

 ❖ Vasomotor menopause symptoms (hot flashes)

Gabapentin (Neurontin) has the reputation of being a well-tolerated though not a particularly powerful antiepileptic drug (AED). 

The name derives from its structural similarity to GABA, the brain’s chief inhibitory neurotransmitter. Despite its name and structure, gabapentin does not affect GABA activity in any way. Gabapentin does not bind GABA receptors (as do benzodiazepines and barbiturates), inhibit GABA reuptake (like tiagabine), or block degradation of GABA (like vigabatrin). Gabapentin blocks voltage-gated calcium channels (as do lamotrigine, topiramate and pregabalin).

Gabapentin is the #1 prescribed medication of the AED class, and the #11 overall prescribed drug. Most commonly, gabapentin is prescribed for conditions other than seizure disorders, many of which are off-label. It is widely prescribed for neuropathic pain. Gabapentin is sometimes used adjunctively for bipolar disorder, but it has little, if any, mood stabilizing efficacy. It does have anxiolytic properties.

Gabapentin may cause modest weight gain. Some patients experience sedation, dizziness, ataxia, fatigue, and dyspepsia. There is a small risk of DRESS Syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms), which is potentially fatal. 

Neurontin is excreted unchanged in urine, making it immune from CYP interactions. There are no genetic polymorphisms that influence its metabolism. In other words, no one is a poor metabolizer or ultrarapid metabolizer of gabapentin.

As of 2020, gabapentin is not a DEA controlled substance. Several US states have regulated gabapentin since 2017 as a result of gabapentin being detected in up to a third of the state’s fatal overdoses. In 2020 the FDA required a label warning about the risk of life-threatening respiratory depression for patients with respiratory risk factors (COPD, the elderly, those taking opioids). Of 9,174 single-drug exposures to gabapentin reported to Poison Control, there were 109 major serious outcomes and 8 deaths (Nelson & Spyker, 2017).

Gabapentin was initially regarded as having no abuse potential, but issues have arisen. Prison physicians no longer commonly prescribe it due to high rates of diversion. About 20% of individuals who abuse opioids will also overuse gabapentin because it can potentiate the opioid high. Otherwise, only 1–2% of patients overuse gabapentin.

Gabapentin is similar in structure and mechanism to pregabalin (Lyrica). Gabapentin and pregabalin constitute the gabapentinoid class of medication. Side effects attributed to pregabalin, such as peripheral edema, may also apply to gabapentin.

A gabapentin withdrawal syndrome is possible. It can include disorientation, anxiety, palpitations, diaphoresis, and abdominal cramps. Sudden withdrawal of any antiepileptic can precipitate a seizure, even for an individual without a seizure disorder.

Gabapentin has non-linear pharmacokinetics because its absorption in the gut becomes saturated at doses beyond 900–1,200 mg per single dose. In terms of what actually gets absorbed ( bioavailability), 900 mg of gabapentin equates to 540 mg and 2400 mg equates to 816 mg (Carlat Psychiatry Report).

To address the absorption problem, gabapentin can be taken in extended release GRALISE [gra LEEZ] formulation taken once daily with dinner. Gralise is gabapentin extended release.

Dosing of Gabapentin

The lowest-strength capsule is 100 mg. The minimum effective dose is generally 300 mg TID. For seizure disorder, start 300 mg TID. For other conditions, the label recommends starting 300 mg QD x 1 day, then 300 mg BID x 1 day, then 300 mg TID. The maximum total daily dose is 3,600 mg, which is probably too high for psychiatric conditions. The author’s target dose is 300–600 mg TID and occasionally as high as 900 mg TID. For patients with opioid use disorder, it is recommended not to exceed 900 mg daily (300 mg TID) due to risk of overdose (Gomes et al, 2017). For nightmares or improvement of sleep quality, a reasonable dose is 300–900 mg HS. As for any antiepileptic drug, taper to discontinue.

Copyright 2024, CaferMed Publishing

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