Kratom and Phenibut: A Concise Review for Psychiatric Trainees

As of 2020, kratom is listed as a schedule I controlled substance due to its stimulant and hallucinogenic properties and is banned in six states: Alabama, Arkansas, Indiana, Rhode Island, Vermont, and Wisconsin (4). Otherwise, it is legal to sell and possess. It is sold as a supplement and is available through online retail and supplement stores.

The active ingredients of kratom are 7-hydroxymitragynine (a highly selective µ and κ opioid receptor agonist) and mitragynine (which acts on various brain receptors, including 5-HT_2A serotonergic, alpha 2-adrenergic, and dopamine receptors). At low doses, it can produce the stimulating effects of increased motivation, sociability, talkativeness, and increased energy. At high doses, it is known to produce analgesic effects and is used as maintenance for opioid withdrawal (2).

Online retailers recommend a dose of 4 to 10 grams per day, with a maximum dose of 50 grams per day. Kratom can be ingested as a powder, capsule, liquid extract, or tea. It has a half-life of approximately 24 hours and is metabolized by the liver (5). It does not show up on the standard urine drug screen, but mitragynine can be detected by gas chromatography–mass spectrometry and liquid chromatography–tandem mass spectrometry (LC-MS) (2).

Toxicity from kratom has been associated with seizures, agitation, psychosis, hallucinations, paranoia, arrhythmias, hypothyroidism, intrahepatic cholestasis, nephrotoxicity, and death (2). From 2011 to 2017, U.S. poison control centers reported that the most common side effects were agitation-irritability (22.9%) and tachycardia (21.4%) (3). The same study reported 11 deaths linked to kratom use, including two from kratom exposure alone (3). However, no causality of deaths has been established with kratom, because causes of deaths linked to kratom are confounded by the use of other substances.

Symptoms of withdrawal include nausea, sweating and chills, mydriasis, muscle and body aches, tremors, fatigue, diarrhea, rhinorrhea, and lacrimation (6). Neuropsychiatric symptoms of withdrawal include insomnia, restlessness, irritability and hostility, anxiety, mood disturbances, and hallucinations (6). There are no validated tools to monitor for symptoms of withdrawal. However, because of kratom’s opioid-like properties, the Clinical Opiate Withdrawal Scale (COWS) has been used in case reports (6, 7). There have been only a few case reports describing supervised kratom detoxification. The recommended management for withdrawal is similar to that for opioid withdrawal, with supportive therapy in managing the hyperadrenergic state. Symptoms are typically managed with symptom-triggered clonidine based on the COWS score, in addition to a scheduled anxiolytic (hydroxyzine or gabapentin), prescribed over the course of 4 to 5 days (6, 7). Concurrent use of scheduled dihydrocodeine and lofexidine, with decreased doses over 4 days based on clinical improvement, has also been reported to successfully manage symptoms of withdrawal (8).

There is still a scarcity of literature regarding maintenance therapy for kratom dependence. There have been two case reports of successfully transitioning patients to buprenorphine-naloxone maintenance therapy (9). To date, there are no studies on the effectiveness of naltrexone for kratom dependence (6).

Phenibut is still an uncontrolled substance in the United States, and it is legal to sell and possess phenibut (11). It has not been approved for clinical use in the United States.

Phenibut is used as an anxiolytic, muscle relaxant, and sleep aid and for cognitive enhancement. It acts mainly as a GABA-B receptor agonist, with some activity at the GABA-A receptor, in addition to stimulating dopamine receptors and antagonizing β-phenethylamine (endogenous anxiogenic) (11).

Phenibut is available and sold in the United States as a supplement through online retail. It can be ingested as a capsule or in powder form. Phenibut has a half-life of 5.3 hours (12). It does not show up on the standard urine drug screen. Its plasma concentration can be determined from LC-MS (13). Online retailers suggest a daily dose of 250 mg to 500 mg, with a maximum daily dose of 1,500 mg.

Toxicity is associated with altered mental status, hypertension, tachycardia, dystonia, pupillary dilation, agitation, delirium, tonic-clonic seizures, and respiratory depression. At least three case reports of phenibut toxicity have described severe agitation requiring IV sedation and subsequent intubation and mechanical ventilation (14, 15). Rhabdomyolysis secondary to agitation has also been reported (14). To date, no deaths have been reported with phenibut toxicity.

Symptoms of phenibut withdrawal include heart palpitations, anxiety, insomnia, tremors, agitation, mood lability, hallucinations, disorganization, and delusions. Symptoms of withdrawal can be heterogeneous. Hardman et al. (11) described a patient with withdrawal symptoms resembling serotonin syndrome or neuroleptic malignant syndrome (fever, tachycardia, rigidity, and inducible clonus), which did not respond to cyproheptadine. Currently, there are no validated scales to monitor symptoms of phenibut withdrawal. The Clinical Institute Withdrawal Assessment of Alcohol Scale–Revised has been used in some cases, with mixed utility (12, 16). Benzodiazepines (chlordiazepoxide, lorazepam, diazepam, valium, and nitrazepam) have been used as either a scheduled taper or as-needed medications based on the severity of withdrawal symptoms (12, 16–18). Antipsychotics (haloperidol and olanzapine) in conjunction with benzodiazepines have been used to manage agitation and aggression due to withdrawal (11). In one case report, withdrawal symptoms were successfully managed with phenobarbital taper, starting at an initial dose of 64.8 mg four times daily over the first 24 hours and then tapered down by 25%–50% every 2 to 3 days over 9 days (19). In addition, at least two case reports have described the use of scheduled baclofen tapers to successfully manage symptoms of withdrawal due to its similarity in molecular structure and mechanism of action to phenibut (12, 20). In a report by Ahuja et al. (12), baclofen taper was started at 5 mg three times daily for 2 days, followed by 5 mg twice daily on day 3 and then a dose deescalation by 2.5 mg daily until discontinuation of baclofen. Samokhvalov et al. (20) substituted baclofen for phenibut (1 gram of phenibut to 8–10 mg of baclofen) over 9 weeks, and then baclofen was tapered off over the following 12 weeks.

To the best of our knowledge, there are no studies about maintenance therapy for phenibut dependence.