Nootropics, colloquially known as “smart drugs,” are a broad category of compounds marketed for their ability to improve memory, concentration, and alertness. They can be divided into two categories: prescription and nonprescription drugs. Prescription nootropics, such as methylphenidate, amphetamines, and modafinil, are among the most widely misused pharmaceuticals on the market, while nonprescription nootropics have little evidence that they benefit cognition. In fact, many have substantial addictive potential and can cause dangerous psychoactive and adverse medical effects.

The use and availability of nootropics have exploded in recent years. Kratom, for instance, is a tropical leaf from Southeast Asia with both opioid (at higher doses) and stimulant-like (at lower doses) properties that is highly addictive and can cause fatal overdose. Nearly unknown in Western medicine until recently, kratom is now used by millions of people who easily obtain it online, at smoke shops, or at gas stations (Groff D et al, J Addict Dis 2022;40(1):131–141). For more on kratom, see CATR Jan/Feb 2021.

Assessing use

Nootropic use is seldom screened for in clinical settings, and most patients will never have been asked about these drugs. Given their easy over-the-counter (OTC) and online availability, patients may not view them as medications or drugs at all and so may not report use. Apart from prescription stimulants, nootropics are not included in routine urine drug screens, so it is important to directly ask patients about their use during intake interviews and periodically over the course of treatment. 

Keep in mind that few patients will be familiar with the term “nootropics,” so we recommend asking patients whether they are taking anything OTC meant to enhance memory or boost energy levels. Naming a few specific nootropic agents can be helpful; Some common ones are ginseng, ginkgo, vinpocetine, L-theanine, kratom, khat, phenibut, and tianeptine. And we always like to include a broad catch-all screening question such as, “Do you take any OTC or herbal products at all?”

Two up-and-comers

Of all the available OTC nootropics, phenibut and tianeptine are two that have become particularly concerning in recent years due to their growing popularity, addictive properties, and potential to cause significant harm. Here, we’ll outline what you need to know about each.

Phenibut 

Known colloquially as “pbut” or “party powder,” phenibut was first synthesized in the Soviet Union in the 1960s. It has two main mechanisms of action: It is a GABA-B agonist, like baclofen, and a voltage-gated calcium channel inhibitor, like gabapentin and pregabalin. It is still prescribed today in Russia and some post-Soviet states for alcohol withdrawal and anxiety-related conditions (Lapin I, CNS Drug Rev 2001;7(4):471–481). In the US, it is marketed as an OTC nootropic and anxiolytic.

As might be expected from a GABA agonist, phenibut typically gives feelings of relaxation and anxiolysis but causes CNS depression when taken in excess. Its effects can be profound, including the need for hospitalization and even intubation (in severe cases). Treatment of phenibut intoxication, like that of other GABA agonists, is primarily supportive. Severe intoxication that compromises airway integrity should be managed in the ICU (Weleff J et al, J Addict Med 2023;17(4):407–417). 

Phenibut can cause physiologic dependence with only a few days of use, and drug cessation can result in a severe withdrawal syndrome. Withdrawal symptoms can vary widely, but they include seizure, agitation, and delirium as well as unusual movement disorders such as catatonia, rigidity, and tremors, likely due to glutamate and dopamine dysregulation.

There is no standardized protocol for phenibut withdrawal management, but it is typically treated like withdrawal from other GABAergic agents, such as alcohol or benzodiazepines: with tapering doses of barbiturates, benzodiazepines, or baclofen (as well as adjunctive GABA modulators like gabapentin). While there is no firmly established pharmacologic treatment for phenibut addiction, evidence suggests that baclofen might be an effective option (Weleff et al, 2023).

Tianeptine

First synthesized in France in the 1960s, tianeptine was initially touted as a rapid-acting tricyclic antidepressant. However, its mood-altering effects likely have less to do with serotonin and norepinephrine, and more to do with mu-opioid agonism (Samuels BA et al, Neuropsychopharmacology 2017;42(10):2052–2063). Tianeptine is still legal in France but is now classified as a synthetic opioid and scheduled as a narcotic. 

In the US, tianeptine is unregulated and widely available as part of supplement mixtures under the brand names ZaZa and Tianna. Companies typically do not advertise tianeptine’s opioid agonism, though it has become common knowledge among those who use the drug, earning it the street names “gas station dope” and “gas station heroin.” In 2018, Michigan became the first state to ban its sale, with several others following suit, though it is still widely available online.

Fueled by mu-opioid agonism, tianeptine is highly addictive. And its short half-life of only 2.5 hours can lead to rapid dose escalation; case reports include descriptions of people using 1,500–5,000 mg daily, over 100 times the prescribed dose (Springer J and Cubala WJ, J Psychoactive Drugs 2018;50(3):275–280). Like phenibut, many professionals are unaware that tianeptine is widely misused, and it is not detected by routine urine immunoassays.

Clinically, tianeptine should be managed like other opioids; symptoms of intoxication and withdrawal, as well as the risk of overdose, are essentially identical. Patients experiencing tianeptine overdose should receive naloxone as soon as possible (Ari M et al, Hum Exp Toxicol 2010;29(9):793–795). Withdrawal can be treated with buprenorphine or alpha-2 adrenergic agonists like clonidine along with supportive care. Like other opioids, studies have shown that buprenorphine may be useful as maintenance treatment for tianeptine addiction (Trowbridge P and Walley A, J Addict Med 2019;13(4):331–333).

CARLAT VERDICT

Seldom discussed among medical professionals, nootropics are drugs that are marketed for pro-cognitive effects (unsupported by evidence) but carry significant medical and addictive risks. Many are unregulated and sold OTC, so be sure to routinely ask your patients if they are using nootropics. Phenibut and tianeptine are two of the most worrying agents that can cause serious harm. In terms of treatment approaches, think of phenibut as a GABA agonist and tianeptine as an opioid.