Ephedra, DMAA, DMBA, DMHA: how a pre-workout stimulant gets removed and replaced

Every few years a new stimulant turns up in pre-workout and weight-loss supplements. It sells for a while under a botanical name, it draws a letter from the Food and Drug Administration, and it is replaced by a near neighbour that the letter did not mention. The compounds change. The sequence does not.

This piece walks that sequence five times. The backbone is a set of analytical papers in which researchers bought the products and measured what was in them, because that is the one part of the story a label will not tell you. Where a paper found that the label and the contents disagreed, both numbers are given. Nothing here is a dose, and no product is named except as the subject of an analysis or an enforcement document.

Why the sequence exists

Under the Dietary Supplement Health and Education Act of 1994 (DSHEA) a supplement reaches the shelf before anyone outside the company has looked at it. The Government Accountability Office described the position in 2009: "Under DSHEA, dietary supplements are broadly presumed safe, and FDA does not have the authority to require them to be approved for safety and efficacy before they enter the market, as it does for drugs."[1] FDA's own ingredient directory says the same in fewer words: "As a reminder, FDA does not approve dietary supplements for safety and effectiveness."[2]

Removal runs the other way, one ingredient at a time. Announcing warning letters in April 2015, FDA set out the rule it works under: "Under existing law, including the Dietary Supplement Health and Education Act passed by Congress in 1994, the FDA can take action to remove products from the market, but the agency must first establish that such products are adulterated (e.g., that the product is unsafe) or misbranded (e.g., that the labeling is false or misleading)."[3] Pieter Cohen, the Harvard internist whose collaborations produced most of the analyses below, put the consequence plainly in 2014: "The FDA is charged with the unenviable task of identifying and removing dangerous supplements only after they have caused harm."[4]

Each action names an ingredient. The next ingredient is not named, because it has not been sold yet, or because it differs from the named one by a single carbon. That is the whole mechanism, and the rest of this article is the mechanism running.

Ephedra: the only one that took a rule

What it is. Ma huang, the dried stem of Ephedra sinica, contains ephedrine and a family of related amines. FDA's 2004 rule lists them: "The ephedrine alkaloids, including, among others, ephedrine, pseudoephedrine, norephedrine, methylephedrine, norpseudoephedrine, methylpseudoephedrine, are chemical stimulants that occur naturally in some botanicals (Refs. 1 through 5), but can be synthetically derived."[5] The same document notes that "ephedrine from Ephedra (Ephedra sinica Stapf) is chemically indistinguishable from synthetic (-)-ephedrine manufactured by a pharmaceutical company."[5] Unlike every compound that followed it, ephedra really is a plant and its stimulant really is in the plant.

How far it spread. GAO told Congress in July 2003 that "The dietary supplement industry has estimated that as many as 3 billion servings of dietary supplements containing ephedra are consumed each year in the United States."[6]

What FDA did, and how long it took. The first move was a proposed rule in June 1997 that would have capped the amount per serving and limited use to a week. At that point FDA had "more than 800 reports of illnesses and injuries (AER's) associated with the use of more than 100 different dietary supplement products that contained, or were suspected to contain, ephedrine alkaloids."[7] In April 2000 FDA withdrew the cap and the time limit after a GAO review: "However, GAO expressed concerns about the use of the reported adverse events in supporting the proposed dosing level and duration of use limit, and concluded that the agency needed additional evidence to support these restrictions."[8] In March 2003 the comment period was reopened, by then with "approximately 17,000 adverse event reports received overall by FDA".[9]

The evidence review FDA commissioned from RAND was published in JAMA that month. It found that "Use of ephedra or ephedrine and caffeine is associated with increased risk of psychiatric, autonomic, or gastrointestinal symptoms, and heart palpitations." and that "There are no data regarding long-term weight loss, and evidence to support use of ephedra for athletic performance is insufficient."[10]

The final rule was published on 11 February 2004: "This rule is effective on April 12, 2004."[5] Its finding was categorical: "We conclude that dietary supplements containing ephedrine alkaloids are adulterated under section 402(f)(1)(A) (21 U.S.C. 342(f)(1)(A)) of the act because they present an unreasonable risk of illness or injury under the conditions of use recommended or suggested in labeling, or if no conditions of use are suggested or recommended in labeling, under ordinary conditions of use."[5] FDA was explicit that it was weighing rather than counting: "``Unreasonable risk,'' thus, represents a relative weighing of the product's known and reasonably likely risks against its known and reasonably likely benefits."[5] It conceded the limit of its own evidence: "Furthermore, we agree that the RAND report did not conclude that a causal relationship between ephedra and the reported adverse events had been shown."[5] And it explained why it wrote a rule rather than suing product by product: "it is more efficient to declare these products adulterated as a category than to remove them from the market in individual enforcement actions in which we would have to establish, for each individual product, that they present a significant or unreasonable risk."[5]

A Utah district court set the rule aside for low-dose products in 2005. The Tenth Circuit reversed on 17 August 2006, holding that "Congress unambiguously required the FDA to conduct a risk-benefit analysis under DSHEA." and "Accordingly, the district court's decision is reversed, and we remand for entry of judgment in favor of defendants."[11] The Supreme Court's docket closes the matter in four words: "May 14 2007 Petition DENIED."[12] Seven years from proposal to rule, and three more to the end of the litigation. Ephedra is the only stimulant in this article removed by rulemaking rather than by letter, and the 2004 rule is still the only time FDA has used that power on a supplement ingredient.

What replaced it. Three FDA scientists wrote in 2006 that "Following the marketing ban of ephedra-containing supplements in April 2004, many manufacturers substituted the herb Citrus aurantium for ephedra and marketed the products as" ephedra-free supplements.[13] Bitter orange was the first replacement. The second was a decongestant from the 1940s.

DMAA: a nasal inhaler with a geranium story

What it is. 1,3-dimethylamylamine, PubChem CID 7753, is 4-methylhexan-2-amine. PubChem's whole description of it is "Methylhexaneamine is an alkylamine."[14] It is a straight aliphatic amine, not an alkaloid and not a phenethylamine. The Eleventh Circuit summarised its history in 2019: "The earliest known identification or use of DMAA occurred in 1944. In that year Eli Lilly & Co. synthesized and patented DMAA for use as a nasal decongestant. For marketing reasons, Eli Lilly asked the FDA to withdraw its approval of this use in 1983."[15] Cohen's 2012 account gives different dates, placing the launch in 1948 and saying that "By the 1970s, it had been withdrawn as an approved pharmaceutical."[16] The two sources agree on the shape and disagree on the years.

The geranium story. DSHEA admits a botanical or a constituent of a botanical. DMAA entered supplements around 2006 labelled as geranium extract, and Cohen wrote in 2012 that "Remarkably, the evidence to support the sale of DMAA-containing supplements hinges on a single study."[16] That study was a 1996 paper in a Chinese regional journal. He added: "This lack of evidence has not deterred multiple supplement companies from marketing DMAA as if it were isolated from geranium."[16]

The analytical literature then did what the 1996 paper had not. An Australian anti-doping laboratory reported in 2011: "This communication shows that geranium oils do not contain methylhexaneamine and that products labelled as containing geranium oil but which contain methylhexaneamine can only arise from the addition of synthetic material."[17] A Texas group used stereochemistry in 2012: "The stereoisomeric ratios of DMAA in the synthetic standards and in all the commercial supplements were indistinguishable."[18] ElSohly's group at Mississippi used authenticated plant material the same year: "The data show that none of the authenticated P. graveolens essential oils or plant material, nor any commercial volatile oil of Pelargonium (geranium oil) contain MHA at detectable levels (limit of detection: 10 ppb)."[19]

Two papers found the opposite, and both were paid for by the company with the most to lose. A University of Memphis group reported in 2012 that "The reported concentrations of 1,3-DMAA ranged from 68 to 496 ng/g and 1,4-DMAA ranged from 13 to 162 ng/g." and acknowledged: "The authors would like to acknowledge and thank USP Labs, LLC for funding portions of this work."[20] A contract laboratory's paper the same year carried the line "This research was financially supported by USPlabs LLC."[21] Nanograms per gram is parts per billion. In 2015 four laboratories split the same samples and reported that "None of the laboratories detected MHA in any of the samples at or around the 10 ppb detection level of the procedure used."[22] The Department of Defense's 2013 review recorded the industry's own position: "industry admits that the DMAA used in the supplements is synthetic in origin, coming from multiple sources."[23]

How far it spread. Cohen in 2012: "Surprisingly, DMAA is currently used as an ingredient in roughly 200 sports supplements, many sold in major franchises throughout the United States, with sales topping $100 million in 2010 alone".[16] The World Anti-Doping Agency had already acted for the 2010 season, recording that "methylhexeneamine, a non-therapeutic substance, were added to the closed list of non-specified stimulants."[24]

What FDA did. The military moved first. The Department of Defense panel's report opens: "Since May 2011, four Soldiers who died following physical exercise were found to have traces of dimethylamylamine in their blood analyses."[23] DMAA products were pulled from military exchanges in December 2011. The panel's own conclusion was careful: "The existing evidence does not conclusively establish that DMAA-containing substances are causally-associated with adverse medical events."[23] The Armed Forces Medical Examiner went further the other way: "It was the opinion of the AFMES that DMAA did not play a significant role in the deaths of these four Service members."[23] The panel still recommended keeping the products off the shelves, and they stayed off.

FDA followed in April 2012: "The U.S. Food and Drug Administration today issued warning letters to ten manufacturers and distributors of dietary supplements containing dimethylamylamine, more popularly known as DMAA, for marketing products for which evidence of the safety of the product had not been submitted to FDA."[25] The same release gave the count then on file: "The agency has received 42 adverse event reports on products containing DMAA. While the complaints do not establish that DMAA was the cause of the incidents, some of the reports have included cardiac disorders, nervous system disorders, psychiatric disorders, and death."[25] The letters carried the legal theory that every later letter would reuse: "Synthetically produced dimethylamylamine is not a vitamin, mineral, amino acid, herb or other botanical."[26] A year later the count had doubled: "FDA has received 86 reports of adverse events involving products containing DMAA. These events include psychiatric disorders, heart problems, nervous system disorders, and death."[27] The largest seller gave in that summer: "On July 2, 2013, as a result of follow-up legal action by FDA, the dietary supplement firm USPlabs voluntarily destroyed its DMAA-containing products located at its facility in Dallas, Texas."[28]

One company did not give in, and the case it lost is now the law on what a botanical is. A federal judge in Atlanta ruled in April 2017: "It is significant to this Court that, while studies might have found the presence of DMAA in geraniums, no one has ever extracted DMAA from geraniums for any commercial, medicinal or other purpose. It has merely been detected."[29] The Eleventh Circuit affirmed in August 2019: "The fact that DMAA can be found in trace amounts in geraniums, if true, says absolutely nothing about whether consuming the substance is safe."[15] Its holding was that DMAA is neither a botanical nor a constituent of one: "And it is not generally recognized by qualified experts, as adequately shown through scientific procedures, to be safe under the conditions of its intended use."[15] The Supreme Court declined review in October 2020,[30] and FDA's page records the end: "The products were destroyed on November 12, 2020."[31]

The company that had destroyed its stock in 2013 was prosecuted anyway, for what it had told its customers. The Department of Justice's account of the 2019 guilty pleas: "According to the indictment, the defendants told some of their retailers and wholesalers that USPlabs products contained natural plant extracts, when in fact they contained a synthetic stimulant manufactured in a Chinese chemical factory."[32] The sentence followed in 2020: "On Oct. 13, 2020, U.S. District Judge Sam A. Lindsay sentenced former USPlabs CEO Jacobo Geissler, 44, of University Park, Texas, to 60 months' imprisonment."[33]

What replaced it. The Dutch public-health institute RIVM, whose chemist Bastiaan Venhuis co-authored most of the papers below, wrote in 2018: "Shortly after the FDA banned DMAA from dietary supplements, the analogue DMBA, also called nor-DMAA, was discovered in different supplements".[34] DMAA itself did not leave. Cohen wrote in 2014: "Despite a concerted effort by the FDA to remove the stimulant, DMAA remains in dozens of supplements."[4] In products bought in 2017 his group reported: "In one product, 24 ± 7.6 mg of 1,3-DMAA was combined with 21 ± 11 mg of 1,4-DMAA."[35]

DMBA: one carbon shorter

What it is. 1,3-dimethylbutylamine is DMAA with one methylene group removed from the chain. It was sold as AMP citrate and under a handful of other names. Cohen, Travis and Venhuis in 2015: "DMBA is an analogue of the pharmaceutical stimulant, 1,3-dimethylamylamine (DMAA), which was recently banned by the US Food and Drug Administration."[36] The botanical story this time was tea. RIVM on the two Chinese reports behind it: "Both groups did not use reference standards to prove their findings and other groups could not confirm their findings with similar experiments, so there is no strong scientific evidence for the natural occurrence of DMBA".[34]

How far it spread, measured. The 2015 paper is the first in the series to use the method that every later one repeats: buy everything on sale with the suspect name on the label, and measure it in two laboratories against a reference standard. "We obtained all dietary supplements sold by US distributors that listed an ingredient on the label, such as AMP Citrate, that might be a marketing name for DMBA."[36] "Fourteen supplements met our inclusion criteria and were analyzed by two separate laboratories using ultra high performance liquid chromatography (UHPLC) - mass spectrometry and a reference standard."[36] The result: "The identity of DMBA was confirmed in 12 supplements in the range of 13 to 120 mg DMBA per serving."[36] And the point of the title: "DMBA has never before been detected in supplements. The stimulant has never been studied in humans; its efficacy and safety are entirely unknown."[36]

The paper went online on 8 October 2014. The next day a trade magazine quoted the NSF International chemist who co-authored it, John Travis: "While regulatory authorities work to remove harmful stimulants such as ephedrine and DMAA from supplements, new synthetic stimulants such as DMBA continue to crop up to take their place".[37] That is the pattern stated by someone who measured it, in October 2014, before FDA had said a word about DMBA.

What FDA did. Six months later: "On April 28, 2015, the FDA issued warning letters to 14 companies regarding a total of 17 products for which the product labeling identifies DMBA as a dietary ingredient."[38] The letters themselves are dated 24 April. Their reasoning is the DMAA letter with one word changed: "Synthetically produced DMBA is not a vitamin, mineral, amino acid, herb or other botanical."[39]

The same month showed how long FDA can hold a finding. Its own chemists had published in October 2013 that "β-Methylphenethylamine, a non-natural compound, was found in 9 of the 21 dietary supplement products."[40] in supplements sold as Acacia rigidula extract. Nothing followed until Cohen's group re-tested: "Over a year after the FDA reported its findings, we analyzed Acacia rigidula dietary supplements to determine if BMPEA had been removed."[41] It had not: "More than half (11/21; 52.4%) of the Acacia rigidula supplement brands contained BMPEA."[41] FDA's letters came out on 23 April 2015 and cited the agency's own work from two years earlier: "research conducted by the FDA in 2013 established that BMPEA is not a constituent or extract of Acacia rigidula".[3]

A year after that, methylsynephrine. "On March 31, 2016, the FDA issued warning letters to 7 companies regarding a total of 8 products marketed as dietary supplements for which the product labeling lists methylsynephrine as a dietary ingredient."[42] Cohen's analysis appeared a week later: "We analyzed 27 brands of supplements labelled as containing a synonym of oxilofrine ('methylsynephrine') and found that oxilofrine was present in 14 different brands (52%)".[43] Fourteen brands found, eight products warned.

What replaced it. The 2018 follow-up is the paper that measures whether letters work. "We analyzed supplements purchased in 2014 and the same brands purchased again in 2017 to determine the presence of prohibited stimulants before and after the FDA issued public notices."[44] "Of the 12 supplements purchased in 2017, a total of 9 (75%) contained at least 1 of the 4 stimulants subject to FDA notices, and 6 (50%) contained 2 or more."[44] And the sentence that is this article's thesis in nine words: "Second, 1 stimulant was introduced only after FDA enforcement action."[44]

DMHA and octodrine: back after seventy years

What it is. 2-amino-6-methylheptane, sold as DMHA or 2-aminoisoheptane, is DMAA with one more carbon rather than one fewer. Octodrine is its old drug name. A Hertfordshire group reviewed it in 2018: "Originally developed as a nasal decongestant in the 1950’s, it has recently been re-introduced on the market as a pre-workout and ‘fat-burner’ product but its use remains unregulated."[45] RIVM dates the inhaler a decade earlier and adds the oral products: "DMHA was the active pharmaceutical ingredient in Eskay’s oralator, and was produced by the Smith, Kline & French Laboratories in the 1940’s"[34] and "In Europe, but not in the Netherlands, DMHA was sold between the 1960’s and mid 2000’s as an active ingredient in three registered multi-ingredient tablets."[34] The two documents disagree by a decade on when the inhaler appeared. On the human evidence they agree: "The safety of Octodrine as an individual drug remains unknown due to the lack of any placebo-controlled trial but animal experiments suggest a potential for adverse cardiovascular effects."[45]

The botanical cover this time was walnut bark, or an aconite, or a Kigelia. RIVM's verdict on all three amines at once: "All three aliphatic amines described in this fact sheet have been marketed as natural products, but scientific proof for these claims is not available."[34]

How it spread. The Hertfordshire review states the succession in one sentence: "With DMAA and AMP Citrate already phasing or phased out of current supplements, this drug was brought back on market as an alternative in pre-workout and ‘fat-burner’ products in 2016."[45]

What the measurement found. Cohen's group, this time with a Department of Defense co-author, went looking: "We analyzed six brands of supplements that listed an ingredient on the label (e.g., Aconitum kusnezoffii, DMHA or 2-amino-isoheptane) that might refer to an analog of 1,3-DMAA."[35] Six products, four stimulants: "Two previously unidentified 1,3-DMAA analogs (2-amino-6-methylheptane [octodrine] and 1,4-dimethylamylamine [1,4-DMAA]) and two banned stimulants (1,3-DMAA and 1,3-dimethylbutylamine [1,3-DMBA]) were identified."[35] "Octodrine was found at a dose (±95% CI) of 72 ± 7.5 mg per serving."[35] The label meant nothing: "In three different products labeled as containing Aconitum kusnezoffii, Cohen found three different stimulants."[46] And the timing: "Cohen said he and his collaborators in June shared their findings with the FDA."[46] That was June 2017.

What FDA did. Twenty-two months later: "The FDA issued 9 warning letters to companies whose products are marketed as dietary supplements and labeled to contain DMHA."[47] The letters were dated 10 April 2019, and the one to the company that had lost the DMAA case was less sure of its ground than the 2012 letters had been: "We also note that we have questions about whether DMHA is, in fact, a dietary ingredient."[48] The agency resolved its own question in 2023: "After further research and consideration, FDA concluded that DMHA is an unsafe food additive, as explained above."[49]

The same week in April 2019 FDA launched a list for ingredients it had not yet decided about. 1,4-DMAA, the positional isomer found alongside octodrine, went on it, with this caveat attached: "Inclusion on the Dietary Supplement Ingredient Advisory List does not necessarily indicate that the FDA has determined that the ingredient is unsafe; it means FDA is taking steps to further evaluate the ingredient."[50] The list lasted four years: "As the agency is instituting the Ingredient Directory, we are also retiring the FDA Dietary Supplement Ingredient Advisory List".[51]

What replaced it. Nothing replaced DMHA, because nothing removed it. It is the dominant stimulant on this shelf today, and the newest FDA finding in this article is about it.

What is on the shelf now

The successors are no longer one compound at a time. They are a botanical name on the front and whatever is cheapest inside.

Higenamine is a plant alkaloid with beta-agonist activity, found in aconite and nandina. Cohen's group in 2019: "The stimulant has been studied in clinical trials in China [9–11] but has never been approved as a drug by the US Food and Drug Administration (FDA)."[52] "Twenty-four products were analyzed."[53] "The quantity of higenamine (±95% CI) ranged from trace amounts to 62 ± 6.0 mg per serving."[53] The labels: "Five products (5/24; 21%) listed an amount of higenamine, but none were accurately labeled; the quantity in these supplements ranged from <0.01% to 200% of the quantity listed on the label."[53] "On 1 January 2017, WADA prohibited higenamine in sports".[52] FDA's letters came in May 2022, five years after the measurement: "The dietary supplements sold by the companies listed above contain one or more of the following ingredients: 5-alpha-hydroxy-laxogenin, higenamine, higenamine HCl, hordenine, hordenine HCl, and octopamine."[54]

Deterenol and phenpromethamine are the two for which there has never been a letter. In 2021 Cohen's group bought products labelled as containing deterenol, a beta-agonist that was offered to FDA as a supplement ingredient right after the ephedra rule: "following the prohibition of ephedra alkaloids in supplements in 2004, a manufacturer submitted an application to the FDA to introduce deterenol into supplements".[55] FDA refused it in 2004, and seventeen years later it was back: "We identified 9 experimental stimulants and 8 different combinations of prohibited stimulants in weight loss and sports supplements in 17 brands of supplements labeled as containing deterenol."[55] Among them was a compound last sold by Merrell as a nasal inhaler: "The FDA approved Vonedrine as a nasal inhaler in 1943 and it remained available until Merrell Co. withdrew the inhaler in 1960".[55] The paper's own summary: "These cocktails of stimulants have never been tested in humans and their safety is unknown."[56] And its observation about the agency: "To our knowledge, 2 of the stimulants detected, deterenol and phenpromethamine, have not been subject to any FDA enforcement actions or consumer warnings."[55] That was true in 2021. FDA's ingredient directory, revised on 1 May 2026, lists DMAA, DMBA, DMHA, BMPEA, methylsynephrine and higenamine; deterenol and phenpromethamine are not on it.[2]

The botanical generation. In 2023 the group measured 57 products sold on five plant names: alpha-yohimbine from Rauwolfia, methylliberine, halostachine, turkesterone and octopamine. The framing sentence is the thesis of this article as a research question: "Since the US Food and Drug Administration (FDA) banned ephedra from dietary supplements in 2004, supplement manufacturers have promoted a complex variety of alternative botanical compounds for sports enhancement."[57] "Twenty-three of 57 products (40%) did not contain a detectable amount of the labeled ingredient."[57] Where the ingredient was present, "the actual quantity ranged from 0.02% to 334% of the labeled quantity".[57] "Seven of 57 products (12%) were found to contain at least 1 FDA-prohibited ingredient".[57] One of those was not a stimulant at all: "The mechanism of action of omberacetam is unknown; it is marketed in Russia as Noopept."[57]

The orchid. The newest paper, July 2025, concerns products sold as an extract of Eria jarensis, an orchid said to supply N,N-dimethylphenethylamine. "None of the 12 Eria jarensis supplements analyzed were accurately labeled."[58] "Products that listed caffeine on the label contained quantities ranging from 0.1 to 665 mg/serving size."[58] "In addition, two of these products contained the United States Food and Drug Administration-prohibited stimulant 1,4-dimethylamylamine."[58] The authors' explanation is the same one GAO gave in 2009: "The United States Food and Drug Administration does not evaluate the safety or quality of supplements prior to market introduction, and our findings reflect the consequences of this regulatory framework."[58]

FDA's newest finding is dated 3 April 2026, and it concerns DMHA and the isomer that went on the advisory list in 2019. "The Addall XL 30 capsules contain 2-amino-6-methylheptane (DMHA), an unlawful ingredient in dietary supplements, as well as undeclared 1,4-DMAA".[59] The products were "sold online and at retail locations such as gas stations and convenience stores nationwide".[59] FDA asked for a recall in January 2026. "The firm declined to recall Addall XL capsules."[59] The agency issued an alert instead. Fourteen years after the first DMAA letters, that is where the enforcement toolkit still ends.

Tianeptine: an antidepressant in a gas station

The last compound is not a stimulant and not a near neighbour of anything above. It belongs here because it travels the same channel, under the same dietary-supplement label, and because the same name means two different things depending on the country. This site's page on the molecule is at tianeptine; this section is about the market and the law.

What it is. The CDC's 2018 description: "Tianeptine (marketed as Coaxil or Stablon) is an atypical tricyclic drug used as an antidepressant in Europe, Asia, and Latin America."[60] Michigan's legislative analysts counted the markets in 2018: "Since 2016, it has been available in approximately 66 countries in Europe, Asia, and Latin America under a number of tradenames, including Stablon and Coaxil."[61] In the United States it is a drug that was never approved: "Tianeptine is used as a prescription drug in some European, Asian, and Latin American countries, but it is not approved as a drug in the United States."[62]

What it does at the opioid receptor. For decades it was described as a serotonin-modulating antidepressant. In 2014 a Columbia group characterised it in cell assays: "Herein, we report the characterization of tianeptine as a μ-opioid receptor (MOR) agonist."[63] It was selective: "In contrast, tianeptine was inactive at the κ-opioid receptor (KOR, both human and rat)."[63] The CDC's 2018 summary of the field: "Animal and human studies show that tianeptine is an opioid receptor agonist".[60] FDA's 2025 letter to clinicians puts it more strongly than the 2014 paper did: "It is believed to act via glutamate modulation and is a full mu- and weak delta-opioid receptor agonist."[64] The 2014 abstract's own words are an efficacious mu agonist and a full delta agonist at much lower potency, so the two sources differ on which receptor gets the word full. What happens at the quantities in gas-station products is described by the DEA from case reports: "recent case reports have described the use of tianeptine for its euphoric properties similar to other opioids, such as heroin, morphine, and fentanyl."[65] And the clinical confirmation, from the HHS evaluation the DEA relies on: "HHS also noted that naloxone administration has been shown in some cases to reverse tianeptine overdose, which supports that tianeptine effects are mediated, at least in part, through its mu opioid agonist activity."[65]

How it spread. The poison-centre curve is the clearest record. "During the first 14 years of the study period (2000–2013), NPDS received a total of 11 tianeptine exposure calls."[60] Then: "The total number of tianeptine exposure calls increased from five in 2014 to 38 in 2015, 83 in 2016, and 81 in 2017".[60] FDA's 2025 figure: "Annual poison control center cases involving tianeptine exposure, as reported by the National Poison Data System, have increased nationwide, from 4 cases in 2013 to about 350 cases in 2024."[66] The CDC had already named the channel in 2018: "Although tianeptine is not FDA approved in the United States, it is readily available for purchase online as a dietary supplement or research chemical."[60]

What FDA said, and when. The first letters were dated 7 November 2018 and posted on the 20th. FDA's release: "Each of these products is marketed as a dietary supplement and declares tianeptine sodium on the label."[67] The legal position was set then and has not moved: "In addition, dietary supplements containing tianeptine are adulterated under the Federal Food, Drug, and Cosmetic Act because tianeptine is an unsafe food additive and should not be present in dietary supplements."[67] One of the two companies had been selling it as a kratom substitute; FDA quoted its website: "Now, these four alternatives can replicate the benefits of Kratom with perfection."[68]

A February 2022 letter shows the online channel in a single list of what one seller offered: "“Tianeptine Sodium Powder,” “Tianeptine Sulfate Powder,” “PEA Capsules,” “Phenibut Capsules,” “Synephrine Powder,” “Noopept Powder,”"[69] That is the nearest the regulatory record comes to placing tianeptine on the pre-workout shelf: beside synephrine and the racetam that turned up in Cohen's 2023 analysis. None of the analytical papers cited in this article has reported tianeptine in a sports supplement. FDA's standing page, current since February 2023, states the classification: "FDA considers tianeptine to be a substance that does not meet the statutory definition of a dietary ingredient and is an unsafe food additive."[62]

The event that changed the tempo was in New Jersey. Between June and November 2023 the state poison centre saw a cluster around one product: "During this period, the center received 20 exposure calls from health care facilities regarding tianeptine use in 17 unique patients."[70] "Among the 20 encounters, 13 of the 17 patients were admitted to an intensive care unit, and seven of the 17 underwent endotracheal intubation. There were no deaths."[70] The bottles were not what they said: "All bottles were labeled as containing kavain and tianeptine; analysis identified variable compositions, including the presence of the two SCRAs".[70] That analysis was the poison centre's and a forensic laboratory's, not FDA's. The full case series published in 2025 counted higher: "We became aware of a cluster of 34 patients in New Jersey who became ill following ingestion of the tianeptine containing-product Neptune’s Fix, the rate of which (4.6 cases per month) far exceeded the background rate for this substance of 0.5 cases per year."[71]

FDA's alert followed on 21 November 2023. On 11 January 2024 it wrote to the trade associations for the stores that sell the product: "We are reaching out because most consumers report purchasing this product at local gas stations or convenience stores across the country."[72] "At least twelve states have banned the sale of tianeptine."[72] The distributor agreed to a recall on 23 January 2024: "Neptune Resources, LLC has agreed to voluntarily recall all lots of Neptune’s Fix Elixir, Neptune’s Fix Extra Strength Elixir and Neptune’s Fix Tablets to the consumer level."[73] FDA's May 2025 letter repeated the New Jersey finding as its own: "In 2024, there was a cluster of illnesses in New Jersey associated with the product “Neptune’s Fix,” which was found to contain tianeptine and synthetic cannabinoid receptor agonists."[64] The CDC dates those cases to 2023. The same letter lists the trade names FDA knows: "Product names include, for example, Tianaa, Zaza, Neptune’s Fix, Pegasus, and TD Red."[73]

The scheduling question, with dates. Michigan was first, in 2018, and scheduled only one salt: "The bill would amend the Public Health Code to classify tianeptine sodium as a Schedule 2 controlled substance."[61] By December 2025 the count was twenty. A legislative tracker lists fourteen states, Alabama, Delaware, Florida, Georgia, Indiana, Kansas, Kentucky, Louisiana, Minnesota, Nebraska, Nevada, Ohio, Utah and Virginia, that "list tianeptine as a Schedule I controlled substance; five states", Arkansas, Michigan, North Carolina, Oklahoma and Tennessee, in Schedule II, and Mississippi, which "lists tianeptine as a Schedule III controlled substance".[74]

Federally the record has three dated statements and they must be read in order. FDA, 8 May 2025: "In the U.S., tianeptine is not currently scheduled under the Controlled Substances Act."[64] DEA's own fact sheet, dated May 2026, still described tianeptine as not federally controlled.[75] Then, on 8 July 2026, DEA published a proposed rule to place tianeptine in Schedule I. The proposal rests on an evaluation DEA had asked for on 7 September 2023, when it "submitted it to the then-Assistant Secretary for Health of HHS with a request for a scientific and medical evaluation of available information and a scheduling recommendation for tianeptine."[65] HHS answered on 18 July 2025 with a Schedule I recommendation: "HHS noted that tianeptine is a tricyclic antidepressant that has been shown to have pharmacological effects similar to opioids currently scheduled under the CSA, such as morphine (schedule II) and fentanyl (schedule II)."[65] Schedule I rather than a lower schedule because "There are no tianeptine products approved for medical use in the United States."[65] The comment period closed on 7 August 2026. As of the date on this article no final rule has been published, so tianeptine is proposed for Schedule I and is not yet in it. A page that says it is unscheduled is correct only with a date on it.

The sentence that stays true

Cohen's group wrote in 2021, after measuring deterenol products that also contained DMAA, DMBA and oxilofrine: "This pattern was again evident in the current study in which the FDA has taken enforcement action regarding several of the experimental stimulants detected (i.e., 1,3-DMAA, 1,3-DMBA and oxilofrine), but the prohibited stimulants remain present in supplements despite FDA warnings."[55] Five years and one refused recall later, nothing in the record contradicts it.

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