Drugs from Gas Stations and Other Notes from the Field...

 

The Food and Drug Administration has not approved tianeptine for use in the United States; however, it is readily purchased in elixir formulations online or at gas stations informally referred to as “gas station heroin”  - from reference 1

 I shot the photo at the top of this post at my local gas station.  A couple of months ago they installed this neon sign advertising Kratom for sale and another selling Delta-10 THC.  Both compounds are intoxicants and are a part of the multigenerational drug epidemic that the United States finds itself in.   Depending on how you are reading about it that epidemic may seem restricted to fentanyl or in some cases amphetamines – but make no mistake about it there is a general trend in making all intoxicants more easily accessible and even making it seem like they are a legitimate business. Even the fentanyl story is only partially told.  The backdrop of excessive prescription opioid prescribing is rarely told – apart from a dramatized version.  The only good that has come of this is that all the hype about medicinal cannabis seems to be rapidly dwindling along with the lack of medical evidence that it has any such properties.

That brings me to the latest gas station intoxicant – tianeptine. It was originally intended to be an antidepressant based on a very general tricyclic structure.  I made the graphic below for a rapid structural comparison with standard tricyclic antidepressants (nortriptyline) and selective serotonin reuptake inhibitors (escitalopram). It is obviously not structurally like either class of compounds and has a unique moiety – the 5,5 dioxo structure on the central cycloheptane ring.

In terms of receptor affinities, the first property that jumped out at me was that tianeptine had none of the usual receptor or transporter affinities expected of typical antidepressants in the PDSP database.  The only affinity in that data set was for the mu opioid receptor (MOR). 

 

	NET	SERT	DAT	5-HT2A	5-HT1A	MOR
tianeptine	-	>10,000	>10,000	>10,000	>10,000	383 nM
nortriptyline	1.8 nM	15 nM	1,140 nM	294 nM	5 nM
escitalopram	6,514 nM	1.1 nM	>10,000	>10,000	>10,000

A recent CDC report (1) describes a spike in tianeptine ingestions and complications due to contamination from synthetic cannabinoid receptor agonists (SCRAs) between June and November 2023.  Fourteen of the 17 exposure calls involved patients drinking an elixir called Neptune’s Fix – a mixture of tianeptine and kavain or Piper methysticum root.  Six of the patients ingested other compounds including benzodiazepines, Kratom, trazodone, tramadol, and gabapentin.  Nine had previously used tianeptine. Thirteen of the 17 patients were admitted to intensive care units (ICU) and 7 required intubation and ventilatory support.  There were cardiovascular complications including conduction abnormalities, hypotension, tachycardia, and a cardiac arrest. All the patients had altered mental status.

Six samples of the Neptune’s Fix preparation from 2 of the patients were analyzed by gas chromatography-(GS-MS) and compared with a standard database of compounds of interest.  All of the bottles were labelled tianeptine and kavain. Two of the samples contained THC and CBD.  Two of the samples contained the SCRAs ADB-4en-PINACA and MDMB-4en-PINACA. 

The overall message of the report is that tianeptine preparations available as unregulated preparations can potentially be addictive and may contain adulterants that can produce severe adverse effects requiring resuscitation or ICU admission.  This has been noted in previous literature about SCRAs including severe psychiatric effects.  There have been 144 synthetic cannabinoids identified since 2014.  In some circles these compounds are referred to as JWH compounds after the organic chemist who first synthesized and researched them.

The way that tianeptine is described in the literature seems to parallel the interests of the authors.  The FDA references are uniformly negative because they are focused on severe side effects including death and addiction. Authors who are interested in the opioidergic system in depression will describe how it is a legal antidepressant in several countries and minimize both potential addiction and severe side effects. Either way it maps well onto the current American pro-drug culture. The sheer number of new intoxicants and widespread access to these intoxicants is staggering. Hundreds of new compounds in the past ten years.  Addictive compounds readily available at gas stations?  Those compounds laced with additional problematic intoxicants?  The so-called War on Drugs is obviously non-existent at this time. 

One of the questions I always get from people in response to posts about contaminated, adulterated, and counterfeit intoxicants is why?  Why would drug dealers or semi-legitimate businesses want to kill off or injure their customers?  What is their motivation? The most obvious one is that they don’t care.  There always seems to be a significant number of people out there interested in a new or higher high so demand is never a problem.  The second is marketing.  In a previous post I described a case where fentanyl was being pressed into tablets that looked like Xanax bars and the purchasers were not only aware of that but preferred to purchase those tablets even after directly observing them being made. A third possibility is ignorance. People looking to find intoxicants and sell them on the street are not medicinal chemists – even though they may talk like it. Some of these compounds vary in potency by a factor of a hundred or a thousand.  The fourth is a lack of accountability.  Even the most cynical conceptualization of the pharmaceutical industry recognizes the fact that the products are approved, manufactured, and monitored according to standards. Manufacturers are subject to regulatory bodies, criminal and civil liability, and accountability at the business level from a board of directors and at the shareholder level. It is fairly easy to find that the industry has paid tens of billions of dollars in civil and criminal penalties over the past 30 years. None of these incentives applies at the level of small companies marketing unapproved but unregulated drugs or street sales of illicit drugs. For that matter it probably also does not apply at the level of legal cannabis dispensaries. Even though legally prescribed and regulated medications have risks – unregulated and street drug risk is much higher.  As demonstrated in this post that risk starts with what is really in the bottle complicated by even higher risk adulterants. 

I always think of the former President of Mexico Vincente Fox in these situations.  When asked about the American drug problem and the involvement of Mexico he characterized the problem as “America’s insatiable appetite for drugs.”  When I think about people going into a gas station and buying Neptune’s Fix or Kratom or Delta-10 THC and not really knowing what they are getting in the bottle – he can’t be wrong.

George Dawson, MD, DFAPA

Supplementary:  On not caring that I mentioned in the above post.  I think there is a case to be made that the same attitude can fuel legitimate retail sales of drugs that reinforce their own used including alcohol, cannabis, and tobacco. Increasing liquor stores will increase alcohol consumption by increasing access.  That increased access comes with smaller distances to liquor stores, home delivery, placing liquor stores in proximity to other retail stores and supermarkets, and the commoditization of alcohol – you will always be able to find a cheaper drink. Since a significant portion of any population are problematic drinkers all this increased access directly impacts them. The people that create all this access, typically argue that the intoxicants are legal, they run a legitimate business, and not creating all this access puts them at a disadvantage compared to other sellers.  That argument leaves out the significant morbidity and mortality associated with alcohol and ironically that argument is typically used when advocates are trying to legalize another intoxicant as in:  “Our new intoxicant is not as dangerous or lethal as alcohol.”

 

References:

1:  Counts CJ, Spadaro AV, Cerbini TA, et al. Notes from the Field: Cluster of Severe Illness from Neptune’s Fix Tianeptine Linked to Synthetic Cannabinoids — New Jersey, June–November 2023. MMWR Morb Mortal Wkly Rep 2024;73:89–90. DOI: http://dx.doi.org/10.15585/mmwr.mm7304a5.

2:  El Zahran T, Schier J, Glidden E, et al. Characteristics of Tianeptine Exposures Reported to the National Poison Data System — United States, 2000–2017. MMWR Morb Mortal Wkly Rep 2018;67:815–818. DOI: http://dx.doi.org/10.15585/mmwr.mm6730a2

3:  Samuels BA, Nautiyal KM, Kruegel AC, Levinstein MR, Magalong VM, Gassaway MM, Grinnell SG, Han J, Ansonoff MA, Pintar JE, Javitch JA, Sames D, Hen R. The Behavioral Effects of the Antidepressant Tianeptine Require the Mu-Opioid Receptor. Neuropsychopharmacology. 2017 Sep;42(10):2052-2063. doi: 10.1038/npp.2017.60. Epub 2017 Mar 17. PMID: 28303899; PMCID: PMC5561344.

4:  Nobile B, Ramoz N, Jaussent I, Gorwood P, Olié E, Castroman JL, Guillaume S, Courtet P. Polymorphism A118G of opioid receptor mu 1 (OPRM1) is associated with emergence of suicidal ideation at antidepressant onset in a large naturalistic cohort of depressed outpatients. Sci Rep. 2019 Feb 22;9(1):2569. doi: 10.1038/s41598-019-39622-3. PMID: 30796320; PMCID: PMC6385304.

5: Wikipedia contributors. Nortriptyline. Wikipedia, The Free Encyclopedia. December 20, 2023, 17:01 UTC. Available at: https://en.wikipedia.org/w/index.php?title=Nortriptyline&oldid=1190922632

Accessed February 4, 2024.  Wikipedia table was used for nortriptyline because the PDSP database was no longer working.

6:  Jelen LA, Stone JM, Young AH, Mehta MA. The opioid system in depression. Neurosci Biobehav Rev. 2022 Sep;140:104800. doi: 10.1016/j.neubiorev.2022.104800. Epub 2022 Jul 30. PMID: 35914624; PMCID: PMC10166717.

7:  FDA.  Tianeptine Products Linked to Serious Harm, Overdoses, Death.  https://www.fda.gov/consumers/consumer-updates/tianeptine-products-linked-serious-harm-overdoses-death

8:  FDA.  Tianeptine in Dietary Supplements.  https://www.fda.gov/food/dietary-supplement-ingredient-directory/tianeptine-dietary-supplements

9:  FDA.  FDA warns consumers not to purchase or use Neptune’s Fix or any tianeptine product due to serious risks.  https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-consumers-not-purchase-or-use-neptunes-fix-or-any-tianeptine-product-due-serious-risks