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

Synthetic Cannabinoids and Life Threatening Coagulopathy

Just when I thought that renal failure was the only unexpected complication of synthetic cannabinoids - it turns out they can also cause bleeding or more specifically Vitamin K dependent antagonist coagulopathy.   The basic mechanism of action is noted in the above diagram on the action of warfarin on Vitamin K dependent mechanisms that can lead to an anticoagulated state.  Warfarin and similar Vitamin K antagonists block the function of the vitamin K epoxide reductase complex.  That blocks the recycling of Vitamin K epoxide and eventual depletion of Vitamin K.  That is turn leads to no gamma carboxylation of Vitamin K dependent coagulation factors (depicted here as descarboxy prothrombin being converted to prothrombin (Factor II), but factors VII, IX, and X are also involved).  

The anticoagulated state can be used therapeutically to prevent embolic strokes or recurrent pulmonary emboli, but warfarin has a very narrow therapeutic index and it needs to be monitored closely in patients who are also watching their diet and drug interactions to prevent excessive anticoagulation and bleeding that can be fatal. The warfarin effect can be reversed by Vitamin K administration.

The CDC issued an outbreak alert last month about an outbreak that occurred in the midwest - largely Illinois about unexplained bleeding.  The time frame where this was noted was the previous year.  People were presenting to emergency departments with unexplained bleeding ( no exposure to anticoagulants or anticoagulant containing rat poison and no medical explanation for the bleeding).  In their Clinical Action Alert they explain the symptoms of coagulopathy including bleeding from the gums, nose, gastrointestinal tract, genitourinary tract, excessive bruising, unexplained abdominal of flank pain, mental status change, feeling faint, and collapse.  There were a total of two fatalities at the time of the alert and medical evaluation and treatment with Vitamin K and fresh frozen plasma suggested that the toxicity was due to brodifacoum a long acting Vitamin K antagonist found in rat poison.

Ninety four people were involved through April 5, 2018.  Since that time the Illinois web site following this outbreak reports 164 cases including 4 deaths since March 2018.  They name a few of the brands commonly sold including K2, Spice, Black Mamba, Bombay Blue, Genie, and Zohai but emphasize that there are a large number of these compounds as listed in a previous post on this blog.  As previously noted, synthetic cannabinoids are basically highly concentrated organic chemical that are sprayed in plant material to facilitate smoking.  When I checked the medical literature to see if these cases were written up and specific biochemical analyses done - I found the only reference brodifacoum was a study done (1) that looked at the results of applications to areas around marijuana growing operations.  Anticoagulant based rodenticides are apparently used to prevent damage to the crop and are described as being used extensively.  This study looked at marijuana growers on California and the relationship to wildlife species.  In this case a threatened species the northern spotted owl was necropsied and it was demonstrated that the liver and blood contained high concentrations of brodifacoum.  The authors point out a basic ecological principle that if the target of the rodenticide is rodent - it will be concentrated to higher levels in the predators higher in the food chain.  The alarming situation here is the fact that dead wildlife from rodenticide poisoning have been found around 22% of 41 marijuana growers in 3 California counties.

The message from the CDC and the Illinois Department of Public Health (IDPH) was clear.  Be aware of the problem, recognize coaglopathies, and be prepared to intervene.  The IDPH advises consumers to watch for bleeding and bruising if they have used these compounds and if it occurs to seek emergency assistance.  The CDC discusses the high cost of Vitamin K therapy and possible shortages, the need to warn post op patients not to use these compounds, and concern that some of the affected patients may be plasma donors.

Addiction docs and acute care psychiatrists need to have a higher index of suspicion, especially in settings where people are admitted rapidly for detoxification and stabilization and if the patient gives a history of synthetic cannabinoid use.  The commonest current coagulopathy in those settings is probably alcohol related and that is relatively rare.

Additional concerns would include the possibilities that the rodenticide could be sprayed on some cannabis plants and be ingested or smoked by people who believe they are using cannabis.  An associated concern is that the contaminated synthetic material was considered plant waste from cannabis products and just used as a carrier for the synthetic cannabinoids.  That is a potential reason why the synthetics were contaminated with brodifacoum in the first place.

As far as I know there have been no reports of the problem in cannabis smokers who were not using synthetic cannabinoids.

The authors of reference 1 point out that since cannabis is not regulated as an agricultural product there are no regulations about what can be applied to it when it is grown.  It seems like another disadvantage of a laissez-faire approach to drug regulation.

Coagulopathy is just another in a long list of reasons to stay away from synthetic cannabinoids and to beware of other toxic effects from street drugs.  There has always been some concern over what chemicals and biologicals end up in smoked or ingested cannabis. Rodenticide should be added to that list until it is effectively ruled out by sampling and testing of the products being sold.




George Dawson, MD, DFAPA


References:

1:  Franklin AB, Carlson PC, Rex A, Rockweit JT, Garza D, Culhane E, Volker SF,Dusek RJ, Shearn-Bochsler VI, Gabriel MW, Horak KE. Grass is not always greener: rodenticide exposure of a threatened species near marijuana growing operations. BMC Res Notes. 2018 Feb 2;11(1):94. doi: 10.1186/s13104-018-3206-z. PubMed PMID: 29391058;

2: Brodifacoum on ToxNet.

Brodifacoum

3: Minnesota Department of Health.  Health Advisory: Significant Bleeding Associated with Contaminated Synthetic Cannabinoids. April 5, 2018.

4:  Minnesota Department of Health.  Health Advisory Network.  See additional links.  





Graphics:


1:   Mechanism of warfarin slide at the top is from Visiscience slides online per their user agreement.

2:  Brodifacoum chemical structure from PubChem.








 

JWH Compounds Make the NEJM

JWH-018

AMB-FUBINACA

Synthetic cannabinoids have been a problem for over a decade.  There have been sensational news reports that typically occur as a result of aggressive and disorganized behavior when users are acutely intoxicated.  When these compounds initially started to appear on the scene, regulators were far behind the curve.  Some of the first forms were sold in head shops, wrapped in paper and labelled "Not For Human Consumption."  They went by names like K2, Spice, and Plant Food.  They are typically applied to shredded plant material so that they can be smoked.   The chemical structures of these compounds do not resemble typical cannabinoids and the synthesis is relatively straightforward.  That has facilitated black market production.  Apart from easy availability the other draw was that users could take these compounds and not have to worry about standard drug testing protocols in the work place.  The word on the street was that the synthetics were undetectable by typical urine toxicology and that was accurate.  Apart from isolated aggressive incidents there were also deaths associated with their use.  There were some epidemics that clustered in communities and eventually (like most drug epidemics) the sale of the compounds was prohibited and some head shop operators were prosecuted.

From the standpoint of addiction practice, many of these compounds create a dangerous situation for the patient and a dilemma for treatment facilities.  They are highly addictive to some people and unless there is some familiarity with the concept of delirium producing drugs causing addiction, it may not be clear why anyone would continue to use them.  Many people are amnestic for what occurred when they were under the influence.  In some cases they develop life threatening conditions as a result of use and crave the drug when they are being acutely treated for the medical complications.  Another abused drug with this kind of dissociative profile is dextromethorphan.  When used in high doses it leads to delirium and hallucinations and can be highly addictive.


The JWH designation represents the organic chemist John W. Huffman who synthesized the series of compounds as cannabinoid receptor agonists.  The goal of the research was to produce pharmacological probes to study cannabinoid receptors.  He is a coauthor on 30 papers in Medline.  There are several articles in the popular press including several that include his opinion about his original research being used to produce compounds for sale as street intoxicants.     JWH compounds have been in the medical literature since about 2005.  PubChem contains structural information on 281 JWH compounds, 367 protein targets, and 706 bioassays.  PubChem also allows the user to generate 2D and 3D structural similarity comparisons and bioactivity analyses - for example activity at the CB-1 and CB-2 receptor.  As the JWH compounds and other synthetics have evolved they follow a familiar pattern of the development of classes of addictive compounds - subsequent syntheses have increasing activity at the target receptor.

There are other classes of synthetic cannabinoids in addition to the JWH compounds including UR-144, AKB4, AB-CHMINACA, AB-FUBINAC and others.  There are also a number of psychedelic phenethylamines 2C-B, 2C-I, 3C-E, 3C-I, and 2C-P that are often sold as equivalent drugs.  There are obviously no guarantees that purchases from non-medical sources results in the desired chemical or effect.  There is a also a class of synthetic cathinines referred to as Bath Salts, that are structurally similar to amphetamines and are often sold as mephedrone, MDPV, or methylone.  The total number of synthetics and the requirement of relatively sophisticated analysis for detection (gas or liquid chromatography-mass spectrometry) frequently leaves the acute care or addiction physician depending on history alone about what was ingested.

The New England Journal of Medicine has a general review of the issue in the January 19, 2017 edition (1).  Full text of the article is available online.  The article details the current number of new psychoactive compounds as 540 with 177 identified synthetic cannabinoids in 2014.  They have an illustrated timeline of the evolution of these compounds from 2010 to 2016.  The most interesting aspect of the timeline is the evolution of a 50 fold increase in drug potency from JWH-018 in about 2010 to AMB-FUBINACA in 2016.

They also provide an analysis of a mini epidemic of AMB-FUBINACA use in Brooklyn that occurred in 2016.  Of the 33 people exposed - 18 required transport to medical facilities.  An index case is described with features of a blank stare and unresponsiveness 13/15 on the Glasgow Coma Scale.  He had episodic groaning and slowed movement of his extremities.  The term "zombielike" was used as a descriptor but in psychiatry that term is used so frequently by patients and untrained observers that it lacks meaning. The patient was sweating and had normal vital signs with the exception of tachypnea with a respiratory rate of 21.  Screening labs, toxicology, and ECG were all normal.  He recovered in about 9 hours and was discharged.  The authors recovered the original herbal product labelled "AK-47 24 Karat Gold"  and sent that as well as biological samples (blood and urine) from 8 other users for analysis.

The samples were analyzed with liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF/MS).  AMB-FUBINACA was confirmed as the compound in the original packet of material.  The de-esterified product rather than the parent compound was confirmed in the blood and urine of the patients with serum concentrations from 66 to 636 ng/ml.  

In the discussion the authors point out the potency increase with these synthetic compounds.  They illustrate the attractiveness to drug dealers and users - about $3800 of AMB-FUBINACA can produce about a half million dollars worth of product containing about 64 mg of the original compound sprayed over shredded plant material.  That is strong incentive for getting this drug out on the street.  They also discuss the role of inter-agency collaboration in identifying novel intoxicants during similar mini-epidemics.  In this case the entire timeline from case to molecular identification was 17 days.  In many toxicology cases that I have been involved with, it often takes that long to learn that the lab you are using is not able do the necessary analysis.

Treating patients addicted to these compounds will be a challenge in the foreseeable future.  People who changed to synthetics just to escape drug testing in the workplace have ended up addicted to these compounds.  The psychoactive side effects of the compounds frequently results in a downward spiral of job loss, loss of relationships, and social isolation that goes along with the preoccupation of using the drug.  Explaining to the patient and their family that this is a potentially life-threatening addiction is not necessarily a deterrent to further use and fatal outcomes are possible.  Understanding the motivation for using a drug that has never been tested in humans, can result in the loss of days or an entire weekend, and can result in toxidromes that directly or indirectly lead to fatal outcome may be another sign that this is a neurobiologically mediated process that bypasses rational thought.

Prevention would seem like it is the best approach but American society remains fascinated by intoxicants and Americans have plenty of money to spend on these drugs.  Like most political arguments the common sense approach of a better plan for living is lost between the poles of liberalized drug use and prohibition.  I hope that the people at highest risk for using these drugs can learn to avoid them without exposure.          


George Dawson, MD, DFAPA




References:


1. Adams AJ, Banister SD, Irizarry L, Trecki J, Schwartz M, Gerona R. "Zombie"Outbreak Caused by the Synthetic Cannabinoid AMB-FUBINACA in New York. N Engl J Med. 2017 Jan 19;376(3):235-242. doi: 10.1056/NEJMoa1610300. PubMed PMID:27973993. (free full text online).


Attribution:

Molecular structures at the  top of this post are generated from NLM PubChem interface and are public domain.


Additional Analyses Available from PubChem:

I ran two analyses for 281 and 279 JWH compounds.  Additional information is available if you run the analysis for yourself.

Supplementary:

I encountered some stories on the Internet about the chemists who originally synthesized these compounds in the course of their professional careers.  Some of them have felt badly about the morbidity and mortality associated with their use as street drugs.  Others have pointed out that they were not intended for human use and not tested in humans and therefore nobody should be using them.  Keeping in mind the profit motive suggested by the NEJM article and the incentives for gaming the system by finding compounds that are not on the Schedule of Controlled Substances, I don't think that there should be any question that the sellers and buyers of these drugs are responsible for the outcomes.