What Does the DEA Drug Trafficking Report Really Mean?

 

The DEA just published a significant report on the drug threat in the United States. I read the entire document and will review a few of the high spots here highlighting why it is not too relevant for most parts of the country.  I am on record in several places on this blog making similar comments. My basic argument has not changed significantly and that is that the demand for illegal and often fatal drugs is driven by the culture in the US and I would not expect law enforcement to make much of a difference. The case in point is Prohibition and the ban on alcohol.  Of course it was not a real ban.  Criminals still bootlegged alcohol into the country, religious groups found a way to circumvent the law, and there are always people producing illegal alcohol as a significant percentage of alcohol consumed every year.

These facts are most often distorted into the argument that Prohibition or any War on Drugs is doomed from the outset. That argument is most frequently used to implicitly suggest that any attempt to legally restrict intoxicants will be righteously overcome by people with a natural right to pursue intoxication.  That is extrapolated to practically any scenario short of negligent homicide due to intoxication or drug dealing. But even the drug dealing scenarios are being rapidly modified to allow possession of certain amount of cannabis or in some cases legitimizing drug dealing as a useful occupation. The direct and indirect costs of drug use to both individuals and society are typically ignored by anyone without a medical or public health interest. Intoxication is a cultural right, a right of passage, and every effort of being made to expand the availability of intoxicants to everyone in the US.

The DEA (1) states their role is to expand awareness, preserves lives, and provide intelligence to law enforcement that might be useful for resource allocation and prioritization.   Synthetic opioids and stimulants are described as the biggest threats.  Both can be easily mass-produced by the cartels in Mexico.  Fentanyl alone has accounted for a massive increase in mortality due to its potency and low therapeutic index – accounting for 74,225 deaths in 2022.  China is implicated as the main source of precursor drugs to produce fentanyl.

The report clearly states that two Mexican cartels are responsible for the drug flow into the US and the most significant drug crisis in the history of the US.  Further – the cartels have penetrated most states in the US to varying degrees.  The Internet has facilitated drug sales in the US and made these transactions more difficult to track.  The cartels are also producing methamphetamine leading to and increase in stimulant associated deaths.  There is also a China connection.  Chinese criminal operations supply precursors for the synthesis or opioids and methamphetamine as well as money laundering operations to make the money from illegal drugs sales useable. 

One of the strategies these criminal enterprises are using is adding additional intoxicants to the drug that users are purchasing.  This has the effect enhancing the intoxicating effects but a much higher risk of overdose and death – especially f the user is naïve to that drug or the seller is ignorant about the potency of the additional intoxicant.  I became aware of this phenomenon about a decade ago when I was being told that users witnessed fentanyl being pressed into alprazolam tablets and sold as alprazolam.  A secondary phenomenon was that many people were not averse to fentanyl but actively sought it out to enhance the period of intoxication.  The DEA report describes the following combinations:  

Fentanyl plus:

Heroin, cocaine, methamphetamine, xylazine, Counterfeit prescription drugs: (oxycodone (M30, Percocet); hydrocodone (Vicodin); or alprazolam (Xanax)

 

The DEA report addresses many of the logistics of the substance use problem and it does raise awareness – especially of the dangers of getting adulterated drugs and the severe side effects including death. It also highlights drug counterfeiting and it gives a great example of an Adderall tablet counterfeited from methamphetamine (see below).  That is especially problematic during a time of Adderall shortages from legitimate suppliers.

 

The unaddressed problem is American culture.  I don’t want to suggest that large groups of sociopaths intent on making money no matter how many people they kill don’t bear some responsibility. I also don’t want to suggest that reducing the availability of these drugs by any means is not a good idea.  But one of the takeaways from reading this report is that law enforcement is clearly not winning and it is a huge burden on them in both the US and Mexico.  Former President of Mexico Vincente Fox characterized the problem well as “America’s insatiable appetite for drugs.”  Right now, it is a multigenerational chronic problem. People can get effective treatment and recover but too many die and too many become chronic users. There needs to be an effective strategy for primary prevention or preventing use in the first place. Suggestions along these lines typical end up caricatured as the 1980s “just say no” public service ads, but this strategy was clearly effective in reducing cigarette consumption and decreasing the population of smokers. It has had the expected effects of decreasing smoking related mortality in both the general population and in smokers who quit.  The same population-wide benefits would be expected from any public health measure that effectively reduced the use of alcohol, stimulants, opioids, cannabis, or any other intoxicants.  What are the cultural factors that keep this drug epidemic going.  Here are a few:

1:  Cultural acceptance of substance use as a rite of passage:  The stories are endless. Fraternity and sorority hazing involving excessive alcohol use.  High school graduation parties associated with multiple driving while intoxicated deaths. Incarceration from assaults and homicides from barroom fights. Consumption of alcohol and other intoxicants in high school well before the legal age for consumption has been reached. Much of this has to do with immaturity and the Decade of the Brain did inform us that just on a biological basis human brains do not mature until the mid 20s and in the case of men possibly even later. Immersing an immature brain in intoxicants is generally not a recipe for success and may be a developmental risk for substance use disorders and mental illnesses.

2:  Consumerism and the selling of intoxicants:  This is a widespread phenomenon in the US.  Alcohol commercials typically suggest success, sexual attractiveness, popularity, sophistication, and glamour.  Identification with Hollywood A-listers is a plus and many of them are marketing their own brands to capitalize on that fact. The expensive packaging is often more significant than any difference in taste or quality. The only downsides are a very brief allusion to the Surgeon General’s warning about alcohol use in pregnancy or a disclaimer to “use responsibly.”  Not much about cancer, cirrhosis, pancreatitis, or dementia risk.

3:  Your right to intoxicants:  The subculture of users has a mixed agenda in promoting this idea.  There are a few people who believe that their lives are better by using drugs or alcohol, that they are using these substances in a controlled manner and “not hurting anybody.” And therefore, anyone should have the right to use them under these conditions.  On the face of it – few people would argue that point – even though it does assume that their self-report about use and its consequences is accurate.  A subgroup is promoting widespread intoxicant use as a business.  Many in this group see it as a get rich quick scheme. Many see it as a diversity equity inclusion (DEI) issue.  That is – minority groups sustained harm from excessive from legal penalties against cannabis and other drugs and therefore they should be given advantages in setting up businesses to profit from that discrimination.  Many want to extend cannabis law changes to include all drugs and legalize access to everything. The DEA report stands in contrast to mass legalization because it estimates how much the country would be awash in fentanyl if it was legal. It also ignores why substances were controlled in the first place and what happened when physicians started to prescribe more opioids both as "dope doctors" in the early 20th century maintaining people in addiction and in the late 1990s leading to the beginning of the current opioid epidemic.

4:  Cannabis misinformation:  There has not been much reflection of the medical cannabis period of the early 21^st century.  Cannabis was touted as a miracle drug whose benefit was being neglected due to archaic drug laws and the lack of modern research. Nothing was said about cannabis being around for over 700 years and having no clear cut indications for use.  That led to a patchwork of states passing medical cannabis laws, making each of those states a Mini-FDA with their own indications for use and in some cases limited forms of cannabis that could be dispensed for those indications.  Just as it became apparent that cannabis really was not much good for medical applications or even pain – the real motivation for the medical cannabis Trojan Horse became apparent.  That was of course recreational use. The Biden administration is currently considering rescheduling cannabis form a Schedule I to a Schedule III substance. That takes it off the experimental/no medical application category but still suggests that it will be prescribed and supervised by a physician.

5:  Widespread promotion of hallucinogens and psychedelics as miracle drugs: Building on the success of promoting cannabis as a medicine – we are now seeing frequent hype about the wonderful effects of psychedelics along with practically no discussion of the side effects. MDMA and LSD are being seen as wonder drugs that successfully treat depression, anxiety, PTSD, and substance use disorders. The cannabis promoters successfully promoted cannabis as a nearly completely benign substance and the hallucinogen/psychedelic promoters have used the same tactic.  I only recently read an account where the following side effects during a clinical trial of an LSD based drug were listed: illusion, nausea, euphoric mood, headache, visual hallucination, mydriasis, altered state of consciousness, anxiety, blood pressure increase, and abnormal thinking (all in significant numbers). In my clinical experience I have treated people with permanent side effects from this drug class after a single dose.

6:  Better living through chemistry:  There is a current wave of euphoria in the popular culture about GLP-1 agonists like Ozempic and Monjauro. It has been accompanied by FDA approved indications but also a very public reexamination of the usual prescriptions of diet and exercise for weight loss. The pendulum seems to have swung to the point that all excessive weight is a diseases state that can only be approached with a powerful drug that has potentially powerful side effects.  From a cultural perspective this class of drugs has led to the realization of the American dream that we can tune our bodies like we tune our cars and if we have the right drugs – we can have whatever kind of body or mind that we want. More longstanding evidence of this attitude is evident from anabolic androgenic steroid use and stimulant use for - both for performance enhancement.  All three are grand illusions. Hominid biology has evolved to incredible complexity over the past 2 millions years.  Any group of people may look alike but there are hidden differences in physiology and pharmacological response. One person’s medication is another person’s poison. As a result there are very few miracle drugs and some intoxicants have been around for centuries making it even less likely.

7:  Sobriety is a subculture:  In most societies certain religions and life philosophies are the most likely promoters of sobriety.   Most sobriety in the US is not thought about too much.  There are about 60% of people who never drink. There is a group of people in active recovery who had a problem with intoxicants and were successful in discontinuing them.  There is a small movement right now of young people who are not in recovery promoting sobriety.  The cultural resistance against substance use in the US seems trivial compared with the promoters.

8:  Treatment is secondary prevention: A standard political approach to the drug epidemic these days is to suggest that more availability of treatment centers and providers is a needed approach.  This is correct in so far as treatment for these conditions has always been deficient. Treatment has had a role in terminated localized drug epidemics in both Chicago and Washington DC.  There is a question about how well it will work now that just about every county in the US is awash with opioids and methamphetamine.   A logical approach may be to prevent new users from entering this cycle – in other words decreasing the incidence of the problem. Unfortunately there are fewer resources to address the unestablished problem and a lot of pessimism about that approach.  

9: Intoxicant use is a choice: Even though there is obvious evidence out there that a significant percentage of the population develops uncontrolled use of drugs and/or alcohol denial and rationalizations about this continues to persist. It has to in order to maintain the myth that people with substance abuse disorders really have a moral defect rather than a biological propensity.  In other words – repeatedly telling them to stop and blaming them for the problem is all that is required. That approach ignores the real problem that if you are biologically disposed – all it takes is access to substances to keep that process going. The moral approach also allows for a legalization position by simply stating that the people who cannot control their use are irresponsible.  

10:  Deaths of despair: This popular concept was popularized by Dean and Case (2) to explain increased mortality due to intentional injury and drug overdoses caused by hopelessness due to economic problems and the associated stress. Deaths due to alcohol and drug use were seen because of economic stress rather than a consequence of excessive use for other reasons including the cultural factors that have been specified. The concept minimizes the facts that severe drug and drug problems exist in populations that have no economic stress and that most of the people with severe economic stress do not have drug and alcohol problems. It also minimizes the fact that we are still in the midst of a multi-decade drug epidemic and there is no end in sight.  

Where does all of this leave us?  Not in a very good place. The DEA is describing its efforts to intercede in what is a massive effort from several countries to import highly dangerous substances into the United States. Although it is never overtly discussed this is clearly a national security problem. The immediate problems of deaths and morbidity from drug addiction seem to depends very little on how successful the DEA is in its efforts. The reason for that is the massive promotion of drugs at the cultural level both in direct advertising and false political philosophy equating drug use with freedom. It parallels the use of the Second Amendment to promote the widespread dissemination of firearms – even though there is no similar amendment for drug use. All the popular myths about drug use need to be actively countered and the advantages of a sober life need to be promoted. Those myths are a more subtle but equally dangerous threat to what the DEA is describing in this report.   

 

George Dawson, MD, DFAPA

 

References:

1:  Drug Enforcement Administration. National Drug Threat Assessment.  US Department of Justice.  May 2024.  57p.

2:  Case A, Deaton A. Rising morbidity and mortality in midlife among white non-Hispanic Americans in the 21st century. Proc Natl Acad Sci U S A. 2015 Dec 8;112(49):15078-83. doi: 10.1073/pnas.1518393112. Epub 2015 Nov 2. PMID: 26575631; PMCID: PMC4679063

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