Adulterants Present in the San Diego County Fentanyl Supply: A Laboratory Analysis of Seized Law Enforcement Samples

doi:10.21203/rs.3.rs-3138105/v1

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Adulterants Present in the San Diego County Fentanyl Supply: A Laboratory Analysis of Seized Law Enforcement Samples

https://doi.org/10.21203/rs.3.rs-3138105/v1

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published 29 Mar, 2024

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Background

The opioid epidemic is one of the worst public health crises ever to face the US and emerging evidence suggest its effects are compounded by the presence of drug adulterants. Here we report our efforts to characterize the adulterants present within the local fentanyl supply of San Diego County, obtained from undifferentiated drug samples seized by local law enforcement over the calendar year 2021.

Methods

Thirty two participating local law enforcement agencies across San Diego submitted 4838 unknown individual illicit drug samples (total of 312 kg) to the San Diego County Sheriff’s Department Regional Crime Laboratory for identification.

Results

Qualitative analysis of these samples via FTIR and GC-MS identified methamphetamine (38.7%), fentanyl (20.8%), diacetylmorphine (heroin) (10.2%), codeine (5.8%) and alprazolam (4.3%) as the most common illicit substances and the presence of 52 unique adulterants. The most common adulterants included 4-methylaminoantipyrine (4-MAAP) (10.9%), mannitol (9%), acetaminophen (8.5%), methamphetamine (4.2%), diacetylmorphine (heroin) (3.6%), tramadol (1.9%), and xylazine (1.7%). Several additional pharmacologically active adulterants and contaminants of interest were also identified.

Conclusion

This analysis is vital for public health use and harm reduction efforts at the level of the individual consumer. Continued direct surveillance of the drug supply is necessary for the detection of potentially harmful adulterants that may pose serious threats to the public.

Adulterant

Contaminant

Opioid

Fentanyl

Drug abuse

Xylazine

Pharmacosurveillance

Pharmacovigilance

Forensic Toxicology

Toxicology

According to a nationwide survey conducted in 2020, 6.6% of individuals over the age of 12 reported at least one substance use disorder of an illicit drug of abuse in the prior year.1 In the same year, more than 105,000 deaths were associated with drug overdoses; nearly 75% of these were attributed to opioid abuse.² Within this context, there is an on-going public health concern related to the presence of “adulterants” and “contaminants” within drug supplies.^3–5

Adulterants are pharmacologically active or inactive ingredients added to increase bulk as a cost saving measure, produce synergistic drug effects to enhance or improve the effects of the diluted drug, help enhance drug absorption, or reduce the amount of drug necessary to achieve the desired effect.^6,7 Potentially harmful adulterants have historically been associated with morbidity and mortality.^8–13 On the other hand, contaminants are unintentional and have no role in augmenting the intended drug. They are commonly precursors or by-products of manufacturing or storage, remnants of low quality manufacturing techniques and storage practices.⁶ The landscape of drug adulterants specifically is complex and rapidly evolving, often subject to various economic and law-enforcement pressures experienced by illicit drug manufacturers. Consequently, routine public health surveillance of the drug supply is necessary.⁶

Here we report our efforts to characterize the adulterants present within our local fentanyl supply of San Diego County. By analyzing seized fentanyl samples, we aim to provide insight into current adulteration trends and raise awareness of potentially harmful and clinically relevant adulterants in the drug supply.

From January 4, 2021 to December 30, 2022, 32 participating local law enforcement agencies across our county submitted 4838 unknown individual illicit drug samples (total of 312 kg) to the County Sheriff’s Department Regional Crime Laboratory for identification.

Seized drug samples were initially analyzed using presumptive colorimetric testing and confirmed using FTIR and/or GCMS. FTIR was performed using a Thermo Scientific Nicolet iS10 infrared spectrometer with a Specac Golden Gate Attenuated Total Reflectance (ATR) attachment. The analyzed sample was directly placed onto a diamond crystal for analysis and pressure was applied via a sapphire fitted anvil to create a uniform spread on the diamond crystal. The FTIR optical bench collected 32 scans at a resolution of 4.000 cm-1 with a sample gain of 8.0 and optical velocity of 0.6329 with the aperture set to 80.00. Omnic (Thermo Scientific: Version 8.3) was used for acquisition and analysis. The analyte spectrum was compared to our own created and verified reference spectrum library.

Gas chromatography–mass spectrometry (GC-MS) is mostly commonly employed in routine analysis, the samples were prepared by dissolving approximately 1 mg of analyte in a suitable solvent (ethanol, methanol, chloroform, methylene chloride, or other suitable solvent). Liquid-liquid extractions were used when necessary and analyzed as filtrates. Proadifen was added to 1.5 mL of the extract as an internal reference at a concentration of approximately 1 mg/mL in a sample vial for monitoring instrument conditions. 1 µL was injected onto an Agilent 7890 Gas Chromatograph fitted with a crossbonded diphenyl dimethyl polysiloxane (5%) column (e.g. Restek Rxi-5Sil MS). The injection is generally on pulsed spitless mode with a pulse pressure of 50 PSI and held for 30 seconds. Column length was 15 meters, with an internal diameter of 0.25mm and film thickness of 0.25um. General method parameters started at 80°C and increased up to 280°C at a rate of 20°C per minute with a 12-minute run time. Eluents were introduced into an Agilent 5977 mass spectrometer set to positive ion polarity. Fragmentation was by electron impact ionization at 70 eV. The MS was operated in full scan with a mass window of 25 to 600 m/z at a threshold of 150 with a scan speed of 781.

Following analysis of these samples, 39 individual drugs of abuse were identified. The most commonly identified substances were methamphetamine (38.7%), fentanyl (20.8%), diacetylmorphine (heroin) (10.2%), codeine (5.8%) and alprazolam (4.3%). Figure 1 details the relative percentages of each individual substance identified and Fig. 2 details the ten most common substances by weight.

Of the 4838 total samples tested, 1007 (20.8%) were confirmed to contain fentanyl. Qualitative analysis via FTIR and/or GC-MS of these fentanyl samples revealed the presence of 52 unique adulterants (Fig. 3). The most common included 4-methylaminoantipyrine (4-MAAP) (10.9%), mannitol (9%), acetaminophen (8.5%), methamphetamine (4.2%), diacetylmorphine (3.6%), tramadol (1.9%), and xylazine (1.7%). Various fentanyl analogues were also identified, namely fluorofentanyl, acetylfentanyl, benzylfentanyl, and methyl acetyl fentanyl. Several other opioids were detected including diacetylmorphine (heroin), morphine, 6-monoacetylmorphine, oxycodone, codeine, methadone, fluonitazene, protonitazene, and isotonitazene. Table 1 details the complete list of opioid adulterants found.

A large number of pharmaceutical non-opioid adulterants were detected. These included acetaminophen, dextromethorphan, methamphetamine, xylazine, lidocaine, cocaine, alprazolam, procaine, caffeine, clonazepam, levamisole, phenobarbital, etizolam, delta 9-tetrahydrocannabinol, carisoprodol, bupivacaine, and diazepam. Table 2 details the complete list of pharmaceutical non-opioid adulterants. The diluents mannitol and sorbitol were also detected.

In terms of contaminants, several fentanyl precursors were noted. Among those precursors, 4-anilino-N-phenethylpiperidine (4-ANPP) and phenethyl-4-anilino-N-phenethylpiperidine (phenethyl 4-ANPP) were the most common. Other contaminants identified include 1-hexadecanol and 1-hexadecene. Table 3 highlights a complete listing of contaminants found within submitted fentanyl samples.

San Diego is an epicenter for opioid trafficking given its large population and proximity to the US-Mexico border. This results in more opioid seizures than at any other domestic port of entry. In 2022, more than 2300 kilograms of fentanyl were seized by San Diego- based law enforcement officers, accounting for nearly 60% of all trafficked fentanyl nationwide.^14,15 Given this proximity to upstream trafficking, it is possible that the drug supply in San Diego and the surrounding region is likely to be closer to the original trafficked product, containing fewer adulterants and contaminants than would be seen in locations distant from the entry point.

Notably, several opioid adulterants were identified, of which diacetylmorphine (heroin) was the most common. This is consistent with the Drug Enforcement Agency’s Fentanyl Signature Profiling Program, which also found diacetylmorphine (heroin) was the most common opioid adulterant in domestic illicit fentanyl supplies.¹⁶ Fentanyl analogs fluorofentanyl, acetyl fentanyl, and benzylfentanyl have been implicated in overdoses and deaths.^17–20 The benzimidazole opioids flunitazene, protonitazine, and isotonitazene, are highly potent and have been associated with several fatalities.¹⁶

Of the many pharmaceutical non-opioid adulterants identified, a large number were sedative-hypnotic drugs of various classes, including benzodiazepines, carisoprodol, phenobarbital, and xylazine. Co-ingestion of sedative-hypnotic agents and opioids can produce synergistic euphoric effects as well as potentially synergistic respiratory depression. ²² The combination of opioids and xylazine, or “tranq dope,” in particular, is a concerning emerging phenomenon occurring across the United States. Though the highest prevalence of xylazine overdoses and deaths has, thus far, been observed in the Northeastern United States, our data show that xylazine adulteration is present in a small percentage of recently trafficked fentanyl in our geographic region as well.²³ Acetaminophen is commonly used as a bulking agent.²⁴

We suspect that the presence of stimulant adulterants such as methamphetamine, cocaine, and caffeine is likely intentional. Combining opioids and stimulants in a single ingestion is known to produce a synergistic, longer lasting euphoric effect. The combination also limits the adverse effects of either alone.^21,25,26 However, it is also possible this data represents cross-contamination with other drugs during manufacturing and/or trafficking.

Though possibly adulterants of unclear value, it is more likely that the detected local anesthetics and levamisole are associated with cocaine and not added intentionally to the fentanyl. Local anesthetics are commonly used to mimic the anesthetic qualities of cocaine, whereas levamisole is reported to cause synergistic effects with cocaine.^27–30

In terms of contaminants, the most common were fentanyl precursors, 4-ANPP and phenethyl 4-ANPP. Though both possess mild mu-opioid receptor agonism, these more likely represent sequelae of poor manufacturing processes than adulterants. ^20,30,31

The results of this study are limited by several factors. First, we analyzed convenience samples submitted by participating law enforcement agencies, which do not necessarily represent a true random sample of the drug supply in our county. Second, we cannot account for drug sample storage, processing, and handling by distributers prior to analysis, allowing for the possibility of contamination after seizure. Third, this study is limited in terms its generalizability. Though our findings reflect regional trends and likely reflect the state of the supply early in the domestic trafficking pipeline, they may not necessarily be reflective of drug adulterant trends nationally. Fourth, our analysis was qualitative rather than quantitative and did not generate relative composition data. Consequently, we could not report relative concentrations of drug versus adulterants nor the proportion of pure samples. Finally, this study lacks individual case details or any outcomes data from the sample’s use.

Ultimately, we feel this information is vital for public health use and harm reduction at the level of the individual consumer. Continued direct surveillance of the drug supply is necessary for the detection of potentially harmful adulterants that may pose serious threats to consumers. However, the extent to which these unique adulterants impact drug use as well as associated morbidity and mortality remains uncertain and an area of interest for further study.

Table 1

Pharmacologically active opioids identified within 1007 samples of illicit fentanyl.
Pharmacologically Active Opioids
Fentanyl Analogues	Synthetic (Benzimidazole) Opioids	Non-Fentanyl Opioids
Fluorofentanyl	Fluonitazene	Diacetylmorphine
Acetyl fentanyl	Protonitazene	Tramadol
Benzylfentanyl	Isotonitazene	Morphine
Methyl acetyl fentanyl		6-Monoacetylmorphine
		Oxycodone
		Codeine
		Methadone
		Noscapine

Table 2

Pharmacologically distinct non-opioid adulterants identified within 1007 samples of illicit fentanyl
Non-Opioid Adulterants
Stimulants	Sedative-Hypnotics	Anesthetics	Other
Methamphetamine	Xylazine	Lidocaine	Acetaminophen (Analgesic, antipyretic)
Cocaine	Alprazolam	Procaine	Dextromethorphan
Caffeine	Clonazolam	Bupivacaine	Delta-9-tetrahydrocannabinol (Cannabinoid)
Benzeneethanamine (amphetamine analogue)	Clonazepam		4-methylaminoantipyrine (Metamizole metabolite, analgesic)
	Phenobarbital		Papaverine (Phosphodiesterase inhibitor)
	Etizolam		Levamisole (Anthelminthic)
	Carisoprodol		Mannitol, sorbitol (Diluents)
	Diazepam

Table 3

Contaminants identified within 1007 samples of illicit fentanyl
Fentanyl Precursors	Others
4-Phenyl]amino-1-phenethylpiperidine (4-ANPP)	Phenothrin (Pyrethroid)
4-anilino-N-phenethylpiperidin (Phenethyl 4-ANPP)	1-hexadecene, 1-hexadecanol (surfactants)
Fluoro Phenethyl-4-ANPP	Phenylpropanamide (fentanyl degradation product)
Fluoro-4-ANPP
Meta-methyl 4-ANPP
4-anilino-N-phenethylpiperidin (Phenethyl 4-ANPP)
1-Propionyl-4-Anilinopiperidine
4-Anilinopiperidine
1-Phenethyl-4-Propionyloxypiperidine
1-Phenethyl-4-Hydroxypiperidine
4 N-Methyl Norfentanyl

Ethics approval and consent to participate: IRB approval for this study was not necessary as it did not include any interactions or interventions with human subjects or include any access to identifiable private information.

Consent for publication: Not applicable

Availability of data and materials: All relevant data sets made available by the San Diego County Sheriff’s Department Regional Crime Laboratory. In accordance with California state and San Diego local regulatory requirements the collected data sets cannot be made public due to their sensitive nature. Please email Ms. Jennifer Harmon at [email protected] to discuss requesting data from this study.

Competing interest: All authors declare no competing interest.

Funding: None

Authors Contribution: Dr. Galust was responsible for study conception, manuscript drafting, data analysis, and data interpretation. Drs. Seltzer, Friedman, Hardin, and Clark were responsible for manuscript drafting with substantial revisions. Mr. Salamat was responsible data acquisition, data analysis, and manuscript drafting. Ms. Harmon was the principle investigator and responsible for manuscript drafting with substantial revisions. All listed authors have approved the submitted version. All authors have agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature. All listed authors have approved the submitted version.

Acknowledgements: Not applicable

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No competing interests reported.

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Adulterants Present in the San Diego County Fentanyl Supply: A Laboratory Analysis of Seized Law Enforcement Samples

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