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Molecular Insights and Clinical Outcomes of Drugs of Abuse Adulteration: New Trends and New Psychoactive Substances

Annagiulia Di Trana
Diletta Berardinelli
Eva Montanari
Paolo Berretta
Giuseppe Basile
Marilyn A. Huestis
4,* and
Francesco Paolo Busardò
Department of Excellence of Biomedical Science and Public Health, University “Politecnica delle Marche” of Ancona, Via Tronto 71, 60124 Ancona, Italy
National Centre on Addiction and Doping, Istituto Superiore di Sanità, 00161 Rome, Italy
IRCCS Orthopedic Institute Galeazzi, 20157 Milan, Italy
Institute of Emerging Health Professions, Thomas Jefferson University, 1020 Walnut St., Philadelphia, PA 19144, USA
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(23), 14619;
Submission received: 27 October 2022 / Revised: 18 November 2022 / Accepted: 21 November 2022 / Published: 23 November 2022
(This article belongs to the Special Issue Molecular Insights of New Psychoactive Substances (NPS) 2.0)


Adulteration is a well-known practice of drug manufacturers at different stages of drug production. The intentional addition of active ingredients to adulterate the primary drug may enhance or mask pharmacological effects or may produce more potent drugs to increase the number of available doses and the dealer’s profit. Adulterants found in different drugs change over time in response to different factors. A systematic literature search in PubMed and Scopus databases and official international organizations’ websites according to PRISMA guidelines was performed. A total of 724 studies were initially screened, with 145 articles from PubMed and 462 from Scopus excluded according to the criteria described in the Method Section. The remaining 117 records were further assessed for eligibility to exclude articles without sufficient data. Finally, 79 studies were classified as “non-biological” (n = 35) or “biological” (n = 35 case reports; n = 9 case series) according to the samples investigated. Although the seized samples analyses revealed the presence of well-established adulterants such as levamisole for cocaine or paracetamol/acetaminophen for heroin, the reported data disclosed new adulteration practices, such as the use of NPS as cutting agents for classic drugs of abuse and other NPS. For example, heroin adulterated with synthetic cannabinoids or cocaine adulterated with fentanyl/fentalogues raised particular concern. Notably, adulterants play a role in some adverse effects commonly associated with the primary drug, such as levamisole-adulterated cocaine that may induce vasculitis via an autoimmune process. It is essential to constantly monitor adulterants due to their changing availability that may threaten drug consumers’ health.

1. Introduction

In 2020, about 284 million people consumed drugs within the previous year, representing an increase of 26% compared to 2010. Cannabis products remain the most abused compounds all over the world, while the highest prevalence of drug-related deaths is attributed to opioids [1]. Over recent decades, the drug market continuously evolved in response to several factors, including recent laws banning substances and precursors, but also events involving the entire world such as the recent SARS-CoV-2 pandemic [2]. Between 2010 and 2020, an alarming increase in drug seizures was observed in Europe, reflecting a 477% increase in methamphetamine seizures, 278% increase in herbal cannabis seizures, 266% increase in cocaine seizures, and a decrease in heroin seizures [3]. Although seizures data reflect only partially the drug supply chain, it suggests that drug market dynamics are changing.
Besides the threat of illicit drug consumption, adulteration with other active compounds represents an additional risk for drug users, exposing them to unanticipated intake of a wide range of pharmacologically active substances. Adulteration is a well-known practice of drug manufacturers at different stages of drug production [4,5]. Different from drug dilution and drug counterfeiting, the intentional addition of active ingredients to adulterate the primary drug may enhance or mask pharmacological effects or may produce more potent drugs to increase the drug dealer’s profit [6]. Furthermore, most of the adulterants are not internationally banned unless they are controlled under national health or food regulations [7]. Adulterants found in different drugs changed over time in response to different factors, such as controls implementation. In the last decades, the increased controls on methylenedioxymethamphetamine (MDMA) and its synthetic precursors affected the drug manufacturing process leading to poorer quality “ecstasy” tablets with increased adulterants [8]. On the other hand, some cutting agents frequently reoccur in the manufacturing process such as levamisole for cocaine or paracetamol and xylazine for heroin [4,5,7].
Recently, concerns were raised by the adulteration of low ∆-9-tetrahydrocannabinol (THC) cannabis products with more powerful synthetic cannabinoids [9]. Besides synthetic cannabinoids, other new psychoactive substances (NPS)-adulterated classical drugs of abuse have provoked a wave of fatal intoxications around the world. Fentanyl and its analogues were employed for decades as heroin adulterants; but recently “nitazenes”, new synthetic benzimidazole opioids with high potencies, are found as common opioid-cutting agents [10,11].
Here, we review the most recent reports of adulterants detected in seized drugs of abuse including NPS. Furthermore, we reviewed reported cases of adulterated drug intoxications published in the literature from 2017 to 2022, focusing on clinical signs, pharmacological peculiarities, reported intoxication symptoms, and toxicological analyses performed on different human specimens.

2. Results

A total of 724 studies were initially screened, with 145 articles from PubMed and 462 from Scopus excluded according to the criteria described in the Method Section. The remaining 117 records were further assessed for eligibility to exclude articles without sufficient data. Finally, 79 studies were classified as “non-biological” (n = 35) or “biological” (n = 35 case reports; n = 9 case series) according to the samples investigated. All results are summarised in Table 1, Table 2 and Table 3 and Figure 1 and Figure 2.

2.1. Non-Biological Samples

The literature search yielded 35 studies (Table 1) on seized cocaine (n = 20), opioids (n = 14), amphetamine-like stimulants (n = 8), NPS (n = 2), and THC (n = 2). Although most manuscripts considered one adulterated drug, different substance classes were investigated in 7 studies [12,13,14,15,16,17]. Cocaine was the most frequently adulterated drug, whereas the highest number of adulterants were detected in amphetamine-like stimulants that were adulterated with 22 different substances [12].
Levamisole and phenacetin were the most prevalent cocaine adulterants, followed by caffeine. The reported adulteration with local anaesthetics such as lidocaine, benzocaine, or procaine [12,13,16,18,19,20,21,22,23,24,25] is a known practice to mimic the highly pure cocaine anaesthetic effect on the mucosa. Although fentanyl traces were detected in cocaine samples seized in the USA [26], other drugs of abuse or pharmaceuticals were rarely reported in cocaine street samples [12,13,16]. The investigated opioids were heroin, fentanyl, morphine, opium, and “crack heroin”. The largest number of adulterants were found in fentanyl samples [27,28], primarily synthetic opioids, synthetic cathinones, caffeine, and acetaminophen. Paracetamol/acetaminophen and caffeine were confirmed as the most common opioids cutting agents according to Tittarelli et al. [5]. Fentanyl/fentalogues adulterated heroin was reported in 3 cases in Canada and in the USA [13,29,30], whereas heroin adulterated fentanyl was detected only in the USA and Canada [27]. Other psychotropic substances such as cocaine, methamphetamine, and benzodiazepines were detected in opioids seized samples. Lead was the most prevalent adulterant in opium samples, but it was detected also in heroin, methamphetamine, and ecstasy seized in Iran [15,31]. It was proposed that lead was added to heroin and other drugs during the first phases of the supply chain, to increase the weight of the batch and obtain more profit.
Amphetamine-type stimulants were adulterated with the most varied compounds, primarily other stimulants, most likely to boost the expected effect. Furthermore, the highest number of NPS (19 different substances in total) were detected in MDMA and methamphetamine seized in the USA and Canada [12,32].
Only 3 studies investigating NPS composition revealed that these adulteration practices also occurred with these compounds that were also used as adulterants of classic drugs [12,31,33] Although data are not sufficient to establish a trend, it seems that NPS are adulterated to enhance some desirable effects with substances producing these effects, such as the synthetic cannabinoids or NBOMe adulterated α-methyltryptamine [33].
Cannabis adulteration was the least investigated phenomenon since it was reported in only 2 studies. In this regard, Oomen et al. analysed a large number of samples recently seized in Europe, showing 24% of samples were adulterated with a potent synthetic cannabinoid, MDMB-4en PINACA, [34]. It was apparent that cannabis was adulterated more frequently in e-cigarette cartridges than in flowering tops or edibles.
The quality and quantity of adulterants identified in psychotropic drugs are affected by the analytical approach, as typical targeted methods do not reveal unexpected molecules [23,35]. Examples are on-site drug screening devices that contain antibodies that are specific for a class of drugs and do not react with adulterants. Conversely, the identification and structural characterization of adulterants was primarily conducted via two-step analysis by mass spectrometry and subsequently, nuclear magnetic resonance (NMR) [24,33,36]. Capillary electrophoresis and electrochemical methods are also available [14,23,27,36,37], but the gold standard are hyphenated techniques based on liquid or gas chromatography coupled to mass spectroscopy [12,15,17,20,22,28,29,30,38,39,40,41,42,43,44].

2.2. Biological Samples

A total of 35 case reports of drug adulterants’ intoxications are included (Table 2). Adulterants were analytically detected in biological matrices in only 15 cases and identified compounds were levamisole (n = 7), 5F-MDMB-PICA (n = 1); lead (n = 1); sildenafil (n = 1); etizolam and caffeine (n = 1), and lysergic acid diethylamide (LSD) (n = 4) [33,42,45,46,47,48,49,50,51,52]. In the remaining 20 cases, adulterants were only hypothesized based on the observed symptoms, disease or indirect sequelae or confiscated drug analysis. Suspected substances were levamisole (n = 10), methaqualone and several benzodiazepines, caffeine and acetaminophen (n = 1), 5F-MDMB- PINACA (n = 7) and phenethylamine (n = 1), asbestos (n = 1) [33,42,44,45,46,47,52,53,54,55,56]. Considering all of the reported cases, levamisole was the most prevalent adulterating agent in street cocaine (n = 17 cases) [33,42,44,45,46,47,54,57,58,59,60,61,62].
In this regard, the most interesting association between an adulterant and resultant disease occurred with levamisole and perinuclear or cytoplasmic anti-neutrophil cytoplasmic antibodies (p- or c-ANCA) positivity. P- or c-ANCA are two autoantibodies which target different neutrophil proteins: myeloperoxidase (MPO) associated with p-ANCA and proteinase3 (PR3) associated with c-ANCA. Generally, ANCA positivity is a marker of autoimmune pathologies including systemic autoimmune vasculitis, necrotising crescentic glomerulonephritis, inflammatory bowel disease and other autoimmune pathologies [63]. In levamisole-adulterated cocaine intoxications [33,44,45,46,47,54,57,58,59,60,61,62] the p- or c-ANCA positivity was associated with Cocaine Induced Midline Destructive Lesions (CIMDL) (n = 5) [44,57], vasculitis (n = 8) [33,47,58,59,60,61], membranous glomerulonephritis (n = 4) [58,62], pyoderma gangrenosum (n = 1) [54], neutropenia complicated with bowel necrosis (n = 1) [46], and cerebral white matter dysfunction (n = 1) [45]. These autoimmune pathologies were more frequent in women (100% ANCA positivity) than men (90% of ANCA positivity) [64]. Vasculitis was also observed in a p-ANCA-negative cocaine user disregarding the expected and known association between p/c ANCA positivity and vasculitis [33].
The average age of the cocaine users that experienced levamisole toxicity due to adulteration was 44 years, including 11 males (average age: 41.8 years) and 7 females (average age: 45.3 years). Age and sex were factors related to levamisole and cocaine exposure in the different pathologies. CIMDL was associated with younger age and female sex (36.3 years, 60% women), older women experienced more vasculitis (46.5 years, 60% female) and older men more glomerulonephritis (42 years).
Levamisole was analytically confirmed in only 7 cases, with suspected exposure based on the clinical manifestations and confirmed cocaine exposure [33,44,45,58,59]. Qualitative levamisole analysis was frequently performed in urine (n = 5), while the quantitative confirmatory analysis was performed on hair (n = 2) with segmental analysis. Levamisole-adulterated cocaine produced toxicity in the nasal septum including CIMDL (2), kidney (2), brain (1) and skin vessels (2).
Adulterated opioids were found in 10 intoxications. The most frequent adulterated opioid was heroin laced with 5F-MDMB-PINACA (n = 8) [52], while methaqualone combined with oxazepam, ketazolam, nordiazepam, pinazepam, and alprazolam was detected in one heroin consumption case [55]. Lead was detected in one opium abuse case characterized by non-specific symptoms including nausea, acute/severe abdominal pain, and vomiting [49]. Patients with severe abdominal pain may undergo unnecessary emergency abdominal surgery, due to a diagnosis of occluded bowel rather than chronic lead intoxication. The average age of individuals experiencing heroin-adulterated intoxication was 30.4 years, with 8 male and two female heroin users reported as exposed to adulterants. Urine was analysed in 10 cases, while serum confirmation was conducted only in 3 cases. Urinalysis revealed the presence of other psychotropic substances combined with heroin including other opioids (n = 7), fentanyl (n = 5), and cocaine (n = 3) [49,52,55].
The most frequent substances detected in serum were 6-acetylmorphine (n = 6), fentanyl (n = 3) and heroin (n = 3), while 5F-MDMB- PICA and cocaine were positive for 1 case [52]. Drug analysis clarified the cause of intoxication revealing the presence of 5F-MDMB- PINACA (n = 7), fentanyl (n = 6) as the most detected analytes. [52] Methaqualone was detected in only one case. [55] While all adulterated heroin cases were associated with other drugs, cocaine was adulterated with levamisole in only 6 out of 17 and was also associated with secondary drugs, such as THC, benzoylecgonine, ecgonine methyl ester, norcocaine and tramadol, cannabinoids, opiates, benzodiazepines, opiates, methadone [45,53,58,59,61]. LSD, γ-hydroxybutyric acid (GHB) and kratom were adulterated in 7 cases, involving only males, with an average age of 30.3 years [48,50,51]. The most investigated biological matrix was urine (n = 5), followed by blood (n = 4), serum (n = 3) and hair (n = 1). In all these cases, quantification was accomplished with sophisticated analytical methods. The adulterants were THC and MDMA for LSD (n = 3), sildenafil (n = 1) for GHB, etizolam (n = 1) for alprazolam and phenylethylamine (n = 1) for kratom [48,50,51].

2.3. Case Series Reports

Among the 9 case series reports, cocaine and heroin were the main adulterated drug identified between 2017 and 2022 (Table 3).
The most frequent cocaine adulterant was levamisole, detected in hair, urine and postmortem brain [43,65,66,67,68,69].
In 2019, Handley et. al. found higher levamisole concentration in urine than in plasma (565 ng/mL vs 10.6 ng/mL), due to its rapid metabolism (t1/2 = 5.6 h). Interestingly, levamisole was more concentrated in brain tissue than in the other matrices (128 ng/mg) suggesting an accumulation in the parenchyma and facilitated passage through the blood–brain barrier [66].
In the series of heroin cases, acetylfentanyl, furanylfentanyl, U-47700, and norfentanyl were the adulterants identified in segmented hair (n = 40), urine (n = 30), and oral fluid (n = 30). Concentrations in hair were 2.3–8600 pg/mg for fentanyl (mean = 860 pg/mg, median = 440) and 2.1–3200 pg/mg for acetylfentanyl [70,71]. Urine and oral fluid analyses were qualitative. Fentanyl and synthetic opioids (acetylfentanyl, furanylfentanyl, norfentanyl and U-47700) were detected in the hair of individuals enrolled in opioid substitution therapy.
Table 1. Adulterants detected in seized samples of cocaine, opioids, amphetamine-type stimulants, and new psychoactive substances (NPS) reported in the literature between 2017 and 2022.
Table 1. Adulterants detected in seized samples of cocaine, opioids, amphetamine-type stimulants, and new psychoactive substances (NPS) reported in the literature between 2017 and 2022.
Drug Class
AnalysisSeizure Yrs
Ref. Drug Class
# Cases
AnalysisSeizure Yrs
Cocaine Opioids
17841Levamisole; phenacetin; caffeine; lidocaineGC-MS2006–2015 Switzerland[20]33Fentanyl 2U-47700; lidocaine; heroin; 6-AM; methoxyacetyl fentanyl; phenyl fentanyl; codeine; methacryl fentanyl; caffeineGEMBE2019
2728Levamisole 433; phenacetin 323; aminopyrine 60; benzocaine 29; lidocaine 22;
caffeine 21
[21]34Fentanyl 46Xylazine 46GC-MS
324Tetramisole 23; levamisole 1LC-MS/MS2013–2016
[43]35Heroin 4Ocfentanil 4;
caffeine 4; paracetamol 4
4351Levamisole 214; lignocaine 103; meth 13; MDMA 10; phenacetin 7; benzocaine 6; THC 4; amphetamine 1; heroin 2GC-MS2015–2016
[12]36Heroin 217;
cocaine 19;
amphetamine 367
Caffeine 852;
nicotine 244; acetaminophen 261; levamisole 8
5292Levamisole 292SVM-DA

[37]37Heroin 11Meth 7; dextromethorphan 3; cocaine 2; diazepam 1GC-MS2015–2016
697Levamisole 92; phenacetin 22; caffeine 14; hydroxyzine 10; benzocaine 6GC-MS
[17]38Heroin 10Lead 10; caffeine 8; chloroquine 3; methadone 3; phenobarbital 2; tramadol 2; acetaminophen 1; meth 2HPLC-MS
717Caffeine 11; lidocaine 10; acetaminophen 9; phenacetin 7; diltiazem 4HPLC-DAD2017
[22]39Heroin 198Quinine/quinidine 44; fentanyl 31;
lidocaine 24;
caffeine 21; levamisole 20; phenacetin 12
896Levamisole 30; lidocaine 26;
phenacetin 13; caffeine 11; quinine/quinidine 12
[13]40Heroin 7Acetaminophen 4; caffeine 4; fentanyl 1GC-MS2018
93Caffeine 3Colorimetric
[21]41Heroin 30Caffeine 30;
noscapine 26; papaverine 22; paracetamol 16; lidocaine 2; dextromethorphan 5
1050Levamisole 17; lidocaine 16CE-C4D2018
[23]42Heroin 3Caffeine 1GC-MS
113Levamisole 3SWV
[36]43Heroin 59
Meth 26
Caffeine 7GC-MS2019
123Levamisole 3CV2018
[14]44Heroin 659Paracetamol 656;
caffeine 656
137Levamisole 5;
Phenacetin 3; caffeine 2; procaine 1; tetracaine 1
[24]45Heroin 14-AP-t-BOC (tert-butyl-4-anilinopiperidine-1-carboxylate)GC-MS
14156Levamisole 58; caffeine 39; quinine/quinidine 27; diphenhydramine 20; phenacetin 17; acetaminophen 17; lidocaine 16; procaine 13; diltiazem 10; xylazine 4; atropine 2; aminopyrine 4; hydroxyzine 3; dipyrone 2; guaifenesin 1; gabapentin 1GC-MS
[25]46Opium 10Lead 10; acetaminophen 8; chloroquine 4; tramadol 2HPLC-MS
1547Levamisole; phenacetin; lidocaine; caffeine DART-HRMS2019
[18]47Opium 10Lead 10AAS2015–2016
161078Levamisole 584;
phenacetin 386;
caffeine 113; lidocaine; ketamine; hydroxyzine
[16]48Morphine 6Codeine 4; thebaine 2; papaverine 2; noscapine 2; 6-AM 1; heroin 1; oxycodone 1; acetylcodeine 1; fentanyl 1; alprazolam 1GC-MS2015–2016
17169Phenacetin 169GC-EA-IRMS6 yrs
[41]49Fentanyl 100Caffeine 96;
etizolam 50; carfentanil 8;
cocaine 7; heroin 6; acetyl fentanyl 1
18306Phenacetin 231; caffeine 196;
aminopyrine 82; levamisole 16; lidocaine 5; benzocaine 1
2019 Uruguay[19]NPS
1945Caffeine 32; phenacetin 30; levamisole 27; lidocaine 15GC-MS2020
4F-α-PVP; DiPT;
Meth 25; DMA 14; MDMA 2;
cocaine 1; methylphenidate 1; lignocaine 1
Lead 10; meth 4;
heroin 2
[15]524-MeO-PCP 2AB-FUBINACA 2; nicotine 2; ketamine 2; amitriptyline 2LC-Q-ToF
Unspecified 104;
methylone 35;
synthetic cathinones 21; methamphetamine 13; benzylpiperazine 8; dextromethorphan 8; mephedrone 5; Amphetamine 4 butylone 4; cocaine 4; ketamine 1; MeO-amphetamine 3; LSD 1
Colorimetric 2010–2015
Ethylone 189; meth 34; MDA 16; cocaine 10; 5-Meo-DALT 8; phenethylamine 7; 2C-T-2 6; DMA 5; dibutylone 3;
DMT 2; amphetamine 2; methylone 2 sildenafil 2; THC 1 methoxetamine 1; 2C-B 1; MDDM 1;
GC-MS2015–2016 Canada[12]54α-MTMDPBP; 25B-NBOMELC-Q-ToF
Caffeine; lidocaineGC-MS
Raman Spectroscopy
[74]55Butyrylfentanyl 2Fentanyl 2; acetylfentanyl 2; 4-ANPP 2LC-Q-ToF
Unknown 259;
dimethylsulfone 36; dimethylsulfone and Caffeine 2; ketamine 2; MDEA 1; cocaine and ketamine 1;
N-Moc-MDMA and T-Boc-MDMA 1
56Ethylphenidate5-Meo-DALT; caffeine; phenacetin; lidocaineLC-Q-ToF
26Methamphetamine 181N-isopropyl benzylamine 37; DMA 30; amphetamine 24; cocaine 15; α-PHP 1; DMMA 1; N-Me-2AI 1; ethylphenidate 1; phenethylamine 1; praziquantel 1;
25C-NBOME 1;
25I-NBOME 1;
ketamine 1; methoxetamine 1;
MDMA 36; THC 36; heroin 3; diazepam 3; alprazolam 1;
quetiapine 5;
lignocaine 7
GC-MS 2015–2016 Canada[12]57IsopropylphenidateMethylphenidateLC-Q-ToF
27Methamphetamine 10Lead 10;
e 6; pseudoephedrine 5; caffeine 3; dextromethorphan 3; ketamine 1; MDMA 1
[15]58MDMB-CHMICAAMB-FUBINACA; 1-(cyclohexylmethyl)-1H-indole-3-carbonyl)valineLC-Q-ToF
28Methamphetamine 219Phenacetin 3;
caffeine 2;
diltiazem 2
4-AcO-DMT; 3-MEC; 4F-α-PVP; Ketamine
Cannabinoids 60MitragynineCaffeineLC-MS/
Cocaine 4; 4-F-AMB 3; MDMA 1; methamphetamine 1; 5-UR-144 1; 5F-AKB48 1; desvenlafaxine 1GC-MS2015–2016
[12]61NM2201 and THJ-018MDMB-CHMICALC-Q-ToF
Opioids 632C-B 465-MeO-DALT 46; MDMA 1GC-MS 2015–2016 Canada[12]
31Crack heroin
Lead 10AAS2015–2016
[31]64NEP 10Caffeine 10GC-MS
Raman spectroscopy
32Fentanyl and analogs 26
Heroin 5
Caffeine 33; AMB-FUBINACA 29; heroin 17; phencetin 10; etizolam 6 AB-FUBINACA 5; fentanyl analogs 6 benzocaine 3; 5F-MDMB-PINACA 3 metformin 2; meth 3 lidocaine 1; acetaminophen 3; dextromethorphan 2; 4Cl-α-PVP 1; UF-17 1; furanyl 5F-MDMB-PICA 1; hydromorphone 1; flubromazolam 1FTIR
Fentanyl immunoassay
Abbreviations: 3-MEC, 3-methylethcathinone; 3-Meo-PCP, 3-methoxyphencyclidine; 4-Aco-DMT, 4-acetoxy dimethyl tryptamine; 4-ANPP, 4-anilino-N-phenylpiperidine; 4Cl-α-PVP, 4-Cl-alpha-pyrrolydinovalerophenone; 4F-α-PVP, 4F-alpha-pyrrolydinovalerophenone; 4-Meo-PCP, 4-methoxyphencyclidine; 4-OH-MET, 4 OH methyltryptamine; 5-MeO-DALT, 5-methoxy diallyltryptamine; 6-AM, 6-acetyl morphine; AAS, atomic absorption spectrophotometry; α-MT, α methyltryptamine; CE-C4D, capillary electrophoresis capacitively coupled contactless conductivity detection; CV, cyclic voltammetry; DiPT, diisopropyltryptamine; DMA, dimethylamphetamine; DMMA, dimethylmethamphetamine; DPT, dipropyltryptamine; FAAS, flame atomic absorption spectrometry; FTIR, Fourier transform infrared spectroscopy; GC-VUV, gas chromatography–vacuum ultraviolet spectrophotometry; GEMBE, gradient elution moving boundary electrophoresis; LSD, lysergic acid dimethylamide; MET, methylethyltryptamine; meth, methamphetamine; MDA, 3,4-methylendioxyamphetamine; MDEA, 3,4-methylendioxyethylamphetamine; MDMA, 3,4-methylendioxymethamphetamine; MDPBP, 3,4-methylendioxy-pyrrolidinobutiophenone; NEP, N-ethylpentylone; SERS, surface-enhanced Raman spectroscopy; SWV, square wave voltammetry; TLC, thin layer chromatography.
Table 2. Clinical symptoms of authentic cases of adulterated cocaine, heroin and new psychoactive substances (NPS) intoxications reported in the literature between 2017 and 2022.
Table 2. Clinical symptoms of authentic cases of adulterated cocaine, heroin and new psychoactive substances (NPS) intoxications reported in the literature between 2017 and 2022.
Clinical DescriptionAdulterantAdulterant
MatrixDrug Analysis
Hx: 52 y F chronic cocaine user admitted with ulcers on extremities; pustule, rash on arms/axilla/temple; longstanding perforation hard palate
Lab: c-ANCA+; LA+
Skin biopsy: superficial neutrophil-rich dermal infiltrate, papillary derma edema
Dx: pyoderma gangrenosum associated with LAC
Tx: prednisone, topical betamethasone
Levamisole * NAUCocaine +[54]
Hx: 31 y F cocaine user admitted with facial pain, chronic fronto-maxillary sinus pain, yellow/green discharge, rhinorrhea, crusting, rash legs
Lab: ESR 2 mm/h; CRP 24 mg/L; WCC 7.7; p-ANCA+; c-ANCA-; anti-PR3+; anti-MPO
Nasal biopsy: ulceration, necrosis surrounded macrophages and fibrotic stroma; chronic inflammatory infiltrate, no vasculitis
Dx: CIMDLs, systemic levamisole vasculitis
Tx: abstinence, mycophenolate, azathioprine, rituximab, surgical debridement
Levamisole *NAUCocaine +[44]
Hx: 30 y F cocaine user, chronic sinusitis, left deviated septum, rhinitis, purulent rhinorrhea, macular rash on hands;
Lab: ESR 5 mm/h; CPR 30 mg/L; WCC 11.1; p-ANCA+; c-ANCA-; anti-MPO-; anti-PR3-
Nasal biopsy: ulceration, acute/chronic inflammation, fibrotic stroma, vessels permeated by inflammatory cells, no fibrinoid necrosis
Dx: CIMDLs and systemic levamisole vasculitis
Tx: abstinence, drug rehabilitation, surgical debridement
Levamisole *NAUCocaine + [44]
Hx: 36 y M cocaine user, severe facial pain, epistaxis, crusting, rhinorrhoea, rash/livedo in thighs; hematuria, proteinuria
Lab: ESR 36 mm/h; CPR 44 mg/L; WCC 8.0; p-ANCA+; c-ANCA-; anti-MPO-; anti-PR3-; IgG4 increase
Nasal biopsy (n = 3): extensive ulceration, fibrin, proliferative fibrosis; acute/chronic inflammatory cells; no vasculitis (1st); geographic necrosis, fibrinoid necrosis foci (2nd); ulcerated mucosa and granulation; no vasculitis (3rd);
Dx: CIMDLs and systemic levamisole vasculitis
Tx: abstinence, steroids; methotrexate; mycophenolate; rituximab, surgical debridement
LevamisoleNAUCocaine +; levamisole +[44]
Hx: 48 y F, severe facial pain, epistaxis, septal perforation with fistula from skin to intra-nasal cavity, soft palate ulceration; hematuria
Lab: ESR 80 mm/h; CPR 48 mg/L; WCC 7,6; p-ANCA+; c-ANCA-; anti-MPO-; anti-PR3 +
Dx: CIMDLs and systemic levamisole vasculitis
Tx: abstinence, steroids, methotrexate, surgical debridement
LevamisoleNAUCocaine +; levamisole +[44]
Hx: 48 y M, previous Chron’s disease and pneumonia, admitted with purpuric rash worsening in four limbsLab: c-ANCA+; ANA+; anti-MPO-
Skin biopsy: leukocytoclastic vasculitis and multiple fibrin thrombi;
Dx: levamisole adulterated cocaine-associated vasculitis
Tx: supportive therapy
Levamisole *NAUCocaine +[60]
Hx: 53 y F cannabis/cocaine user, admitted with extensive, painful retiform symmetric purpura patches in limbs, buttocks/abdomen with necrosis evolution
Lab: neutropenia, thrombocytopenia, CPR 13 mg/L; LA-; anticardiolipin antibody-; cryoglobulins-; c-ANCA+
Skin biopsy: thrombotic vasculopathy
Dx: levamisole-induced vasculitis
Tx: corticosteroids, surgical debridement of necrotic tissue
Levamisole *NAUCocaine +; THC +[61]
Hx 46 y M, increased cocaine use last 3 months, admitted with weakness/fatigue, blood-tinged sputum, cough
Lab (n = 2) creatinine 9.61; GFR 7 mL/min; K+ 7 meq/L (1st); AST 196; ALT 235; total bilirubin 13; A-phosphatase 520 (2nd); ANA+; p-ANCA+; c-ANCA+; anti-α-SME+; anti-HCV+; HCV-RNA-
CT chest: cavitary lesions
Renal biopsy: fibrous glomerular crescents, few cellular crescents (severe kidney damage)
Liver biopsy: isolated intrahepatic bile duct with onion skinning and foci injury, canalicular cholestasis, periportal ductal reaction
Dx: intrahepatic duct injury associated with LAC-induced glomerulonephritis
Tx: dialysis for AKI; ursodeoxycholic/cholestyramine for duct damage
Levamisole *NAUCocaine +[62]
Hx: 29 y M, 3 months cocaine abuse, admitted with severe head-pain, incomprehensible vocalization, amnesia, aggressiveness, agitation, sleep inversion, space/time disoriented;
MRI brain (n = 2): ubiquitous white matter small lesions (1–14 d after adm); additional punctate lesions in corpus callosum, abn meningeal enhancement, contrast agent in CSF (15–31 d after adm);
CSF: protein 224 mg/dL; albumin 37.9;
RFA: multiple segmental occlusion in central retinal artery
Audiogram: bilateral sensorineural hearing loss;
Dx: acute SS associated to LAC;
Tx: methylprenisolone, mycophenolate (at brain damage relapse)
segments (n = 6)
Cocaine >5; BE > 5;
EME 0.07–0.11;
norcocaine 0.58–1;
levamisole 0.07–1.14;
tramadol 1.38–2.16
Hx: 33 y M cocaine abuse history, admitted with 4 weeks of nasal obstruction, dysphagia, otalgia, nasal bridge deformity;
Endoscopy: nasal corridor necrosis;
CT head/chest: nasal cavity extensive bone destruction, multiple small pulmonary nodules;
Lab: leukocytosis, high CRP, high ESR; c-ANCA+;
Nasal biopsy: no vasculitis signs;
Tx: counseling on cocaine cessation
Levamisole *NAUCocaine +; metabolites +[57]
Hx: 59 y M active cocaine use, anamnestic febrile syndrome with neutropenia/agranulocytosis treated and recovered; new ED admission with 4 days abdominal pain/bloody diarrhea probably due to rectal cocaine administration
CT abdomen: rectum/sigmoid/descending colon/caecum/appendix with increased bowel wall thickness
Flexible sigmoidoscopy: sigmoid colon/rectum edema, severe ulceration; bowel ischemia/necrosis
Lab: normal ENA and ANCA+
Dx: neutropenia agranulocytosis induced by levamisole complicated by bowel necrosis
Tx: surgery sigmoid colectomy, ileocecectomy with end ileostomy and descending mucus fistula
Levamisole *NAUCocaine +[46]
Hx: 53 y M crack cocaine user, anamnestic hypertension/dyslipidemia/chronic pain syndrome, developed 2 wks limb rash/hematuria/creatinine increase (150 µmol/L); ED admission with abdomen/thighs/legs purpura and ear necrosis
Lab: urea 24.8 mmol/L; cr 449; PCR 186.8 mg/mmol; Na = 137 mmol/L; K+ = 4.9 mmol/L; ANA -; ENA -; c-ANCA -; p-ANCA +; HCV/HBV/HIV neg;
Renal biopsy: active focal crescentic and necrotizing GN, glomerular capillary wall thickening; tubular epithelial injury; no active vasculitis
Dx: concurrent AAV secondary to LAC and associated MN
Tx: corticosteroids, ACE inhibitor
Levamisole *CEDIA UCocaine metabolites (s) +[58]
Hx: 35 y M tobacco/cannabis smoker, intranasal cocaine use, inhaled crack use; admitted to ED with hemoptysis, iron deficiency anemia
CT chest: bilateral ground glass opacities;
Lab: urea 7.1 mmol/L; Cr 150 µmol/L; Na 136 mmol/L; K+ 4 mmol/L; ANA -; c-ANCA -; p-ANCA +; cryoglobulinus -; HBV/HCV/HIV neg;
Renal biopsy: active segmental fibrinoid necrosis, no arteries vasculitis, diffuse epithelial cell foot process effacement and deposit of immune complex;
Dx: concurrent AAV secondary to LAC and associated MN;
Tx: prednisone, cyclophosphamide
Levamisole CEDIA and LC-MSUCocaine metabolite (s) +;
cannabinoids, opiates, benzodiazepines, levamisole (c) +
Hx: 34 y M cocaine user; anamnestic obesity, hyperpigmented lesions, leukocitoclastic vasculitis due to levamisole; recently admitted to ED with proteinuria associated with fatigue/arthralgias
Lab: urea 4.6 mmol/L; Cr 71 µmol/L; PCR 449.9mg/mmol; Na+ 140 mmol/L; K+ 4.4 mmol/L; ANA-; ENA-; c-ANCA-; p-ANCA+; HBV/HCV/HIV neg
Renal biopsy: no glomerular crescentic or necrotizing injury, glomerular artery wall normal, no artery vasculitis
Dx: development of MN after AAV secondary to LAC
LevamisoleCEDIA and LC-MSUCocaine metabolites (s) +;opiates +; benzodiazepines +; levamisole (c) +[58]
Hx: 68 y M cocaine user, recent haemorrhagic lesions on forearms/face, anamnestic analogous vasculitis 6 months prior
Lab: pancytopenia/neutropenia; ANA+; p-ANCA+; anti-PR3+; anti-MPO+
Skin biopsy: leukocytoclastic vasculitis with subepidermal bullae
Dx: levamisole-induced vasculitis
Tx: 6 months cocaine abstinence
Levamisole *NAUCocaine +[47]
Hx: 58 y M polysubstance user presented 4 d after last cocaine use with painful pruritic rash/polyarthralgyas
Lab: high CRP, leukopenia; p-ANCA-; c-ANCA-; ANA-; RA-; HCV/HIV neg
Skin biopsy:acute/chronic inflammation of superficial derma, acute perivascular inflammation in deeper derma; acute leukocytoclastic vasculitis; eosinophilic infiltrate
Dx: cutaneous levamisole induced vasculitis
Tx: steroids
LevamisoleLC-MS/MSUCocaine +; levamisole (c)+[33]
Hx: 40 y F tobacco and cocaine smoker, methadone and hydroxyzine user; anamnestic HCV+, previous septic shock; admitted with extensive retiform purpura/ bullous necrotic lesion legs/nose/ear/cheeks
Lab: lactate elevated; PCR 180 mg/L; p-ANCA+; ANA+; LA+; cryoglubulinaemia+; RF+; HBV/HIV neg; HCV pos
Skin biopsy: vasculitis, microthrombi/fibrinoid degeneration of vascular walls
Dx: transient renal failure, extensive levamisole induced vasculitis
LevamisoleLC-MS/MSUOpiates; cocaine; methadone +[59]
H segments (n = 2)Levamisole 1–1.78 ng/mg
Hx: 39 y F intravenous cocaine user dead in bathroom with recent needle marks
Autopsy: pulmonary edema, brain/heart/coronary vessels/aorta/kidneys moderately congested
COD: cardiorespiratory arrest due to intravenous cocaine and foreign body pulmonary granuloma
Histology: foreign bodies (asbestos fibers) in pulmonary parenchyma associated with non-necrotising granulomas in lung
Dx: pulmonary granulomatosis due to asbestos fibers related to intravenous cocaine
Asbestos fibers in lungHistologyVHCocaine 40 [53]
B BE 300
Hx: about 20 y M after white drug insufflation (sold as cocaine); presented at ED with hypertension; combative/delirious behaviour; decreased level of consciousness;
Clinical: GCS = 7/15–13/15; pin-pupils; systolic pressure = 123 mmHg; HR = 85;
Dx: poisonings with LSD after nasal insufflation of a white powder sold as cocaine;
Tx: intravenous droperidol; midazolam; intubation (for 12 h).
LSDUHPLC-Q-ToFUCannabis; benzodiazepine +; ketamine +;[48]
Hx: about 20 y M history of cocaine and THC as recreational use; after white drug insufflation (as cocaine); his thoughts were “foggy”; sedation;
Clinical: GCS = 13/15; pin-pupils; BP = 130/70 mmHg; HR = 64; vomiting develops hypokalaemia (K 2.9 mmol/L).
Dx: poisonings with LSD after nasal insufflation of a white powder sold as cocaine;
Tx: anti-emetics; anticonvulsant
LSDUHPLC-Q-ToFUCannabis +; amphetamines +;[48]
Hx: about 20 y M past recreational use of cocaine/LSD; before white drug insufflation (sold as cocaine); smoked THC; drunk alcohol; reported thoughts-clouding; sensation of dying; vivid hallucinations; sedation;
Clinical: HR = 97; BP = 227/145 mmHg; pin-pupils; GCS = 14/15; vomiting developing hypokalaemia (K 2.8 mmol/L);
Dx: poisonings with LSD after nasal insufflation of a white powder sold as cocaine;
Tx: diazepam; droperidol
LSDUHPLC-Q-ToFUTHC +; amphetamines +[48]
MDMA 10;
Hx: about 20 y M 10–15 min after white drug insufflation (sold as cocaine) developed hypersalivation; palpitations; nausea; dissociative state;
Clinical: pin-pupils;
Dx: poisonings with LSD after nasal insufflation of a white powder sold as cocaine
Tx: diazepam
MDMA < 30;
Hx: 28 y M 7 yrs cannabis/tobacco use disorders; 2 yrs inhaled heroin use; Due to reduced heroin supply and high cost used “CUT” heroin to save money and discover new drug; ED admission with time/space disorientation, confused; outburst at minimal provocation; pupils constricted/symmetrical; slurring speech, saliva drooling; wide-based gait, staggering/stumbling; unable to perform a tandem walk;
Brain MRI: no detectable lesions
Lab: ALT 271 U/L; ASL 148 U/L; urea 34 mg/dL; Cr 0.86 mg/dL; anti-HCV-; HCV-RNA 7.27000/mm3; HIV/HBV neg
Dx: cognitive–behavioural and neurological symptoms due to CUT agent;
Tx: sublingual buprenorphine–naloxone for 7 months
Methaqualone, caffeine, oxazepam, Ketazolam, nordazepa, pinazepam, alprazolam, acetaminophen GC-MSUMorphine; benzodiazepines [55]
CDacetaminophen; caffeine; methaqualone; Oxazepam; ketazolam; nordiazepam; pinazepam, alprazolam
Hx: 28 y M anamnestic with treated bipolar disorder, polysubstance abuse including intravenous heroin, found unresponsive at home with packets of “Santa Muerte”; on arrival typical initial opioid toxidrome
Clinical: SpO2 78%; tachycardia, flushing, dry mucous membranes, mydriasis
Chest X-ray chest: pneumonia and ARDS
CT brain: negative
Dx: anticholinergic toxicity after heroin containing 5F-MDMB-PINACA, pneumonia/ARDS
Tx: after 2 doses of naloxone, became agitated and combative; OI for 12 d
5F-MDMB-PINACA LC-MSMS SCocaine +; 6-MAM +; heroin +; fentanyl +; THC +;
alprazolam +
ImmunoassayUCocaine; opiates; fentanyl; THC; benzodiazepines
GC-MS and LC-Q-ToFCD 5F-MDMB-PINACA; Heroin; Fentanyl
Hx: 25 y M intravenous heroin abuse; admitted at ED for typical opioid toxidrome after intravenous ‘heroin’ injection;
Clinical: HR = 102 b/m; BP = 146/89 mm Hg, RR = 24 breaths/min; SpO2 = 98%, flushing, tachycardia, agitation;
Dx: anticholinergic toxicity after heroin containing 5F-MDMB-PINACA;
Tx: 2 doses of naloxone, became anxious and tachycardic so EV lorazepam was added; intravenous fluids, supportive care. He confirmed Santa Muerte use.
5F-MDMB-PINACA ImmunoassayUOpiates+; amphetamine+; barbiturates +; cocaine+[52]
GC-MS/LC-Q-ToF-MSCD5F-MDMB-PINACA; Heroin; fentanyl
Hx: 31 y M history of intravenous heroine abuse; admitted at ED after intravenous “heroin” injection associated to typical opioids overdose symptoms;
Clinical: HR = 163 b/m; BP = 131/81 mmHg, RR = 29 breaths/minute, SpO2 99%; tachycardic, flushed, dilated pupils; full bladder;
Dx: anticholinergic toxicity after heroin containing 5F-MDMB-PINACA, and ARDS;
Tx: after naloxone, became combative, anxious, agitated, so intravenous lorazepam was added; intubated for airway protection
LC-MS-MSSHeroin; 6-MAM, fentanyl
GC-MS/LC-Q-ToF-MS CD 5F-MDMB-PINACA; heroin; fentanyl
Hx: 25 y M admitted at ED after intravenous heroin (found a drug packet labeled “Santa Muerte”);
Clinical: HR = 158 b/m; BP = 215/158 mm Hg; RR = 26 breaths/minute; SpO2 = 99%; urinary retention; anhidrosis;
Dx: anticholinergic toxicity after heroin containing 5F-MDMB-PINACA;
Tx: naloxone; afterwards tachycardia/agitation; so lorazepam and physostigmine to calm him down;
ImmunoassayUCocaine; opiates; THC[52]
LC-MS/MSS5F-MDMB-PICA (5F-ADB); heroin; 6-MAM; fentanyl;
GC-MS LC-Q-ToF/MSCD 5F-MDMB-PINACA; heroin; fentanyl
Hx: 45 y M presented at ED with tachycardia; pinpoint pupils; flushing of skin; drug packet “50 CAL” found in his pocket;
Clinical: HR = 124 b/m; BP = 140/82 mmHg; RR = 22 breaths/minute; SpO2 = 99%; pinpoint pupils; flushing of skin; Dx: anticholinergic toxicity after heroin containing 5F-MDMB-PINACA;
Tx: midazolam/olanzepine to calm; afterward intravenous diazepam; dexmedetomidine infusion in case of agitation returning; 24 hrs in hospital
5F-MDMB-PINACAImmunoassayUOpiates; fentanyl[52]
GC-MS LC-Q-ToF/MSCD5F-MDMB-PINACA; heroin; fentanyl
Hx: 36 y M found unresponsive in the street; after naloxone; agitation; benzo/physostigmine with improvement in agitation behaviour.
Clinical: HR = 130 b/M; BP = 160/100 mm Hg; RR = 24 breaths/minute; oxygen saturation 95%;
Dx: anticholinergic toxicity after heroin containing 5F-MDMB-PINACA;
Tx: naloxone; benzo/physostigmine; intubated to avoid to risk of aspiration from vomiting; found blue packet (“50 CAL”).
5F-MDMB- PINACAImmunoassayUOpiates; fentanyl[52]
GC-MS and LC-Q-ToFCDFentanyl; heroin; 5F-MDMB-PINACA
Hx: 23 y F admitted at ED for severe agitation/combative behavior;
Clinical: HR = 156 b/m; BP = 147/64 mm Hg; RR = 20 breaths/minute;
Dx: anticholinergic toxicity after heroin containing 5F-MDMB-PINACA;
Tx: lorazepam/physostigmine. The patient reported consuming a substance named “50 CAL.”
5F-MDMB- PINACA *ImmunoassayUOpiates; fentanyl[52]
Hx: 27 y M presented at ED after intravenous heroin use; he was admitted with respiratory and CNS depression;
Clinical: HR = 130 b/M; BP = 130–94 mm Hg; RR = 22 breaths/minute; sPO2 = 95%; dilated pupils; dry oral mucous membrane
Tx: lorazepam; physostigmine.
Dx: anticholinergic toxicity after heroin containing 5F-MDMB-PINACA
5F-MDMB- PINACA *ImmunoassayUOpiates; fentanyl[52]
Hx: 36 y F 3 yrs oral opium abuse (dose = 0.3 gr/day); presented at ED with nausea; acute/severe abdominal pain; vomiting; pleuritic chest pain;
Clinical: severe hypochromic-microcytic anemia;
CT abdomen: multiple radiopaque flakes in intestinal lumen and in its wall due to metal deposition;
Dx: lead poisoning in oral opium user;
Tx: intravenous chelators (Ca Na2 EDTA)
leadNABLead 780; lead (7 day after) 460 [49]
Γ-hydroxybutyrate (GHB)
Hx: 29 y M and 34 y M bought two GHB doses that were dissolved in 200 mL of alcohol each; 1st case drunk the whole drink in 10 min; 2nd case drunk 2/3 of his drink;
Clinical: after 20 min 29 y began to accuse chest pain; tachycardia; short of breath; 34 y accused just headache.
Dx: acute intoxication GHB and SLD
SDF BGHB 55–100 (case 1); 37–800 ng/mL (case 2); SDF 340 (case 1), SDF< LOQ;
desMe-SDF < LOQ; desMe-SDF < LOQ
UGHB: 35;700 and 15;500; SDF = 1;270 and SDF 1;220
desMe-SDF = 810 and 1;210
DrinkGHB 7460;7 μg/mL; SDF 521;2 μg/mL
Hx: 49 y M past substance abuse; found dead in his bed; nearby the corpse; a glass with dried; white; crystalline substance; on a shelf/living room; 2 plastic-bags containing white tablets (imprint XANAX);
Autopsy: heart; lungs; liver; kidney: sign of decomposition;
COD: acute intoxication of caffeine and etizolam.
Etizolam and caffeineGC-MS and HPLC-DADFBEtizolam = 770; caffeine = 190
Etoh 24 mg/mL
CBCaffeine 426 mg/mL
H segments (n = 4)Etizolam 0.05–0.11; THC 0.06–0.19; amphetamine 0.42–2;568; cocaine 0.03–0.22.
BEG 0.04–0.07
Stomach contentEtizolam +
DrugCaffeine; etizolam
Hx: 54 y M past history of HCV treated; alcohol use disorder; OUD; admitted at ED with altered mental status after 1 spoon of “Kratom crazy®®” taken for an entire year; in morning he added a table spoon of “Vivazen Botanical De Kratom®®”; headache; vomit; fall asleep; when he woke up; he had incomprehensible speech.
Clinical: BP = 120/70 mmHg; HR = 70; RR 18; sPo2 = 98%;
Lab: glucose = 124 mg/dL; leukocytosis; troponin T = 91 ng/L;
CT brain: large right frontal intraparenchymal haemorrhage with extension to ventricles (40 cm3) and mass effect;
MRI brain: intraparenchymal hemmorrhage with 7 mm midline shift.
Dx: PEA-adulterated kratom intoxicationTx: surgical craniotomy
PEA LC-MS/MSSMitragynine 340[56]
+, positive at screening test; *, suspected without toxicological confirmation. Abbreviations: AAV, ANCA-associated vasculitis; AKI, acute kidney injury; c-ANCA, cytoplasmatic-anti neutrophil cytoplasmic antibody; BE, benzoylecgonine; B, blood; CB, cardiac blood; CD, confiscated drug; Cr, creatinine; CSF, cerebrospinal fluid; CIMDLs, cocaine-induced midline destructive lesions; COD, cause of death; CRP, c-reactive protein; Dx, diagnosis; EME, ecgonine methyl ester; ESR, erythrocyte sedimentation rate; FB, femoral blood; H, hair; HR, heart rate; Hx, history; LA, lupus anticoagulant; LAC, levamisole-adulterated cocaine; MN, membranous nephropathy; NA, not available; OI, orotracheal intubation; p-ANCA, perinuclear-anti neutrophil cytoplasmic antibody; PEA, phenylethylamine; RF, rheumatoid factor; RFA, retinal fluoroangiography; RR, respiratory rate; SDF, sildenafil; SpO2, oxygen saturation; S, serum; SS, Susac syndrome; THC-COOH, 11-Nor-9-carboxy-Δ9-tetrahydrocannabino; Tx, treatment; U, urine; VH, vitreous humour; WCC, white cell count; (s), screening; (c), confirmation.
Table 3. Number of authentic cases of adulterated cocaine, heroin, and new psychoactive substances (NPS) intoxications reported in the literature between 2017 and 2022.
Table 3. Number of authentic cases of adulterated cocaine, heroin, and new psychoactive substances (NPS) intoxications reported in the literature between 2017 and 2022.
Number of CasesAdulterantAnalytical Technique MatricesLOD
Quantification (ng/mL)Reference
DUID (n = 724)Levamisole; PTHITLC-MS/MSH2.5 pg/mg10 pg/mgCocaine 500–800.000 pg/mg (n = 627);
PTHIT 3.5–61,000 pg/mg; levamisole/dexamisole 0.71–1.34
DUID (n = 55)Caffeine
DZ; hydroxyzine; levamisole; lidocaine; benzocaine;
SWATH LC-HRMSU____THC + (n = 19) THC, cocaine + (n = 19); cocaine + (n = 17)[65]
U (n = 100)
PL (n = 8)
U: levamisole (n = 72) average conc.= 565 (4–72,970 µg/L); BE (n = 100) averange conc. = 13,510 (174–251,000 µg/mL); Aminorex not detected
U: metabolites: 4-OH-LEV; LEV sulfoxide; LEV glucuronide; OH-LEV glucuronide;
PL (n = 8): LEV average conc. = 10.6 (0.9–64.1 µg/L); U (n = 8) average conc. =144.50 (50–10,050); aminorex not detected
H (n= 100) CRATOD admissionTHC; lidocaine; phenacetin; levamisole; benzocaine; procaine hydroxyzineLC-MS/MSH______Cocaine (n = 100), BE + (n = 100); CE + (n = 94) THC + (n = 23); lidocaine (n = 92) +; phenacetin + (n = 69); levamisole + (n = 31) benzocaine + (n = 19); procaine + (n = 5); hydroxyzine (n = 2)[67]
Brain tissue (n = 10)
Blood (n = 5)
U (n = 1)
DZ; hydroxyzine; levamisole; lidocaine; phenacetin; procaine; cetirizine GC-MSBrain tissue;
Cocaine 3.6
BE 27 EME 67
CET 71
DZ 26
LEV 14
LID 38
PHE 21
PRO 16
Cocaine 30 BE 93
EME 105
CET 363
DZ 101
HYD 152
LEV 66
LID 81
PHE 132
PRO 121
Cocaine 530.8 ng/g; benzodiazepine 423.1 ng/g; EME 548.7 ng/g; LEV 128.1 ng/mg; LID 73.5 ng/mg; HYD 170.5 ng/g; ALC (BL) 0.86‰; ALC (brain) 0;54‰; ALC (U) 4;97‰[65]
U (n = 3665)LevamisoleImmunoassay
U______Cocaine + (n = 51); levamisole + (n = 27); methamphetamine/MDMA + (n = 23); cannabis metabolites + (n = 12); heroin or metabolite + (n = 2).[69]
H (n = 55)LevamisoleLC-MS/MSH___Levamisole 0.002 pg/mg;
Cocaine 0.005 pg/mg
H [cocaine + samples > 500 pg/mg]: 4265.4 pg/mg (levamisole); 322.9 pg/mg (MDMA); 253.9 g/week (alcohol); H [cocaine—samples]: 0 (levamisole); 0.99 pg/mg (MDMA); 56.5 g/week (alcohol)[68]
H (n = 40)Fentanyl; acetylfentanyl; furanylfentanyl; U-47700 UHPLC-MS/MSH0.1–0.3 pg/mg 0.3–0.9 pg/mg Fentanyl 2.3–8600 pg/mg (mean = 860 pg/mg; median = 440 pg/mg); acetylfentanyl = 2.1–3200 pg/mg (mean = 160 pg/mg; median = 26 pg/mg); furanylfentanyl = 0.7–42 pg/mg (mean = 8.0 pg/mg; median = 1.6 pg/mg); U-47700 (n = 3/40): 1.4–4.5 pg/mg[70]
OF (n = 30)
U (n = 30)
Fentanyl; norfentanyl; acetylfentanyl; U-47700 LC-Q-ToF-MSOF
Fentanyl 1; norfentanyl 2; acetylfentanyl 1;
carfentanil 1; U-47700 1
___U (n = 29 fentanyl +); OF (n = 27 fentanyl +); norfentanyl; acetylfentanyl; U-47700[71]
Abbreviations: COC= cocaine; BL = blood; BE= benzoylecgonine; CET = HYD metabolite cetirizine; CRATOD, crack cocaine addiction treatment; DZ = diltiazem; EME = ecgonine methyl ester; H = hair; HYD = hydroxyzine; LC-Q-ToF-MS = liquid chromatography quadrupole time-of-flight mass spectrometry; OF = oral fluid; PL = plasma; PTS = patients; phenyltetrahydroimidazothiazole, PTHIT; U, urine.

3. Discussion

Adulteration exposes drug consumers to unexpected threats, due not only to unintentional exposure to a potentially harmful substance but also due to pharmacological interactions between drugs and adulterants [75,76].
Similar to fluctuations in the availability of drugs of abuse, drug adulteration trends also may fluctuate in response to economic and political factors influencing the availability of certain substances [4].
The reported data disclosed new adulteration practices, although the seized samples analyses revealed the presence of well-established adulterants such as levamisole for cocaine or paracetamol/acetaminophen for heroin [5]. In 2022, quinine and quinidine were of particular concern in the USA, due to detection in more than 2,000 street drug samples. However, the reported data showed that quinine and quinidine were already used as cocaine adulterants in 2017 and 2018 [76]. Fentanyl was commonly detected as an adulterant in heroin samples in the USA and in Canada, presumably to enhance drug potency and reduce the amount of heroin needed for each dose [12,38,42,73].
NPS adulteration occurs not only with all classic drugs of abuse but also with other NPS. The wide use of these compounds as adulterants may be related to the ease of distribution due to uncontrolled status and ease of production since they are produced in “kitchen laboratories”. However, it is not clear if certain NPS may be byproducts of the manufacturing process, such as fentanyl in butyrlfentanyl samples seized in Sweden between 2010–2014. Seized samples of kratom, a psychedelic plant containing mitragynine and 7-OH-mitragynine, were adulterated with caffeine and synthetic O-desmethyltramadol (ODT) and sold under the name “Krypton” [77]. ODT, a bioactive metabolite of tramadol, was added to mimic the sedative-narcotic effects of kratom [78,79]. Other adulterated kratom products contained high concentrations of 7-OH-mitragynine. Usually, 7-OH-mitragynine is less than 2% of the mitragynine concentration in kratom; however, in this case, 7-OH-mitragynine was added as an adulterant to increase opioid-like effects [80]. Other synergistic effects were observed in the case of synthetic cannabinoids added to THC [34]. The addition of fentanyl to methamphetamine may lead to greater dependence on the mixture.
Although the reported data covered a limited time range, more recent evidence confirms the changing nature of adulteration practices, such as the xylazine-laced heroin seized in the USA [81,82].
Adulterants may play a role in the adverse effects commonly related to the primary drug, such as vasculitis induced by levamisole-adulterated cocaine [83]. P/c-ANCA positivity suggests that levamisole-induced vasculitis has an autoimmune mechanism. Immune pathologies require glucocorticoids, as was the case of a 29-year-old suffering from multifocal white matter lesions with brainstem and cerebellar involvement after cocaine/levamisole consumption, requiring immediate treatment with corticosteroids [84]. Noteworthy, p/c ANCA positivity was used as evidence of levamisole exposure in the presence of analytically confirmed cocaine positivity. Although, the unexpected negativity of p-c/ANCA despite vasculitis [5] in a case of certain cocaine consumption suggests that toxicological levamisole confirmation in biological matrices is necessary to prove consumption. The most challenging aspect of levamisole quantification in biological matrices may be its short half-life (5–6 h). In these cases, hair analysis may offer the best approach to document exposure to short half-life substances [45,59,67,68,85]. Interestingly, levamisole and cocaine quantification in post-mortem brains suggests they may have synergistic negative effects on the encephalic white matter [68]. Moreover, this synergistic effect was reported in living patients by diffusion tensor imaging and magnetic resonance imaging [86,87] revealing that levamisole increases the risk of white matter damage [87].
Although other adulterants were detected in seized samples, such as phenacetin, benzocaine and lidocaine, these substances were not reported in clinical cases, probably due to the lack of specific analyses of compounds other than principal drugs causing health threats. Noteworthy is the alarming increase in cocaine-related deaths due to fentanyl-adulterated cocaine [88]. Huhn et al. reported the case of a man who continued to test positive for fentanyl in urine for up 19 days [89]. Surprisingly, the new trend of heroin adulteration with synthetic cannabinoids and/or fentalogues was reported in a number of cases. In fact, 5F-MDMB-PINACA and fentanyl were reported in a case series in which the adulterants were confirmed by urine analysis [52]
Apparently, lead adulteration of drugs such as opium, heroin and methamphetamine is a common practice in Iran [49]. In lead-adulterated drugs cases, the diagnosis is always difficult because of unspecific abdominal symptoms caused by chronic lead intoxication. The diagnosis of lead poisoning requires a clear clinical suspicion and sophisticated technological methods to detect it. It is important to highlight lead adulteration of opium because of its potential spread to Europe.
Rarely, cases of LSD-adulterated methamphetamine were reported, characterized by the inconsistency between the type of symptoms appearing in the acute intoxication phase and the substance reportedly taken by the patient. This inconsistency led to toxicological research to detect LSD and adulterants [48]. The state of well-being induced by MDMA including increased activation and emotional excitation is associated with a better response to LSD. The combination of MDMA/LSD enhances the psychedelic experience by inducing positive emotions. On the other hand, this has a minor enhancing effect relating to psychedelic experience. Club drugs, such as methamphetamine, MDMA, ketamine, cocaine, and GHB are often taken in combination with sildenafil, especially when sexual encounters are anticipated [50].

4. Method

A systematic literature search was performed in PubMed and Scopus databases and official international organizations’ websites; according to PRISMA guidelines (12). Keywords “drug of abuse”; “new psychoactive substances”; “fentanyl analogues”; “heroin”; “cocaine”; “amphetamine”; “THC”; “cannabis”; “stimulants”; “synthetic cathinones”; “synthetic opioids”; “opioids”; “opiates”; “phenethylamine”; “synthetic cannabinoids”; were combined with “adulteration”; “adulterants”; and “contaminated”. A total of 3604 scientific articles (1250 from PubMed and 2354 from Scopus) published from 2017 to 2021 were initially screened for eligibility. Two scientists individually evaluated each entry from one database; considering for full text reading only titles and abstracts mentioning analytical assessment of drugs and adulterants in seized materials and/or in drug-related intoxications. Further screening excluded studies according to the following criteria:
Articles not written in English
Commentary; editorial letters; and surveys
Duplicates were removed
Irrelevant studies
Articles were classified by matrix investigated as “biological specimens” or “non biological specimens”. Finally, articles were excluded for insufficient data.

5. Conclusions

Drug of abuse adulteration is a common practice involving a wide range of different active substances added to the primary drugs for pharmacological or profit purposes. The data showed that adulterants are widely added to all the classes of drugs of abuse, including NPS. Furthermore, NPS may be used as adulterants to potentiate the primary drug effect or obtain cocktails exerting unexpected effects on the abusers. However, they represent an additional threat to the users’ health since a synergistic effect is observed in the comparison of certain intoxication symptoms. Moreover, the unexpected presence of certain psychotropic drugs may lead to incorrect treatment of intoxication cases. For these reasons, adulteration practices must be monitored to assess changes in the drug supply and adulterants should be analytically assessed in intoxication cases.

Author Contributions

Conceptualization, F.P.B., M.A.H., A.D.T. and E.M.; methodology, A.D.T., E.M. and D.B.; formal analysis, A.D.T., E.M., D.B., P.B. and G.B.; investigation, A.D.T., E.M., D.B., P.B. and G.B.; data curation, A.D.T., E.M., D.B., P.B. and G.B.; writing—original draft preparation, A.D.T., E.M. and D.B.; writing—review and editing, M.A.H. and F.P.B.; supervision, M.A.H. and F.P.B.; funding acquisition, F.P.B. All authors have read and agreed to the published version of the manuscript.


The review paper was partially funded from the Project “Implementation of the identification and study of the effects of NPS: Development of a multicenter research to enhance the database of the National drug Addiction Observatory and the Early Warning System” and by the project: “National Early Warning System on Drugs (SNAP)” by the Italian Department of Antidrug policies.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


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Figure 1. Adulterants prevalence in cocaine (A), opioids (B), amphetamine-type stimulants (C), new psychoactive substances (NPS, D) and cannabinoids (E) seized samples.
Figure 1. Adulterants prevalence in cocaine (A), opioids (B), amphetamine-type stimulants (C), new psychoactive substances (NPS, D) and cannabinoids (E) seized samples.
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Figure 2. Cocaine, new psychoactive substances (NPS) and heroin adulterants detected in biological samples of intoxication cases reported between 2017 and 2022.
Figure 2. Cocaine, new psychoactive substances (NPS) and heroin adulterants detected in biological samples of intoxication cases reported between 2017 and 2022.
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MDPI and ACS Style

Di Trana, A.; Berardinelli, D.; Montanari, E.; Berretta, P.; Basile, G.; Huestis, M.A.; Busardò, F.P. Molecular Insights and Clinical Outcomes of Drugs of Abuse Adulteration: New Trends and New Psychoactive Substances. Int. J. Mol. Sci. 2022, 23, 14619.

AMA Style

Di Trana A, Berardinelli D, Montanari E, Berretta P, Basile G, Huestis MA, Busardò FP. Molecular Insights and Clinical Outcomes of Drugs of Abuse Adulteration: New Trends and New Psychoactive Substances. International Journal of Molecular Sciences. 2022; 23(23):14619.

Chicago/Turabian Style

Di Trana, Annagiulia, Diletta Berardinelli, Eva Montanari, Paolo Berretta, Giuseppe Basile, Marilyn A. Huestis, and Francesco Paolo Busardò. 2022. "Molecular Insights and Clinical Outcomes of Drugs of Abuse Adulteration: New Trends and New Psychoactive Substances" International Journal of Molecular Sciences 23, no. 23: 14619.

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