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Abstract
Background 3-methylmethcathinone (3-MMC) has been available on the European drug market for several
years, but an increase in its availability seems to have occurred around 2020, associated with reports of harm
and death. We aimed to analyze the composition of the supposed 3-MMC samples purchased and its concordance
with the assumed composition of the drug.
Methods A prospective multicenter (n = 6) study was conducted between February 2021 and September 2021 in
Auvergne-Rhone-Alpes, France. The inclusion criteria were: 3-MMC users over 18 years of age in contact with a com‑
munity-based organization (CBO) called AIDES. Consumption was evaluated with an anonymized questionnaire
and samples of 3-MMC powder were analyzed with a combination of qualitative (GC–MS) and quantitative methods
(UPLC-MS/MS), to compare the assumed and real compositions of the products purchased.
Results We studied 45 samples provided by 33 users. The study population was predominantly male (91%),
with a median age of 40 years, most were university graduates and regular users of 3-MMC. Intravenous drug use
was reported by 15.2% of the population. Most of the users bought their 3-MMC online via the Clear Web. Drug
testing was requested by 86% of the users, highlighting the need for this type of harm reduction strategy. The purity
of the 3-MMC powder samples tested ranged from 21 to 98%. Other NPS drugs, such as 4-CEC (4-chloroethcathi‑
none), 4-MMC, and 2-fluorodeschloroketamine (2-FDCK), supplied as methoxphenidine (MXP), were also detected.
Conclusion This prospective study shows that 3-MMC purity and dose vary considerably. It also describes the char‑
acteristics of 3-MMC users and their expectations of a drug-checking program. Our data suggest that drug-checking
services may be useful in this population. Health associations and laboratories should work together to help increase
access to such programs.
Keywords Chemsex, 3-methylmethcathinone, Harm reduction, Drug checking
8
*Correspondence: Institute of Sociological Research (ISR), University of Geneva, Geneva,
Bruno Revol Switzerland
brevol@chu-grenoble.fr
1
Univ. Grenoble Alpes, Laboratoire de Pharmacologie,
Pharmacogénétique, Toxicologie, CHU Grenoble Alpes, Grenoble, France
2
Univ. Grenoble Alpes, Clinique de Médecine Légale, CHU Grenoble
Alpes, Grenoble, France
3
Univ. Grenoble Alpes, CEIP-Addictovigilance, CHU Grenoble Alpes,
Grenoble Cedex 9, 38043 Grenoble, France
4
CAARUD Pause Diabolo, Lyon, France
5
AIDES, Pantin et Annemasse, Annemasse, France
6
Laboratoire de Recherche Communautaire, Coalition PLUS, Pantin,
France
7
Univ. Grenoble Alpes, Laboratoire HP2 Inserm, U1300 Grenoble, France
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Willeman et al. Harm Reduction Journal (2023) 20:96 Page 2 of 8
Sample collection, evaluation of consumption, gas chromatography coupled to mass spectrometry (GC–
and reporting of the results MS) screening, 50 µL supernatant was evaporated to dry-
A meeting focusing on DCS and 3-MMC was organized ness and reconstituted by adding 50 µL ethyl acetate.
at each center. Communication was based on flyers dis-
tributed at each center and on social networks, with the Chromatography methods
catchphrase “3-MMC, what’s in your powder?”. In paral- Quantitative liquid chromatography method Ultrahigh-
lel with usual harm reduction practices, drug users were performance liquid chromatography (UHPLC) was per-
asked to provide samples (a small quantity of powder in formed on an I-class Acquity system (Waters Milford,
a 1.5-mL Eppendorf tube) and to complete a question- USA). Chromatographic separation was achieved with
naire. Users were informed about the study protocol by an Acquity HSS T3 column (100 mm × 2.1 mm, 2.5 µm)
a letter explaining the reasons for performing the study (Waters). Mobile phase A consisted of 5 mM ammonium
and the way in which the study would be performed. The formate, 0.1% formic acid, and mobile phase B consisted of
program focused on 3-MMC users, but was also open to 0.1% formic acid in ACN. The following gradient was used:
other NPS users. The questionnaire was anonymous and 0–0.5 min: 13% B; 0.5–10 min: 13–50% B; 10–10.75 min:
contained questions about the subject’s consumption 50–95% B; 10.75–12.25 min: 95% B; 12.25–12.5 min:
(self-reported drug use, 3-MMC consumption frequency, 95–13% B; 12.5–15 min: 13% B. Each analytical run lasted
routes of administration, desired effects, buying habits) 15 min. The retention times were 2.62 min for 3-MMC
and expectations of DCS (wanting to know the true com- and 2.58 for 4-MMC and 4-MMC-d3. The flow rate of the
position of the products consumed, their purity, the pres- mobile phase was 0.4 mL/min. Oven temperature was set
ence of adulterating agents, and expected analysis time). to 40 °C, and the injection volume was 1 µL. Analytes were
The results were initially communicated individually to quantified on a Xevo TQ-XS (Waters) tandem mass spec-
the participants. Once all the analyses had been com- trometer, by positive electro-spray ionization (ESI) for
pleted, collective feedback meetings were organized. 3-MMC or 4-MMC and 4-MMC d3, the internal stand-
ard (IS). Quantitative analysis was performed in multiple
Analytical methods reaction monitoring (MRM) mode and the precursor-to-
Chemicals product ion transitions were 178.3 > 91.1 and 181.3 > 91.1
Analytical standards (3-MMC, 4-MMC) and the inter- for 3-MMC/4-MMC and IS, respectively. Data were ana-
nal standard (4-MMC-d3, IS) were purchased from LGC lyzed with MassLynx (v4.2, Waters).
Standards (Luckenwalde, Germany). LC–MS-grade The method was validated according to the Food and
acetonitrile was purchased from VWR (Leuven, Bel- Drug Administration “Bioanalytical Method Validation
gium). Ultrapure water with a resistivity ≥ 18.0 MΩ.cm
was produced with the Milli-Q Plus® system (Millipore,
Guidance for Industry” [15]. The linearity range was
0.1–100 ng/mL (coefficient of determination r2 of 0.997);
Molsheim, France). Other chemicals used were pur- the limit of quantification was set at 0.1 ng/mL, corre-
chased from Carlo Erba reagents (Val-de-Reuil, France) sponding to 0.1% purity. Inter-day accuracies were 103.2
or VWR. and 99% and inter-day precisions were 7.4% for internal
quality controls of 5 and 60 ng/mL, respectively. Intra-
Sample treatment day accuracies were 100.6% and 101.6%, whereas intraday
Stock solutions of 3-MMC were prepared in methanol precisions were 2.8% and 4.7%, respectively (n = 6).
at a concentration of 1 mg/L. Calibrators (7 levels from
0.1 to 100 ng/mL) and quality controls (QC) (2 levels: 5 Qualitative gas chromatography We distinguished
and 60 ng/mL) were then prepared in water. The powder between 3-MMC and 4-MMC and performed untargeted
samples were photographed, weighed, and dissolved in screening on an Agilent Technologies system combining
methanol at a concentration of 1 mg/L. Samples of the a 7890D Network GC System with a 5977 network mass
3-MMC stock solutions in methanol were then diluted selective detector equipped with a high-efficiency source.
in water by adding 10 µL of IS solution (1 µg/mL) to Indeed, despite the close retention times of 3-MMC and
obtain a theoretical concentration of 100 ng/mL 3-MMC 4-MMC on LC–MS/MS, this GC–MS method made it
if the powder was 100% pure. Samples were immedi- possible to distinguish between these isomers, with reten-
ately vortexed for 10 s and then centrifuged for 10 min at tion times of 8.70 and 8.87 min, respectively.
2,000 × g. The resulting supernatants (200 µL) were trans- Samples were injected onto a DB-5 MS UI col-
ferred to integrated injection-ready micro-insert glass umn (30 m-0.25 mm internal diameter; 0.25 µm
vials for quantitative analysis by liquid chromatography film thickness) by pulsed split-less injection at an
coupled to tandem mass spectrometry (LC–MS/MS). For injector temperature of 250 °C. Temperature condi-
tions were as follows: initial temperature of 70 °C for
Willeman et al. Harm Reduction Journal (2023) 20:96 Page 4 of 8
Table 2 3-MMC buying patterns by users Table 3 Drug-checking services implementation expectations
by users
n %
Full sample %
Type of suppliers (n = 33) (n = 46)
Internet 27 87.0
Do you wish a more frequent drug-checking
Street 3 6.5
service? (n = 44)
Others 3 6.5
Yes 38 86.4
Are you sure about the supplier reliability? (n = 39)
Expectations for drug checking? (n = 43)
Yes 29 74.4
True composition 35 81.4
Was it your first choice from the website? (n = 39)
Purity 28 65.1
Yes 31 79.5
Adulterant 28 65.1
Search engine (n = 34)
Other 1 2.3
Clearweb 29 85.3
Expected analysis time? (n = 44)
Darknet 5 14.7
2–4 days 18 40.9
Who did advise you 3-MMC (n = 45)
1–2 weeks 20 45.5
Surroundings 21 46.7
1 month or more 6 13.6
Internet website 11 24.4
Why did you enrolled the study? (n = 43)
None 12 26.7
Support the program 32 74.4
Influencing buying criteria (n = 42)
True composition 31 72.1
Price 32 76.2
Evaluate new 3-MMC seller 12 27.9
Formulation 28 66.7
Unexpected side effect 5 11.6
Quantity 24 57.1
Unexpected product aspect 3 7.0
Purity 12 28.6
No or mild effect 2 4.7
Dose 3 7.1
Packaging 3 7.1
Price (n = 43)
0 to 20 euros per gram 25 58.1 study of 3-MMC users engaging in chemsex in France,
20 to 40 euros per gram 18 41.9 purity ranged from 51 to 88% [13]. In 2021, the SINTES
network in France analyzed 11 3-MMC samples, report-
ing purity values ranging from 42 to 98% [19]. We also
Discussion found that purity was highly variable (21 to 98%). This
This study provided a clearer description of the 3-MMC variability may lead to unexpected effects, a complete
products consumed, particularly in the “chemsex” con- absence of effect, or poisoning, because the dose con-
text. The purity of the 3-MMC samples ranged from 21 sumed may vary according to the purity of the product.
to 98%, and a 77% match was found between the pre- Knowledge about the purity of the sample would help
sumed identity of the drug and the drug actually received users to adapt the quantity taken, thereby enabling them
by users. Unexpectedly, we also detected other NPS, such to avoid complications. Interestingly, one sample con-
as 2-FDCK. 4-CEC and 4-MMC, are also synthetic cathi- tained no psychoactive substance, but this sample was
nones, pharmacologically similar to 3-MMC and with not obtained from an internet vendor. One of the 45 sam-
a similar commonly used dose. However, 2-FDCK is a ples was in tablet form, all the others being in the form
potentially dangerous substance with effects very differ- of powder or crystals. In the samples analyzed here,
ent from those of 3-MMC. contrary to the beliefs of users, purity was not higher
Most of the 3-MMC users studied men and the median for crystals than for powders. Tablets have also been
age of the study population was 40 years. Flores Anato obtained in customs seizures, along with capsules and
et al. identified a population of younger people and MSM liquid products, albeit in smaller amounts than powders
who practice chemsex, with a median age of 33 years, as [18].
3-MMC users in a pre-exposure prophylaxis (PreP) pop- DCS can be useful to identify NPS. Indeed, new syn-
ulation in Canada [16]. The population of 3-MMC users thetic cannabinoids have been identified in this way, by
in our study consisted largely of MSM practicing chem- gas or liquid chromatography-mass spectrometry [20].
sex, although 3-MMC use seems to be expanding into the We detected 2-fluorodeschloroketamine (2-FDCK), sold
party scene [17]. as methoxphenidine (MXP), an emerging and potentially
The purity of the 3-MMC obtained in customs seizures dangerous NPS [21, 22], thereby confirming its pres-
has been reported to range from 45.7 to 100% [18]. In one ence in France. Drug checking for amphetamine-type
Willeman et al. Harm Reduction Journal (2023) 20:96 Page 6 of 8
Table 4 Samples toxicological analysis: identification, purity, and pharmacologically active adulterant identified
Expected product Aspect GC–MS & UPLC-MS/MS Purity Pharmacologically
identification active adulterant
identified
Funding 13. Marillier M, Batisse A, Richeval C, labrouve V. CHEMSEX, NPS & risk reduction
This research received no specific grant from funding agencies in the public, management: preliminary results of a pilot study. Toxicol Anal Clin 2017; 29:
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14. Strong C, Huang P, Li C-W, Ku SW-W, Wu H-J, Bourne A. HIV, Chemsex, and
Availability of data and materials the need for harm-reduction interventions to support gay, bisexual, and
The datasets used and/or analyzed in this study are available from the cor‑ other men who have sex with men. Lancet HIV 2022; https://doi.org/10.
responding author on reasonable request. 1016/S2352-3018(22)00124-2.
15. Research C for DE and. Bioanalytical method validation guidance for indus‑
try. US food and drug administration 2020. https://www.fda.gov/regulatory-
Declarations information/search-fda-guidance-documents/bioanalytical-method-valid
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F20210126201110. among individuals consulting for PrEP at a large sexual health clinic in Mon‑
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Competing interests 18. European monitoring centre for drugs and drug addiction. EMCDDA initial
The authors declare that they have no competing interests. report on the new psychoactive substance 2-(methylamino)-1-(3-methyl‑
phenyl)propan-1-one (3- methylmethcathinone, 3-MMC). In accordance
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