Self-Reported Adverse Effects Associated With New Psychoactive Substance Use in a Sample of Adults From 20 US Cities

Abstract

Introduction:

As new psychoactive substances (NPS) continue to emerge both in the US and globally, research is needed to determine the extent of adverse effects associated with NPS use beyond poisonings or mortality to inform prevention and harm reduction efforts in this population.

Methods:

Data were from the National Drug Early Warning System Rapid Street Reporting study, which uses a venue-intercept design to survey adults (≥ 18 years) in US cities over weekend periods. Between January 2022 and November 2023, 6039 individuals were surveyed in 20 cities regarding their use of a range of NPS and other common drugs. Those reporting past 12-month use of a drug were asked if they experienced a harmful or very unpleasant effect after use.

Results:

Overall, among those reporting any past 12-month NPS use (n = 259), over a quarter (27.03%) reported experiencing an adverse effect related to the use of at least one NPS in the past 12 months. Among those reporting NPS use, those who also reported past 12-month opioid use had over two times the prevalence of reporting an adverse effect related to NPS use (adjusted prevalence ratio 2.66, 95% confidence interval 1.41, 5.01). Symptom profiles were broadly similar between NPS and common drug classes.

Discussion and Conclusions:

Adverse effects from NPS appear to be common among those self-reporting NPS use, particularly among those reporting polysubstance use. More data are needed to determine event-specific adverse outcomes involving the use of NPS and other drugs.

1 |. Introduction

New psychoactive substances (NPS) are substances which typically have not yet been placed under the control of international drug conventions but may pose a threat to public health [1]. However, not all NPS are ‘new’, and many substances are still referred to as NPS even after being controlled. As a drug category, NPS includes a large and diverse range of substances with a diverse range of associated effects. A wide variety of NPS have been identified on the market both in the US and globally by early warning systems [2–4], including 1245 NPS reported to the United Nations Office on Drugs and Crime by 142 countries and territories since 2012 [4]. Although the annual number of NPS identified for the first time has declined since 2016, the total number of known NPS reported each year has remained steady and continues to present a major public health concern [2, 4, 5].

Compared to the use of more common illicit substances which have been the subject of extensive research, the use of NPS has been described as relatively more dangerous, since neither the scientific community nor the general public tend to have a sufficient understanding of the risks involved with their use when they emerge. Zamengo et al. [6] characterised three types of risks specific to NPS use: the risk relative to predicting the actual (i) dose of the NPS product, (ii) ingredients in the NPS product, and (iii) effects of consuming the NPS product. In addition to the dynamic nature of the NPS market and rapidly changing compounds, the varying potencies and incorrect labelling of NPS products can lead to uncertainty and unpredictability in their effects [7, 8]. However, the extent to which NPS use leads to specific adverse effects remains unclear. Many sources of data on adverse outcomes related to NPS use (e.g., case reports) are limited in that morbidity and mortality data typically only capture more severe poisoning cases, while emergency department and poison centre data typically only capture cases in which the individual sought treatment [9]. Each drug is also associated with its own risk of poisoning, and low-frequency events or events with less serious health outcomes are likely to be overlooked when examining harms [10], meaning that estimates of risk associated with the use of specific NPS may be biased due to an overrepresentation of severe outcomes [9].

More research is needed on adverse outcomes of NPS use beyond poisonings and mortality to improve our understanding of effects experienced and, ultimately, whether the use of various classes of NPS is associated with a higher likelihood of adverse events compared to the use of more common substances. To this end, the present study used survey data collected in 20 US cities as part of the National Drug Early Warning System (NDEWS) Rapid Street Reporting (RSR) study to: (i) examine the prevalence of self-reported adverse effects related to the past 12-month use of NPS; (ii) understand how those who self-report an adverse effect from NPS use differ from those who do not; and (iii) examine specific symptoms reported among those who experienced an adverse effect.

2 |. Methods

2.1 |. Sample

Data came from the NDEWS RSR study, which involved 23 data collection visits to 20 unique US cities between January 2022 and November 2023 (described in Table S1). As a component of the NDEWS monitoring system to detect signals of emerging drug trends [11], the RSR study involved cross-sectional surveys of community-recruited adults across cities designated as NDEWS sentinel sites. These include areas in the US selected for surveillance of new and emerging drug trends, the majority of which are former Community Epidemiology Work Group member sites [11–13]. Once a month over the two-year study period, teams of interviewers travelled to the selected city over a weekend (Friday afternoon to Sunday afternoon) and were joined by several local study interviewers. Participants were recruited to be interviewed based on an entertainment venue-intercept design [14, 15], which identified popular venues where individuals tended to visit or congregate. Individuals approached at the given venue were eligible if they were 18 years or older and lived in the US. After providing informed consent, those who met eligibility criteria were administered the rapid, anonymous survey on a study tablet, which assessed the use, correlates of use and adverse effects associated with the use of over 90 drugs. The survey was administered away from others at the venue for privacy and typically took an average of 7.5 min to complete. Participants were compensated at the end of the survey for their time with a $2 bill (USD). All study protocols were approved by the University of Florida Institutional Review Board.

2.2 |. Measures

The rapid survey assessed the past 12-month use of over 90 individual drugs or drug classes, grouped into 14 lists on the survey (Table S2). Participants were shown one list per page on the study tablet and were asked to indicate whether they had used each individual drug in the past 12 months [16]. For the purposes of this study, over half of these individual drugs or drug classes were considered novel drugs and were grouped into common NPS classifications guided by previous publications and government reports [2, 9, 17, 18]. Of note, synthetic cannabinoids were included in the survey as a general category (‘synthetic marijuana/synthetic cannabinoids such as Spice or K2’); the survey did not assess individual synthetic cannabinoids. Regarding novel opioids, the survey included individual items for the past 12-month use of fentanyl and fentanyl analogues; for the purposes of this study, fentanyl analogues were considered novel opioids, whereas fentanyl was not considered an NPS. Participants were also given the ability to report the names of other substances that the survey did not ask about, and these responses were manually reviewed and coded accordingly. For comparisons with common drug classes, several NPS subclasses were further grouped for the purposes of this study into broader categories based on main pharmacological effect, including novel stimulants (synthetic cathinones, phenethylamines and aminoindanes) and novel hallucinogens (psychedelic phenethylamines, lysergamides, novel tryptamines and novel dissociatives). A new indicator variable was also created to represent the past 12-month use of any NPS.

For each individual drug participants reported using in the past 12 months, they were also asked whether they had experienced any adverse effects in the past 12 months after using the drug with this stem question: ‘In the past 12 months, have you experienced a harmful or very unpleasant effect after using [drug]?’ This definition was based on previous sources in which a drug effect was perceived as harmful and/or unpleasant [19, 20]. Then, after ascertaining if any adverse effect was experienced in the past 12 months after using at least one drug on the list, the survey asked participants about specific symptoms experienced during the adverse effect(s) reported after using the endorsed drug(s). Regarding specific symptoms, participants were presented with a checklist and asked to select all that applied, which included the following options: anxious or tense, jumpy or easily startled, nauseated or vomited, overdose, paranoid or suspicious, hallucination, seizure, unconscious or passed out, chest pain and/or fatigue. The list also included an ‘other effect’ checkbox, which allowed the participant to describe additional symptom(s) that the survey did not ask about.

While the past 12-month prevalence of any reported adverse effect was available for all > 90 individual drugs queried on the survey, specific symptom profiles were available for the broader drug lists: common psychostimulants, common hallucinogens/club drugs, cannabis, synthetic cathinones, benzodiazepines, prescription opioids, other opioids, 2C series, tryptamines, dissociatives, synthetic cannabinoids, other psychedelics and euphoric stimulants. Consequently, while symptoms related to the use of NPS were of interest, symptoms related to the use of novel benzodiazepines and novel opioids were unable to be distinguished from those related to the use of prescription benzodiazepines and common opioids.

At the beginning of the survey, demographic information was also collected, including participant age, gender identity, self-identified race and ethnicity and years of education. Other survey-related information was also examined to account for differences according to location from where the participant was recruited, including the city in which the survey was conducted, which was further categorised by US Census region (Midwest, Northeast, South and West).

2.3 |. Analyses

First, to examine the prevalence of adverse effects related to NPS use, the prevalence of self-reported past 12-month use was determined for all individual NPS and NPS subclasses, with the prevalence of an adverse outcome calculated relative to past 12-month use of each drug or drug class. We calculated descriptive prevalence estimates with 95% confidence intervals (CI) using the Wilson score method. To contextualise these adverse outcomes related to NPS use, the prevalence of reported use and adverse effects for NPS subclasses was plotted alongside those involving common drugs and drug classes. Second, to understand how those who self-reported an adverse effect from NPS use differed from those who used NPS but did not report an adverse effect, bivariable analyses were first conducted to determine significant differences in sociodemographic and substance-related characteristics according to the reporting of an adverse effect related to NPS use. All independent variables were then examined simultaneously in a multivariable generalised linear model (GLM) (using Poisson and log link) with experiencing an adverse effect related to NPS use as the binary dependent variable, which generated adjusted prevalence ratios (aPR) and associated 95% CIs for each independent variable. GLM was utilised rather than logistic regression because the prevalence of the outcome was greater than 10% [21, 22]. Finally, to examine specific symptoms reported among those who experienced an adverse effect from NPS classes and how they might differ from pharmacologically similar common drug classes, symptom profiles were plotted for NPS and similar common drug classes, including symptoms describing adverse effects related to the use of: (i) synthetic cannabinoids versus cannabis; (ii) novel hallucinogens (psychedelic phenethylamines, lysergamides, novel dissociatives) vs. common hallucinogens (psilocybin, ecstasy, LSD, ketamine and PCP); and (iii) novel stimulants (synthetic cathinones, other phenethylamines, aminoindanes) vs. common stimulants (cocaine, methamphetamine and prescription stimulants). All analyses were conducted using RStudio (version 4.1.0).

3 |. Results

The sample included 6039 individuals surveyed between January 2022 and November 2023. Overall, 4.29% (n = 259) reported any past 12-month NPS use, and 27.03% of those reporting NPS use (n = 70) experienced an adverse effect related to their NPS use. Past 12-month use of specific NPS and NPS classes and the proportion reporting an adverse outcome relative to past 12-month use are presented in Table 1. For broad NPS categories, over a third (35.00%, 95% CI 18.12%–56.71%) of participants who reported using novel benzodiazepines in the past 12 months reported experiencing an adverse effect after using, followed by 32.35% (95% CI 19.13%–49.16%) of those who used novel opioids, 28.33% (95% CI 18.51%–40.77%) of those who used novel stimulants, 25.33% (95% CI 19.05%–32.85%) of those who used synthetic cannabinoids, and 17.46% (95% CI 10.04%–28.62%) of those who used novel hallucinogens. Within the novel stimulants category, 36.36% (95% CI 22.19%–53.38%) of those who used synthetic cathinones and 22.58% (95% CI 11.40%–39.81%) of those who used other phenethylamines reported experiencing an adverse effect. Within the novel hallucinogens category, the subclass with the highest percentage of reported adverse effects relative to use was novel dissociatives (40.00%, 95% CI 16.82%–68.73%), followed by lysergamides (19.23%, 95% CI 8.51%–37.88%) and psychedelic phenethylamines (14.29%, 95% CI 5.70%–31.49%); none of the participants reporting novel tryptamine use reported experiencing any adverse effects related to use. Figure 1 contextualises self-reported NPS use and adverse effects related to NPS within the broader context of other drug use. Overall, those who reported past 12-month use of fentanyl had the highest percentage of adverse effects related to use (48.34%, 95% CI 40.51%–56.30%), followed by methamphetamine (37.18%, 95% CI 32.31%–42.40%); outside of these, rarer drugs such as NPS tended to have a higher prevalence of reported adverse effects associated with use than commonly used drugs, with the exception of novel tryptamines.

TABLE 1 |.

Self-reported prevalence of past 12-month new psychoactive substance use and self-report of drug-related adverse effects among those with use (N = 6039).

	Reported past 12-month use		Reported adverse outcome relative to use
	n	% (95% CI)	n	% (95% CI)
Synthetic cannabinoidsa	150	2.48 (2.12–2.91)	38	25.33 (19.05–32.85)
Novel hallucinogens	63	1.04 (0.82–1.33)	11	17.46 (10.04–28.62)
Psychedelic phenethylamines	28	0.46 (0.32–0.67)	4	14.29 (5.70–31.49)
2C-B (Bromo mescaline, Nexus)	14	0.23 (0.14–0.39)	0	0.00 (0.00–21.53)
2C-I (2,5-Dimethoxy-4-iodophenethylamine, Smiles)	4	0.07 (0.03–0.17)	1	25.00 (4.56–69.94)
2C-T-7 (T7, Blue Mystic)	4	0.07 (0.03–0.17)	1	25.00 (4.56–69.94)
Other 2C series substancesb	4	0.07 (0.03–0.17)	1	25.00 (4.56–69.94)
2C-E (2–5-Dimethoxy-4-ethyl-phenethylamine, Europa)	3	0.05 (0.02–0.15)	0	0.00 (0.00–56.15)
DOM (STP)	2	0.03 (0.01–0.12)	0	0.00 (0.00–65.76)
DOB (2,5-Dimethoxy-4-bromoamphetamine)	2	0.03 (0.01–0.12)	0	0.00 (0.00–65.76)
DOC (2,5-Dimethoxy-4-chloroamphetamine)	1	0.02 (0.00–0.09)	0	0.00 (0.00–79.35)
NBOMe	1	0.02 (0.00–0.09)	1	100.00 (20.65–100.00)
Lysergamides	26	0.43 (0.29–0.63)	5	19.23 (8.51–37.88)
1P-LSD	16	0.27 (0.16–0.43)	3	18.75 (6.59–43.01)
ALD-52	11	0.18 (0.10–0.33)	2	18.18 (5.14–47.70)
LSZ (Lysergic acid 2,4-dimethylazetidide)	2	0.03 (0.01–0.12)	0	0.00 (0.00–65.76)
AL-LAD (6-allyl-6-nor-LSD)	1	0.02 (0.00–0.09)	0	0.00 (0.00–79.35)
Novel tryptamines	18	0.30 (0.19–0.47)	0	0.00 (0.00–17.59)
5-MeO-DMT	9	0.15 (0.08–0.28)	0	0.00 (0.00–29.91)
5-MeO-DiPT (Foxy, Foxy methoxy)	6	0.10 (0.05–0.22)	0	0.00 (0.00–39.03)
5-MeO-MiPT (Moxy)	5	0.08 (0.04–0.19)	0	0.00 (0.00–43.45)
4-AcO-DMT (4-HO-DMT,	4	0.07 (0.03–0.17)	0	0.00 (0.00–48.99)
4-acetoxy-N, N-dimethyltryptamine)
AMT (alpha-Methyltryptamine, IT-290, 3-IT)	3	0.05 (0.02–0.15)	0	0.00 (0.00–56.15)
Other novel tryptaminesc	2	0.03 (0.01–0.12)	0	0.00 (0.00–65.76)
Novel dissociatives	10	0.17 (0.09–0.30)	4	40.00 (16.82–68.73)
3-MeO-PCP (3-Methoxyphencyclidine)	4	0.07 (0.03–0.17)	2	50.00 (15.00–85.00)
4-MeO-PCP	2	0.03 (0.01–0.12)	0	0.00 (0.00–65.76)
2-MeO-Ketamine	2	0.03 (0.01–0.12)	0	0.00 (0.00–65.76)
3-MeO-2-Oxo-PCE (MXE, Methoxetamine)	2	0.03 (0.01–0.12)	0	0.00 (0.00–65.76)
Other novel dissociativesd	2	0.03 (0.01–0.12)	2	100.00 (34.24–100.00)
Novel stimulants	60	0.99 (0.77–1.28)	17	28.33 (18.51–40.77)
Synthetic cathinones	33	0.55 (0.39–0.77)	12	36.36 (22.19–53.38)
Methedrone	6	0.10 (0.05–0.22)	0	0.00 (0.00–39.03)
alpha-PVP (Flakka)	5	0.08 (0.04–0.19)	3	60.00 (23.07–88.24)
Mephedrone	5	0.08 (0.04–0.19)	1	20.00 (3.62–62.45)
Methylone	5	0.08 (0.04–0.19)	4	80.00 (3.62–62.45)
Pentylone	4	0.07 (0.03–0.17)	1	25.00 (37.55–96.38)
Dibutylone	3	0.05 (0.02–0.15)	0	0.00 (0.00–56.15)
MDPV (Methylenedioxypyrovalerone)	3	0.05 (0.02–0.15)	1	33.33 (6.15–79.23)
Methcathinone	3	0.05 (0.02–0.15)	2	66.67 (20.77–93.85)
Butylone	2	0.03 (0.01–0.12)	1	50.00 (9.45–90.55)
Ethylone	1	0.02 (0.00–0.09)	0	0.00 (0.00–79.35)
N-Ethylpentylone	1	0.02 (0.00–0.09)	0	0.00 (0.00–79.35)
Bath salts, otherwise unspecified	16	0.26 (0.16–0.43)	5	31.25 (14.16–55.60)
Other phenethylamines	31	0.51 (0.36–0.73)	7	22.58 (11.40–39.81)
MDA (Methylenedioxyamphetamine)	27	0.45 (0.31–0.65)	4	14.81 (5.92–32.48)
6-APB, Benzo Fury	3	0.05 (0.02–0.15)	1	33.33 (6.15–79.23)
MDE (MDEA, 3,4-Methylenedioxy-N-ethylamphetamine, Eve)	3	0.05 (0.02–0.15)	2	66.67 (20.77–93.85)
TMA (Trimethoxyamphetamine)	2	0.03 (0.01–0.12)	1	50.00 (9.45–90.55)
4-FA (4-Fluoroamphetamine)	1	0.02 (0.00–0.09)	0	0.00 (0.00–79.35)
Aminoindanes	2	0.03 (0.01–0.12)	2	100.00 (34.24–100.00)
MDAI (5,6-Methylenedioxy-2-aminoindane)	2	0.03 (0.01–0.12)	2	100.00 (34.24–100.00)
Novel opioids	34	0.56 (0.40–0.79)	11	32.35 (19.13–49.16)
Fentanyl analogues	31	0.51 (0.36–0.73)	10	32.26 (18.57–49.86)
U-47700	7	0.12 (0.06–0.24)	2	28.57 (8.22–64.11)
Novel benzodiazepines	20	0.33 (0.21–0.51)	7	35.00 (18.12–56.71)
Clonazolam	11	0.18 (0.10–0.33)	2	18.18 (5.14–47.70)
Etizolam	4	0.07 (0.03–0.17)	1	25.00 (4.56–69.94)
Pyrazolam	3	0.05 (0.02–0.15)	1	33.33 (6.15–79.23)
Diclazepam	2	0.03 (0.01–0.12)	1	50.00 (9.45–90.55)
Flubromazepam	2	0.03 (0.01–0.12)	2	100.00 (34.24–100.00)

Note: Since some participants self-reported use of NPS from more than one class and multiple NPS within each class, the percentages above exceed 100%. Estimates are presented with 95% Wilson confidence intervals.

Abbreviation: CI, confidence interval.

^aSynthetic cannabinoids were included in the survey as a general category (‘In the past 12 months, have you used synthetic marijuana/synthetic cannabinoids such as Spice and K2?’); specific synthetic cannabinoids were not queried.

^bOther 2C series substances reported included 2C-D (2,5-Dimethoxy-4-methylphenethylamine), 2C-T-8, and unknown 2C.

^cOther novel tryptamines reported included 4-HO-MET (N-ethyl-4-hydroxy-N-methyltryptamine).

^dOther novel dissociatives reported included 2F-Deschloroketamine (2-Flurodeschloroketamine, 2-FDCK) and 5-MeO-PCP (5-Methoxyphencyclidine).

FIGURE 1 |.

Self-reported prevalence of past 12-month substance use and self-report of experiencing a drug-related adverse effect.

Table 2 presents the results of bivariable and multivariable analyses examining correlates of an adverse effect from any NPS use among those with any past 12-month NPS use. Results from bivariable tests indicated that those who reported an adverse effect from NPS use tended to be older (39.57 years, SD = 13.50, vs. 35.74 years, SD = 13.86, p = 0.046). Reporting an adverse effect from NPS use was more common among those also reporting past 12-month common stimulant use (81.43% vs. 63.49%, p = 0.006), common opioid use (57.14% vs. 25.93%, p < 0.001), or common benzodiazepine use (32.86% vs. 20.11%, p < 0.001). Those reporting an adverse effect from NPS use also tended to report a higher number of common drugs used in the past 12 months compared to those reporting no adverse effect (5.83, SD = 4.33, versus 4.26, SD = 4.13). In the GLM, however, the only remaining significant association with reporting adverse effects was use of common opioids. Among those with past 12-month NPS use, those also reporting use of common opioids (e.g., heroin, fentanyl, prescription opioids) in the past 12 months had over two times the prevalence of reporting an adverse effect associated with NPS use (aPR 2.66, 95% CI 1.41–5.01).

TABLE 2 |.

Correlates of reporting an adverse effect related to NPS use among those self-reporting NPS use in past 12 months.

		Bivariable comparisons		Multivariable model
	Any NPS use (n = 259)	No adverse effect (n = 189)	Adverse effect (n = 70)	aPR	(95% CI)
Age, mean (SD)	36.78 (13.84)	35.74 (13.86)	39.57 (13.50)	1.00	(0.98–1.02)
Gender identity, %
Female	25.48	25.93	24.29	1.00	(Reference)
Male	70.27	70.37	70.00	0.90	(0.49–1.69)
Other identitya	4.25	3.70	5.71	1.09	(0.29–3.27)
Race/ethnicity, %
Non-Hispanic White	43.63	45.50	38.57	1.00	(Reference)
Non-Hispanic Black	25.87	23.28	32.86	1.56	(0.81–2.97)
Non-Hispanic Otherb	10.81	9.52	14.29	1.62	(0.71–3.46)
Hispanic/Latino	19.69	21.69	14.29	0.83	(0.37–1.72)
Education level, %
Less than high school	14.29	13.23	17.14	1.00	(Reference)
High school	31.27	30.69	32.86	1.16	(0.57–2.47)
Some college	29.34	28.57	31.43	1.09	(0.53–2.36)
College	25.10	27.51	18.57	1.02	(0.42–2.53)
Region of study site, %
Midwest	10.42	11.64	7.14	1.00	(Reference)
Northeast	12.74	12.70	12.86	1.54	(0.45–5.77)
South	40.93	38.10	48.57	1.64	(0.63–5.15)
West	35.91	37.57	31.43	0.99	(0.36–3.22)
Where surveyed, %
Park	29.73	31.22	25.71	1.00	(Reference)
Sidewalk	27.80	26.46	31.43	1.42	(0.70–2.89)
Nightlife/festivals	10.04	10.58	8.57	0.98	(0.33–2.64)
Other venue typec	32.43	31.75	34.29	1.20	(0.60–2.47)
Past 12-month common drug use, %
Cannabis	81.08	79.89	84.29	1.42	(0.72–3.02)
Stimulantsd	68.34	63.49	81.43	1.54	(0.82–3.07)
Hallucinogense	51.35	49.21	57.14	1.30	(0.74–2.31)
Opioidsf	34.36	25.93	57.14	2.66	(1.41–5.01)
Benzodiazepinesg	23.55	20.11	32.86	0.98	(0.48–1.97)
Sum of common drugs used in past 12 months, mean (SD)	4.68 (4.23)	4.26 (4.13)	5.83 (4.33)	0.98	(0.89–1.07)

Note: Bolded values indicate p < 0.05. The outcome variable indicates the 27.0% of individuals who reported experiencing an adverse effect from NPS use in the past 12 months. The multivariable model also adjusted for year of data collection.

Abbreviations: aPR, adjusted prevalence ratio; CI, confidence interval; NPS, new psychoactive substance use; SD, standard deviation.

^a‘Other gender identity’ included individuals who identified as trans male, trans female, gender-nonconforming and other.

^b“Non-Hispanic Other” included individuals who identified as Asian, American Indian/Alaskan Native, Native Hawaiian/Pacific Islander, and other.

^c‘Other venue types’ included town square/plaza, transportation station, stadium/arena, college campus, amusement park, courthouse, grocery store, laundromat, library, museum, restaurant, shelter, skate park and other.

^dStimulants included cocaine, methamphetamine, and prescription stimulants (nonmedical use).

^eHallucinogens included psilocybin, ecstasy/MDMA/Molly, LSD, DMT, ketamine and PCP.

^fOpioids included fentanyl, heroin, and prescription opioids (nonmedical use).

^gBenzodiazepines included prescription benzodiazepines (nonmedical use).

Specific symptoms associated with adverse effects related to the use of NPS and pharmacologically similar common drug classes are presented in Figures 2–4. For both synthetic cannabinoid (n = 38) and cannabis (n = 336) use (Figure 2), the most commonly reported symptoms were anxiety (31.58%, 95% CI 19.08%–47.46%, vs. 62.20%, 95% CI 56.91%–67.22%, respectively) and paranoia (31.58%, 95% CI 19.08%–47.46%, vs. 36.61%, 95% CI 31.63%–41.88%), followed by confusion (23.68%, 95% CI 12.99%–39.21%) and unconsciousness (23.68%, 95% CI 12.99%–39.21%) for synthetic cannabinoids, and tachycardia (heart racing; 25.30%, 95% CI 20.95%–30.21%) and nausea/vomiting (21.73%, 95% CI 17.65%–26.44%) for cannabis. Over a third (36.84%, 95% CI 23.38%–52.72%) of those reporting an adverse effect from synthetic cannabinoid use also described other effects in addition to symptoms on the checklist, which included headaches, memory loss, feeling lightheaded and trouble breathing. As shown in Figure 3, for novel hallucinogens (n = 11), anxiety (36.36%, 95% CI 15.17%–64.62%), confusion (36.36%, 95% CI 15.17%–64.62%), and hallucinations (36.36%, 95% CI 15.17%–64.62%) were the most commonly reported symptoms describing adverse effects related to use, followed by nausea/vomiting (18.18%, 95% CI 5.14%–47.70%) and irritation or aggression (18.18%, 95% CI: 5.14%–47.70%). Common hallucinogens (n = 179) were similarly most commonly associated with anxiety (44.13%, 95% CI: 37.06%–51.46%) and confusion (27.93%, 95% CI 21.88%–34.92%), though other top reported symptoms included depression (27.93%, 95% CI 21.88%–34.92%) and tachycardia (27.93%, 95% CI 21.88%–34.92%), which were not endorsed for any adverse effect involving novel hallucinogens. Nearly two-thirds (63.64%, 95% CI 35.38%–84.83%) of those reporting an adverse effect related to novel hallucinogen use described other effects, including mania and ‘bad’ or ‘scary’ thoughts. Finally, symptoms reported to describe adverse effects involving cocaine or methamphetamine use (n = 281), nonmedical prescription stimulant use (n = 56), and novel stimulant use (n = 17) are displayed in Figure 4. Confusion (41.18%, 95% CI 21.61%–63.99%), anxiety (35.29%, 95% CI 17.31%–58.70%) and tachycardia (29.41%, 95% CI 13.28%–53.13%) were most commonly associated with novel stimulant use; while anxiety and tachycardia were also associated with cocaine/methamphetamine and prescription stimulant use, confusion was less commonly reported for these common stimulants (22.42%, 95% CI 17.93%–27.65%, and 12.50%, 95% CI 6.19%–23.63%, respectively). Nearly a fourth (23.53%, 95% CI 9.56%–47.26%) of those reporting an adverse effect related to novel stimulant use described other effects, which included headache, sweating, hives and insomnia.

FIGURE 2 |.

Specific adverse effects reported among those reporting an adverse effect from cannabis or synthetic cannabinoid use. ‘Other effects’ included headache, memory loss, feeling lightheaded, psychosis, trouble breathing, trouble focusing, cough and sweating.

FIGURE 4 |.

Specific adverse effects reported among those reporting an adverse effect from cocaine or methamphetamine, prescription stimulant, or novel stimulant (synthetic cathinone, other phenethylamine and aminoindane) use. ‘Other effects’ included nasal issues, insomnia, headache, memory loss, overheating, sweating, mania, hives and trouble breathing.

FIGURE 3 |.

Specific adverse effects reported among those reporting an adverse effect from common hallucinogen (psilocybin, ecstasy, LSD, ketamine and PCP) or novel hallucinogen (psychedelic phenethylamine, lysergamide and novel dissociative) use. ‘Other effects’ included headache, insomnia, overheating, sweating, bladder issues, memory loss and mania.

4 |. Discussion

The present study examined adverse effects related to past 12-month use of NPS in the context of those related to other substance use, beyond outcomes which only resulted in poisonings or mortality. Overall, among persons reporting any past 12-month NPS use, 27.03% reported experiencing a ‘harmful or very unpleasant effect’ from NPS use. Though reported past 12-month use was lower than most classes of common drugs, many NPS classes were associated with relatively high percentages of adverse effects, including novel benzodiazepines (35.00%), novel opioids (32.35%), and novel stimulants (28.33%). Describing the prevalence of these effects is an important first step in improving public health responses to NPS use, as many adverse outcomes may not result in hospitalisation or death and are therefore unlikely to be captured in traditional surveillance systems such as emergency department or mortality data [9, 10]. Self-reported experiences of adverse effects related to NPS use can help fill these gaps by identifying early signals of harm and characterising the functional and subjective outcomes of use that are less likely to be documented clinically.

In addition to describing the prevalence of self-reported adverse effects related to the use of NPS, the study examined differences between those who reported NPS use and at least one adverse effect from NPS use and those who reported NPS use, but no adverse effects from use. There were no significant associations involving sociodemographic characteristics in the multivariable model, but among those reporting past 12-month NPS use, those also reporting past 12-month common opioid use (heroin, fentanyl and/or nonmedical prescription opioid use) had over two times the likelihood (aPR 2.66) of reporting an adverse effect related to NPS use. This finding corroborates prior research that polysubstance use can additionally complicate the risks of NPS use [23, 24], although because the survey did not query whether more than one drug was involved during the experience of the reported adverse effect, the extent and timing of this use remains unclear beyond the past 12-month period of assessment. Future research should examine more granular data to acquire an understanding of the temporal ordering of use (e.g., same day use, timing between administrations) of NPS and other drugs when assessing adverse outcomes. That concurrent past 12-month common opioid use was significantly associated with reporting an adverse effect related to NPS use and not other classes of past 12-month common drug use may reflect the elevated risk profile of novel opioids relative to other NPS classes [25, 26], given that persons who use traditional opioids are typically more likely to use (or be exposed to) novel opioids. Since all NPS were collapsed into a single category due to cell size limitations, this association may be driven primarily by adverse effects related to novel opioids rather than indicating a broader pattern across all NPS classes, which underscores the need for future research with sufficient subgroup sizes to examine differences stratified by type of NPS. Misclassification of novel opioids as common opioids may have also occurred and could have contributed to the finding. Given the changing nature of the illicit drug market in the US [27, 28], including the increasing prevalence of counterfeit prescription tablets containing fentanyls [29–31], participants may not have known whether they were using fentanyl, fentanyl analogues, other novel opioids such as nitazenes; however, the risk of unknown exposure to NPS is not exclusive to opioids, as many other types of drug products can be adulterated or contaminated with NPS (e.g., ecstasy tablets containing synthetic cathinones; counterfeit benzodiazepine tablets containing novel benzodiazepines) [32–35].

Finally, specific symptoms reported among those who experienced an adverse effect related to NPS classes were examined. Although many NPS are designed to mimic the psychoactive effects of traditional, pharmacologically similar substances, NPS can differ markedly in their potency, pharmacology and duration of action [6], and understanding differences in symptom profiles can help to inform harm reduction efforts and improve clinical recognition of NPS-related presentations. Overall, the symptom profiles from the present study support the idea of broad clinical similarities between NPS and common drugs with similar pharmacological effects [23], with some distinctions. While the most frequently endorsed symptoms among those who experienced an adverse effect related to past 12-month synthetic cannabinoid use were similar to those associated with cannabis use, synthetic cannabinoids were associated with more frequent reports of confusion, unconsciousness, irritation/aggression, hallucinations, overactivity and seizures than cannabis; these symptoms are consistent with the literature describing harms associated with synthetic cannabinoids as involving more cardiovascular and central nervous system effects than those associated with cannabis [10, 23, 25]. Similarly, while symptoms associated with adverse effects involving novel hallucinogens and stimulants were broadly similar to those involving common hallucinogens and stimulants, respectively, both classes of NPS use had more frequent reports of confusion and hallucinations than their pharmacologically similar traditional drug classes, with a higher percentage of those with novel stimulant use also reporting nausea/vomiting, unconsciousness, physical injury, overdose, and seizures compared to those with common stimulant use. Although these comparisons provide insight into the symptom profiles associated with NPS classes and highlight the utility of rapid survey methods for capturing a broad range of adverse effects across both novel and common substances, the relatively small sample sizes for each NPS category limit the stability of estimates, and collapsing different subclasses of NPS within each class may obscure clinically relevant differences in symptoms and acute toxicity. Additional research with larger samples is needed to better characterise the full range of effects associated with individual NPS and NPS subclasses. Future research with the RSR study will also pair self-report survey data with results from saliva testing to confirm exposure to NPS among those reporting adverse effects.

4.1 |. Limitations

First, this survey queried whether adverse effects were experienced in relation to each individual drug used in the past 12 months and, beyond a list of symptoms for a number of drugs and drug classes, did not collect additional information such as the quantity or frequency of use, other drugs consumed simultaneously, or set and setting [36]. In particular, since the survey did not assess whether more than one drug was involved during the experience of the reported adverse effect at the event level, double counting may have occurred in cases of multiple concomitant drug use. Second, based on the definition used for adverse effects, some individuals may have overreported minor effects as serious, while others may have been familiar with certain effects and chosen not to report them as serious; however, this definition of adverse effects is consistent with previous studies [19, 20]. Additionally, the list of symptoms presented to participants may not have adequately captured the individual’s experience (although a type-in option was also included). Third, given that polysubstance use can complicate the experience of adverse effects, there is also the question of whether an individual was able to describe an adverse effect as related to the use of specific individual substances when more than one substance may have been used concomitantly. However, prior work has shown that individuals can reliably report and distinguish the symptoms associated with the use of specific substances [37–39]. Fourth, since the RSR study was based on a venue-intercept design, findings cannot necessarily be generalised to those who did not attend these venues of recruitment during weekend periods. Fifth, given the potential for adulteration of other substances with NPS, particularly regarding fentanyls and counterfeit prescription tablets [27, 29–31, 40], self-reported NPS use likely involved underreporting, and there may have been misclassification in particular among those reporting drugs known to be commonly adulterated (e.g., common opioids, ecstasy). Finally, wide CIs for some estimates indicate low precision due to limited sample size and should be interpreted cautiously.

5 |. Conclusions

This study provides a descriptive account of self-reported adverse effects associated with past 12-month NPS use in a sample of adults surveyed in 20 US cities. The study’s findings have several implications for improving public health responses to NPS-related harms. First, the relatively high prevalence of adverse effects reported among persons who used certain NPS classes—particularly novel opioids, as well as novel benzodiazepines and stimulants—reinforces the need for targeted outreach and communication efforts to address the potential risks posed by these substances, which may not be well understood by persons who use drugs or clinicians. Additionally, the broadly similar symptom profiles reported across novel and common substances within the same general pharmacological classes suggest that symptom-based recognition of NPS use may be limited in real-world settings, where persons may present with effects that mimic those of more traditional drugs. At the same time, these findings challenge the assumption that NPS are always more dangerous or qualitatively different than traditional drugs, especially when the broad category of NPS includes such a wide and heterogeneous range of individual drugs with varied effects and risk profiles [41]. There remains a need for nuanced education and risk communications that are substance-specific and avoid overgeneralising NPS. As a step toward improving surveillance of NPS use and associated harms in the US, these findings can help address gaps in the literature regarding adverse outcomes related to NPS use beyond those severe adverse effects reported in case reports and case series, such as mortality and poisonings, and can help further inform prevention and harm reduction efforts.

Supplementary Material

Supporting Information

Additional supporting information can be found online in the Supporting Information section. Data S1: dar70119-sup-0001-supinfo.docx.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.