In this nationally representative study of NHANES participants, we found higher levels of Cd and Pb in blood and urine among participants reporting exclusive marijuana use when compared with participants who neither used marijuana nor tobacco. Cd and Pb levels were also higher in exclusive marijuana users who reported using marijuana within the last 7 d, with metal levels being lower with increased time since last use. Cd biomarker levels were higher in exclusive tobacco users compared with exclusive marijuana users, either because of differences in frequency of use or differences in Cd levels in the tobacco and cannabis plants themselves. However, blood and urinary Pb levels among those who exclusively used marijuana and those who exclusively used tobacco were similar. Dual marijuana and tobacco users also had higher levels of Cd and Pb compared with participants who used neither marijuana nor tobacco. Taken together, these observations suggest that marijuana use is an important and underrecognized source of Cd and Pb exposure independent of tobacco use and that chronic marijuana use may contribute to adverse health effects associated with chronic, low-level metal exposure.

One other study assessed blood and urinary Cd levels in individuals who use marijuana in the 2009–2016 NHANES cycles. Ngueta et al. found that marijuana users had higher Cd levels, and that Cd levels were positively associated with increased frequency and duration of marijuana use.²⁶ Although the work of Ngueta et al. focused on the relationship between lifetime marijuana use and Cd biomarkers, our study was further able to identify differences in metal levels, including but not limited to Cd, with increasing time since last use among individuals who had recently used marijuana. Furthermore, our analysis more stringently defined exclusive marijuana use by removing underlying metal exposures from tobacco use and assessing multiple metals in addition to Cd. Because tobacco is the predominant source of Cd exposure among cigarette smokers,¹¹ we also evaluated differences in Cd levels stratified by former smoking status, a more robust indicator of past tobacco use than serum cotinine levels. We found that the relationship between exclusive marijuana use and blood Cd levels were the same regardless of former smoking behavior. However, for urinary Cd, the association between exclusive marijuana users and Cd was consistent across smoking status, but it was stronger for former smokers. These sensitivity analyses confirmed blood Cd as a robust, short-term marker of Cd exposure and urinary Cd as a strong, long-term indicator of past cigarette smoking.^46–48 As in our former smoking behavior analysis, urinary Cd was higher among individuals $>30$ years of age, whereas blood Cd was not different between age groups, likely because individuals who used marijuana were younger and thus had a lower body burden of Cd. Females who used marijuana had higher urinary Cd levels compared with males, which has been previously reported and may be explained by differences in divalent metal transporter (DMT1) expression.⁴⁹ We did not find clear differences in urinary metal levels by race and ethnicity, with the exception that participants in the “Other races” group had lower levels of metals than those who did not use marijuana. However, associations between marijuana use and blood Cd levels were somewhat stronger among non-Hispanic White participants.

Although urinary Pb levels are reported to be poorly correlated with low levels of environmental exposures,⁵⁰ we found that blood and urinary Pb levels were both consistently higher among individuals who exclusively used marijuana compared with nonusers. Pb is a heavy metal known to be detrimental to human health, particularly associated with adverse neurodevelopmental effects in children and cardiovascular disease in adults¹⁷; health organizations acknowledge that there is no safe level of Pb exposure.⁵¹ Pb is persistent in the environment,⁵² and poses potential risks from exposure. Our results indicate that marijuana use was one of these unregulated sources of exposure. Contrary to our study, a recent laboratory-based study of aerosols found no Pb in marijuana smoke.⁵ However, the authors reported that the marijuana used in their study was grown in a controlled and contaminant-regulated environment. Thus, our results suggest that not all marijuana is grown in this way and may be contaminated with metals such as Pb. Lower quality fertilizers and irrigation water or soils contaminated with Pb may also contribute to higher Pb levels in the cannabis plant. Finally, a recent study found higher concentrations of Pb in vape aerosols from tobacco/nicotine e-cigarettes, indicating that vaporization may cause metal leaching from vape devices (Ni, Cr, Pb, and zinc), supporting that method of marijuana use may be relevant to our findings.⁸ However, method of use was not collected in NHANES, and information concerning metals in cannabis vape aerosols is limited.

Total blood Hg levels were higher among participants reporting exclusive marijuana use and were lower with increasing time since last use. Total blood Hg levels were measured only in women of childbearing age (16–49 years of age) and 1- to 5-y-old children in NHANES; however, individuals $<18$ years of age were excluded from our analysis. Total blood Hg is a robust measure of short-term total Hg exposure, including inorganic and organic forms.⁵³ Diet, and in particular, fish consumption, is the primary source of organic Hg exposure in the United States.⁵⁴ Our study indicates marijuana may be a source of Hg exposure. However, recent fish consumption may be confounding these results. In our sensitivity analyses, we found that adjusting for seafood consumption did attenuate the estimates for total blood Hg in exclusive marijuana users. Although these estimates were no longer significant, the estimates were still positive.

Tobacco is a documented source of metal exposure.⁵⁵ In our study, we found that exclusive tobacco use was associated with higher levels of Sb, Ba, Cd, Pb, W, and U. As in the cannabis plant, Cd and Pb hyperaccumulate in tobacco plants.^56,57 In addition, Cd and Pb are reported to have a high transfer rate from tobacco plant to cigarette smoke (Cd: 81%–90%; Pb 46%–60%) and are found at higher levels in the lung tissue of individuals who smoke cigarettes.⁵⁸ Tobacco smoke is the main source of Cd exposure followed by consumption of food for the nonsmoking general population.⁵⁹ Tobacco smoking is estimated to increase overall Cd exposure by 15%–30%, although there are discrepancies in reported percentage differences.⁶⁰ In our study, we found that exclusive tobacco users had urinary Cd levels ($0.75\mathrm{\mu }\mathrm{g}/\mathrm{g}$) three times higher than those of exclusive marijuana users ($0.18\mathrm{\mu }\mathrm{g}/\mathrm{g}$). Dual users had similarly higher levels of urinary Cd compared with exclusive tobacco users ($0.64\mathrm{\mu }\mathrm{g}/\mathrm{g}$ and $0.75\mathrm{\mu }\mathrm{g}/\mathrm{g}$, respectively). The general population is exposed to Pb from drinking water, food, air and indoor dust.⁶¹ Unlike Cd, tobacco smoke is not the primary source of Pb. However, we found that exclusive tobacco users had 26% higher blood Pb levels than exclusive marijuana users. Dual users, however, had much higher blood Pb levels of $0.64\mathrm{\mu }\mathrm{g}/\text{dL}$, indicating that cumulative exposures may increase blood Pb levels, as previously reported with Pb from diet.^62,63 Ba has been measured in tobacco plants at high levels ($123.0\mathrm{\mu }\mathrm{g}/\mathrm{g}$), but was reported to have a lower rate of transfer to cigarette smoke.^58,64 Similar to our results, Badea et al. recently found higher levels of Sb and Sr measured in blood serum of participants recruited from Romania who smoke cigarettes.⁶⁵ W and U have been reported as harmful constituents of cigarette smoke,⁶⁶ but in an earlier study of NHANES (1999–2004), the authors did not find a significant difference in urinary W levels in participants who did and did not smoke.⁶⁷ Thus, our study of NHANES 2005–2018 provides updated evidence of metal exposures from cigarette smoking.

To the best of our knowledge, this is the largest known study on biomarkers of metal exposure in participants who exclusively use marijuana in a representative population of U.S. adults. We combined seven NHANES cycles to include 7,254 participants and evaluated 17 metal biomarkers measured in blood and urine in groups of marijuana use. Previous studies have measured metals in marijuana plants, products, or marijuana smoke; here, we used robust biomarkers of metal exposure and internal dose to explicitly quantify blood and urine metal levels among real-world marijuana users. Our study provides rationale to design cohort studies to investigate metal exposures and their health effects among marijuana users. Finally, we used a stringent definition of marijuana use to include current marijuana use and exclude any current cigarette smokers by self-report and serum cotinine to remove potential confounding by tobacco smoke exposure. Serum cotinine is a short-term marker of tobacco exposure and cannot account for long-term exposure. However, sensitivity analyses adjusted for cotinine and subgroup analysis by former smoking were robust when accounting for potential exposure misclassification from long-term tobacco use.

Limitations of the study include the cross-sectional design, small sample of exclusive marijuana users, recall bias, social desirability bias, and potential for exposure misclassification. Because of the cross-sectional design, we can only estimate associations, not causation, between metal biomarker levels and marijuana use, and thus further work is required to corroborate the findings of our study. Participants in states where marijuana use is legal may be more likely to report marijuana use more accurately than those where marijuana use is still criminalized. Similarly, participants, particularly Black and Hispanic populations, historically targeted for illicit drug use may be disinclined to report marijuana use despite decriminalization, which may explain our small sample of individuals who exclusively used marijuana. Although the landscape of marijuana use is changing rapidly, the NHANES drug use questionnaire did not include method of use, such as vape, combustibles, and edibles, and thus we were unable to determine the difference in metal concentrations by method of use. Data from cohorts such as the Population Assessment of Tobacco and Health⁶⁸ or other more contemporary cohorts designed to study cannabis use may help elucidate differences in contaminants by type of marijuana and its origin and methods of use, particularly products growing in popularity, such as cannabis vape, consumables, and use of cannabidiol (CBD) oil. The combination of analytical chemistry analysis, in vitro and in vivo experiments, and epidemiological research will ultimately be needed to adequately answer how the use of marijuana products contributes to metal exposure and the resulting health effects in the U.S. population. Our results highlight the need to design contemporary studies to examine real-world marijuana use and related exposures in the rapidly growing marijuana industry.

We found overall associations between internal metal levels and exclusive marijuana use, highlighting the relevance of marijuana for metal exposure and the importance of follow-up studies to identify the long-term implications of these exposures. Future investigations of cannabis contaminants must assess other contaminants of concern and potential health effects to inform regulatory, industry and other key stakeholders, to safeguard public health and address safety concerns related to the growing use of cannabis in the United States.