Causes of Death

"• In 2020, a total of 3,383,729 resident deaths were registered in the United States, an increase of 528,891 deaths compared with 2019 (2,854,838). The 1-year increase in the number of deaths was a record high, primarily driven by the COVID-19 pandemic.

"• The crude death rate was 1,027.0 deaths per 100,000 population. The age-adjusted death rate, which accounts for the aging of the population, was 835.4 deaths per 100,000 U.S. standard population.

"• The age-adjusted death rate for the American Indian or Alaska Native non-Hispanic population (subsequently, American Indian or Alaska Native) (1,036.2) was 1.2 times greater than for the White non-Hispanic population (subsequently, White) (834.7).

"• The age-adjusted death rate for the Black non-Hispanic population (subsequently, Black) (1,119.0) was 1.3 times greater than for the White population (834.7).

"• The age-adjusted death rate for the White population (834.7) was 1.8 times greater than for the Asian non-Hispanic population (subsequently, Asian) (457.7) and 1.2 times greater than for the Hispanic population (723.6).

"• Life expectancy at birth was 77.0 years.

"• Life expectancy in 2020 for the Hispanic population was 0.5 year higher than for the White population.

"• The 15 leading causes of death in 2020 were:

"1. Diseases of heart (heart disease)
"2. Malignant neoplasms (cancer)
"3. COVID-19
"4. Accidents (unintentional injuries)
"5. Cerebrovascular diseases (stroke)
"6. Chronic lower respiratory diseases
"7. Alzheimer disease
"8. Diabetes mellitus (diabetes) 
"9. Influenza and pneumonia
"10. Nephritis, nephrotic syndrome and nephrosis (kidney disease)
"11. Chronic liver disease and cirrhosis
"12. Intentional self-harm (suicide)
"13. Essential hypertension and hypertensive renal disease (hypertension)
"14. Parkinson disease
"15. Septicemia

"• In 2020, the infant mortality rate (IMR) was 5.42 infant deaths per 1,000 live births.

"• The 10 leading causes of infant death were:

"1. Congenital malformations, deformations and chromosomal abnormalities (congenital malformations)
"2. Disorders related to short gestation and low birth weight, not elsewhere classified (low birth weight)
"3. Sudden infant death syndrome (SIDS)
"4. Accidents (unintentional injuries)
"5. Newborn affected by maternal complications of pregnancy (maternal complications)
"6. Newborn affected by complications of placenta, cord and membranes (cord and placental complications)
"7. Bacterial sepsis of newborn
"8. Respiratory distress of newborn
"9. Diseases of the circulatory system
"10. Neonatal hemorrhage"
 

• Table: Annual Causes of Death in the US

(Editor's Note: The figures below were provisional and have been revised upward since publication. According to the CDC, using data available on August 4, 2024, in calendar year 2022 at least 109,413 people in the US were reported to have died from drug overdose and toxins in the unregulated drug supply. The CDC predicts that the final number of overdose deaths in calendar year 2022 will be 111,029. Source: Ahmad FB, Cisewski JA, Rossen LM, Sutton P. Provisional drug overdose death counts. Centers for Disease Control, National Center for Health Statistics. 2024. Last accessed August 31, 2024.)

"● In 2022, 107,941 drug overdose deaths occurred, resulting in an age-adjusted rate of 32.6 deaths per 100,000 standard population (Figure 1).

"● Overall, the age-adjusted rate of drug overdose deaths nearly quadrupled from 8.2 in 2002 to 32.6 in 2022; however, the rate did not significantly change between 2021 (32.4) and 2022 (32.6).

"● Between 2021 and 2022, the age-adjusted rate of drug overdose deaths for males increased 1.1% from 45.1 to 45.6, while the rate for females decreased 1.0% from 19.6 to 19.4, although this decrease was not significant. 
 

"Deaths involving cocaine and psychostimulants have increased in the United States in recent years; among 70,237 drug overdose deaths in 2017, nearly a third (23,139 [32.9%]) involved cocaine, psychostimulants, or both. From 2016 to 2017, death rates involving cocaine and psychostimulants each increased by approximately one third, and increases occurred across all demographic groups, Census regions, and in several states. In 2017, nearly three fourths of cocaine-involved and roughly one half of psychostimulant-involved overdose deaths, respectively, involved at least one opioid. After initially peaking in 2006, trends in overall cocaine-involved death rates declined through 2012, when they began to rise again. The 2006–2012 decrease paralleled a decline in cocaine supply coupled with an increase in cost. Similar patterns in death rates involving both cocaine and opioids were observed, with increases for cocaine- and synthetic opioid-involved deaths occurring from 2012 to 2017. From 2010 to 2017, increasing rates of deaths involving psychostimulants occurred and persisted even in the absence of opioids."

"By disaggregating monthly trends, we found that unprecedented increases in overdose mortality occurred during the early months of pandemic in the United States. At the peak, overdose deaths in May 2020 were elevated by nearly 60% compared with the previous year, and the first 7 months of 2020 were overall elevated by 35% compared with the same period for 2019. To put this in perspective, if the final values through December 2020 were to be elevated by a similar margin, we would expect a total of 93,000 to 98,000 deaths to eventually be recorded for the year. Values for the remaining 5 months of 2020 have yet to be seen; however, it is very likely that 2020 will represent the largest year-to-year increase in overdose mortality in recent history for the United States."

"The age-adjusted rate for drug overdose deaths in the United States for 2019 was 21.6 per 100,000 standard population (Figure 1, Table). The five states with the highest rates were West Virginia (52.8), Delaware (48.0), District of Columbia (43.2), Ohio (38.3), and Maryland (38.2). The five states with the lowest rates were Nebraska (8.7), South Dakota (10.5), Texas (10.8), North Dakota (11.4), and Iowa (11.5).

"The age-adjusted drug overdose death rate for the non-Hispanic white population in 2019 (26.2 per 100,000 standard population) was 21.3% higher than the national rate (Figure 2). The rate for the non-Hispanic black population (24.8) was 14.8% higher than the national rate. The rate for the non-Hispanic American Indian or Alaska Native population (30.5) was 41.2% higher than the national rate. The rate for the non-Hispanic Asian population (3.3) was 84.7% lower than the national rate. The rate for the non-Hispanic Native Hawaiian or Other Pacific Islander population (9.5) was 56.0% lower than the national rate. The rate for the Hispanic population (12.7) was 41.2% lower than the national rate."

"● In 2018, there were 67,367 drug overdose deaths in the United States, a 4.1% decline from 2017 (70,237 deaths).

"● The age-adjusted rate of drug overdose deaths in 2018 (20.7 per 100,000) was 4.6% lower than in 2017 (21.7).

"● For 14 states and the District of Columbia, the drug overdose death rate was lower in 2018 than in 2017.

"● The rate of drug overdose deaths involving synthetic opioids other than methadone (drugs such as fentanyl, fentanyl analogs, and tramadol) increased by 10%, from 9.0 in 2017 to 9.9 in 2018.

"● From 2012 through 2018, the rate of drug overdose deaths involving cocaine more than tripled (from 1.4 to 4.5) and the rate for deaths involving psychostimulants with abuse potential (drugs such as methamphetamine) increased nearly 5-fold (from 0.8 to 3.9)."

"• In 2017, there were 70,237 drug overdose deaths in the United States.

"• The age-adjusted rate of drug overdose deaths in 2017 (21.7 per 100,000) was 9.6% higher than the rate in 2016 (19.8).

"• Adults aged 25–34, 35–44, and 45–54 had higher rates of drug overdose deaths in 2017 than those aged 15–24, 55–64, and 65 and over.

"• West Virginia (57.8 per 100,000), Ohio (46.3), Pennsylvania (44.3), and the District of Columbia (44.0) had the highest age-adjusted drug overdose death rates in 2017.

"• The age-adjusted rate of drug overdose deaths involving synthetic opioids other than methadone (drugs such as fentanyl, fentanyl analogs, and tramadol) increased by 45% between 2016 and 2017, from 6.2 to 9.0 per 100,000."

"• In 2018, there were 14,666 drug overdose deaths involving cocaine in the United States for an age-adjusted rate of 4.5 per 100,000 standard population (Figure 1)."

"• The age-adjusted rate of drug overdose deaths involving cocaine remained stable from 2009 through 2013 ranging from 1.3 to 1.6 per 100,000, then increased on average by 27% per year from 2013 through 2018.

"• For males, the rate increased from 2.1 in 2009 to 6.4 in 2018. For females, the rate increased from 0.7 in 2009 to 2.6 in 2018. For each year, rates were 2.4 to 3.0 times higher for males than females."

"• Throughout the study period, the rates of drug overdose deaths involving cocaine were highest for the non-Hispanic black population, followed by non-Hispanic white and the Hispanic population (Figure 3).

"• In 2018, the rate of drug overdose deaths involving cocaine in the non-Hispanic black population (9.0 per 100,000) was nearly twice that of the non-Hispanic white population (4.6) and three times that of the Hispanic population (3.0).

"• In general, for each group, the rate remained stable from 2009 through 2013–2014, then increased in subsequent years. The rate for the non-Hispanic white population was the same in 2017 and 2018 (4.6)."

"Among the 42,249 opioid-related overdose deaths in 2016, 19,413 involved synthetic opioids, 17,087 involved prescription opioids, and 15,469 involved heroin. Synthetic opioid involvement in these deaths increased significantly from 3007 (14.3% of opioid-related deaths) in 2010 to 19,413 (45.9%) in 2016 (P for trend <.01). Significant increases in synthetic opioid involvement in overdose deaths involving prescription opioids, heroin, and all other illicit or psychotherapeutic drugs were found from 2010 through 2016 (Table).

"Among synthetic opioid–related overdose deaths in 2016, 79.7% involved another drug or alcohol. The most common co-involved substances were another opioid (47.9%), heroin (29.8%), cocaine (21.6%), prescription opioids (20.9%), benzodiazepines (17.0%), alcohol (11.1%), psychostimulants (5.4%), and antidepressants (5.2%) (Figure)."

"Findings

"The percent of US overdose deaths involving both fentanyl and stimulants increased from 0.6% (n = 235) in 2010 to 32.3% (34 429) in 2021, with the sharpest rise starting in 2015. In 2010, fentanyl was most commonly found alongside prescription opioids, benzodiazepines, and alcohol. In the Northeast this shifted to heroin-fentanyl co-involvement in the mid-2010s, and nearly universally to cocaine-fentanyl co-involvement by 2021. Universally in the West, and in the majority of states in the South and Midwest, methamphetamine-fentanyl co-involvement predominated by 2021. The proportion of stimulant involvement in fentanyl-involved overdose deaths rose in virtually every state 2015–2021. Intersectional group analysis reveals particularly high rates for older Black and African American individuals living in the West.

"Conclusions

"By 2021 stimulants were the most common drug class found in fentanyl-involved overdoses in every state in the US. The rise of deaths involving cocaine and methamphetamine must be understood in the context of a drug market dominated by illicit fentanyls, which have made polysubstance use more sought-after and commonplace. The widespread concurrent use of fentanyl and stimulants, as well as other polysubstance formulations, presents novel health risks and public health challenges."

"In 2019, 70,630 deaths from the toxic effects of drug poisoning (drug overdose) occurred in the United States (1), a 4.8% increase compared with 2018 and the highest recorded number in recent history."

"● The age-adjusted rate of drug overdose deaths involving cocaine increased slightly from 1.6 deaths per 100,000 standard population in 2002 to 2.5 in 2006, decreased to 1.3 in 2010, then increased to 8.2 in 2022; the rate in 2022 was 12.3% higher than the rate in 2021 (7.3) (Figure 5).

"● The age-adjusted rate of drug overdose deaths involving psychostimulants with abuse potential (subsequently, psychostimulants), which includes methamphetamine, amphetamine, and methylphenidate, was 4.0% higher in 2022 than the rate in 2021 (10.4 compared with 10.0).

"● The age-adjusted rate of drug overdose deaths involving psychostimulants increased more than 34 times from 2002 (0.3) to 2022 (10.4), with different rates of change over time."
 

"Preliminary estimates of U.S. drug overdose deaths exceeded 60,000 in 2016 and were partially driven by a fivefold increase in overdose deaths involving synthetic opioids (excluding methadone), from 3,105 in 2013 to approximately 20,000 in 2016 (1,2). Illicitly manufactured fentanyl, a synthetic opioid 50–100 times more potent than morphine, is primarily responsible for this rapid increase (3,4). In addition, fentanyl analogs such as acetylfentanyl, furanylfentanyl, and carfentanil are being detected increasingly in overdose deaths (5,6) and the illicit opioid drug supply (7). Carfentanil is estimated to be 10,000 times more potent than morphine (8). Estimates of the potency of acetylfentanyl and furanylfentanyl vary but suggest that they are less potent than fentanyl (9). Estimates of relative potency have some uncertainty because illicit fentanyl analog potency has not been evaluated in humans."

"From January–June 2020 to July–December 2022, the number of overdose deaths with evidence of smoking doubled, and the percentage of deaths with evidence of smoking increased across all geographic regions. By late 2022, smoking was the predominant route of use among drug overdose deaths overall and in the Midwest and West regions. Increases were most pronounced when IMFs were detected, with or without stimulants. Increases in the number and percentage of deaths with evidence of smoking, and the corresponding decrease in those with evidence of injection, might be partially driven by 1) the transition from injecting heroin to smoking IMFs [Illicitly Manufactured Fentanyl] (3,4), 2) increases in deaths co-involving IMFs and stimulants that might be smoked†††† (1), and 3) increases in the use of counterfeit pills, which frequently contain IMFs and are often smoked (7). Motivations for transitioning from injection to smoking include fewer adverse health effects (e.g., fewer abscesses), reduced cost and stigma, sense of more control over drug quantity consumed per use (e.g., smoking small amounts during a period versus a single injection bolus), and a perception of reduced overdose risk among persons who use drugs (3,5,8). These motivations might also signify lower barriers for initiating drug use by smoking, or for transitioning from ingestion to smoking; compared with ingestion, smoking can intensify drug effects and increase overdose risk (9). Despite some risk reduction associated with smoking compared with injection (e.g., fewer bloodborne infections), smoking carries substantial overdose risk because of rapid drug absorption (5,9).

"Nearly 80% of overdose deaths with evidence of smoking had no evidence of injection; persons who use drugs by smoking but do not inject drugs might not use traditional syringe services programs where harm reduction messaging and supplies are often provided. In response, some jurisdictions have adapted harm reduction services to provide safer smoking supplies or established health hubs to expand reach to persons using drugs through noninjection routes.§§§§ In addition, harm reduction services (e.g., peer outreach and provision of fentanyl test strips for testing drug products and naloxone to reverse opioid overdoses), messaging specific to smoking drugs, and linkage to treatment for substance use disorders can be integrated into other health care delivery (e.g., emergency departments) and public safety (e.g., drug diversion) settings.

"The percentage and number of deaths with evidence of injection decreased across regions and drug categories. Observed decreases might reflect transitions to noninjection routes and response to public health efforts to reduce injection drug use because of its risk for overdose and infectious disease transmission (3,4,10). Despite these declines, more than 4,000 drug overdose deaths had evidence of injection during July–December 2022. Syringe services programs help to engage persons who use drugs in services (10); sustained efforts to provide sterile injection supplies, additional harm reduction tools, and linkage to treatment for substance use disorders, including medications for opioid use disorder, are important for further reduction in the number of overdose deaths from injection drug use. Lessons learned from implementing syringe services programs could be applied to other harm reduction and outreach models to reach more persons who use drugs by any route."

"During 2018, drug overdoses resulted in 67,367 deaths in the United States, a 4.1% decrease from 2017. Among these drug overdose deaths, 46,802 (69.5%) involved an opioid. From 2017 to 2018, opioid-involved death rates decreased 2.0%, from 14.9 per 100,000 population to 14.6 (Table 1); decreases occurred among females; persons aged 15–34 years and 45–54 years; non-Hispanic whites; and in small metro, micropolitan, and noncore areas; and in the Midwest and South regions. Rates during 2017–2018 increased among persons aged ≥65 years, non-Hispanic blacks, and Hispanics, and in the Northeast and the West regions. Rates decreased in 11 states and DC and increased in three states, with the largest relative (percentage) decrease in Iowa (–30.4%) and the largest absolute decrease (difference in rates) in Ohio (–9.6); the largest relative and absolute increase occurred in Missouri (18.8%, 3.1). The highest opioid-involved death rate in 2018 was in West Virginia (42.4 per 100,000).

"Prescription opioid-involved death rates decreased by 13.5% from 2017 to 2018. Rates decreased in males and females, persons aged 15–64 years, non-Hispanic whites, Hispanics, non-Hispanic American Indian/Alaska Natives, and across all urbanization levels. Prescription opioid–involved death rates remained stable in the Northeast and decreased in the Midwest, South, and the West. Seventeen states experienced declines in prescription opioid–involved death rates, with no states experiencing significant increases. The largest relative decrease occurred in Ohio (–40.5%), whereas the largest absolute decrease occurred in West Virginia (–4.1), which also had the highest prescription opioid-involved death rate in 2018 (13.1 per 100,000).

"Heroin-involved death rates decreased 4.1% from 2017 to 2018; reductions occurred among males and females, persons aged 15–34 years, non-Hispanic whites, and in large central metro and large fringe metro areas (Table 2). Rates decreased in the Midwest and increased in the West. Rates decreased in seven states and DC and increased in three states from 2017 to 2018. The largest relative decrease occurred in Kentucky (50.0%), and the largest absolute decrease occurred in DC (–7.1); the largest relative and absolute increase was in Tennessee (18.8%, 0.9). The highest heroin-involved death rate in 2018 was in Vermont (12.5 per 100,000).

"Death rates involving synthetic opioids increased from 9.0 per 100,000 population in 2017 to 9.9 in 2018 and accounted for 67.0% of opioid-involved deaths in 2018. These rates increased from 2017 to 2018 among males and females, persons aged ≥25 years, non-Hispanic whites, non-Hispanic blacks, Hispanics, non-Hispanic Asian/Pacific Islanders, and in large central metro, large fringe metro, medium metro, and small metro counties. Synthetic opioid–involved death rates increased in the Northeast, South and West and remained stable in the Midwest. Rates increased in 10 states and decreased in two states. The largest relative increase occurred in Arizona (92.5%), and the largest absolute increase occurred in Maryland and Missouri (4.4 per 100,000 in both states); the largest relative and absolute decrease was in Ohio (–20.7%, –6.7). The highest synthetic opioid–involved death rate in 2018 occurred in West Virginia (34.0 per 100,000)."

"Of the 70,237 drug overdose deaths in the United States in 2017, approximately two thirds (47,600) involved an opioid (1). In recent years, increases in opioid-involved overdose deaths have been driven primarily by deaths involving synthetic opioids other than methadone (hereafter referred to as synthetic opioids) (1). CDC analyzed changes in age-adjusted death rates from 2017 to 2018 involving all opioids and opioid subcategories* by demographic characteristics, county urbanization levels, U.S. Census region, and state. During 2018, a total of 67,367 drug overdose deaths occurred in the United States, a 4.1% decline from 2017; 46,802 (69.5%) involved an opioid (2). From 2017 to 2018, deaths involving all opioids, prescription opioids, and heroin decreased 2%, 13.5%, and 4.1%, respectively. However, deaths involving synthetic opioids increased 10%, likely driven by illicitly manufactured fentanyl (IMF), including fentanyl analogs (1,3)."

"The percentage of deaths with concomitant involvement of other drugs varied by drug. For example, almost all drug overdose deaths involving alprazolam or diazepam (96%) mentioned involvement of other drugs. In contrast, 50% of the drug overdose deaths involving methamphetamine, and 69% of the drug overdose deaths involving fentanyl mentioned involvement of one or more other specific drugs.

"Table D shows the most frequent concomitant drug mentions for each of the top 10 drugs involved in drug overdose deaths in 2016.

"• Two in five overdose deaths involving cocaine also mentioned fentanyl.

"• Nearly one-third of drug overdose deaths involving fentanyl also mentioned heroin (32%).

"• Alprazolam was mentioned in 26% of the overdose deaths involving hydrocodone, 22% of the deaths involving methadone, and 25% of the deaths involving oxycodone.

"• More than one-third of the overdose deaths involving cocaine also mentioned heroin (34%).

"• More than 20% of the overdose deaths involving methamphetamine also mentioned heroin."

"The number of drug overdose deaths per year increased 54%, from 41,340 deaths in 2011 to 63,632 deaths in 2016 (Table A). From the literal text analysis, the percentage of drug overdose deaths mentioning at least one specific drug or substance increased from 73% of the deaths in 2011 to 85% of the deaths in 2016. The percentage of drug overdose deaths that mentioned only a drug class but not a specific drug or substance declined from 5.1% of deaths in 2011 to 2.5% in 2016. Review of the literal text for these deaths indicated that the deaths that mentioned only a drug class frequently involved either an opioid or an opiate (ranging from 54% in 2015 to 60% in 2016). The percentage of deaths that did not mention a specific drug or substance or a drug class declined from 22% of drug overdose deaths in 2011 to 13% in 2016."

"For the top 15 drugs:

"• Among drug overdose deaths that mentioned at least one specific drug, oxycodone ranked first in 2011,heroin from 2012 through 2015, and fentanyl in 2016.

"• In 2011 and 2012, fentanyl was mentioned in approximately 1,600 drug overdose deaths each year, but mentions increased in 2013 (1,919 deaths),2014 (4,223 deaths), 2015 (8,251 deaths), and 2016(18,335 deaths). In 2016, 29% of all drug overdose deaths mentioned involvement of fentanyl.

"• The number of drug overdose deaths involving heroin increased threefold, from 4,571 deaths or 11% of all drug overdose deaths in 2011 to 15,961 deaths or 25% of all drug overdose deaths in 2016.

"• Throughout the study period, cocaine ranked second or third among the top 15 drugs. From 2014 through 2016, the number of drug overdose deaths involving cocaine nearly doubled from 5,892 to 11,316.

"• The number of drug overdose deaths involving methamphetamine increased 3.6-fold, from 1,887 deaths in 2011 to 6,762 deaths in 2016.

"• The number of drug overdose deaths involving methadone decreased from 4,545 deaths in 2011 to 3,493 deaths in 2016."

"In fully adjusted, prespecified models that accounted for effects of sampling, between-study variation, and potential confounding from former drinker bias and other study-level covariates, our meta-analysis of 107 studies found (1) no significant protective associations of occasional or low-volume drinking (moderate drinking) with all-cause mortality; and (2) an increased risk of all-cause mortality for drinkers who drank 25 g or more and a significantly increased risk when drinking 45 g or more per day.

"Several meta-analytic strategies were used to explore the role of abstainer reference group biases caused by drinker misclassification errors and also the potential confounding effects of other study-level quality covariates in studies.2 Drinker misclassification errors were common. Of 107 studies identified, 86 included former drinkers and/or occasional drinkers in the abstainer reference group, and only 21 were free of both these abstainer biases. The importance of controlling for former drinker bias/misclassification is highlighted once more in our results which are consistent with prior studies showing that former drinkers have significantly elevated mortality risks compared with lifetime abstainers.

"In addition to presenting our fully adjusted models, a strength of the study was the examination of the differences in relative risks according to unadjusted and partially adjusted models, including the effect of removing individual covariates from the fully adjusted model. We found evidence that abstainer biases and other study characteristics changed the shape of the risk relationship between mortality and rising alcohol consumption, and that most study-level controls increased the observed risks from alcohol, or attenuated protective associations at low levels of consumption such that they were no longer significant. The reduced RR estimates for occasional or moderate drinkers observed without adjustment may be due to the misclassification of former and occasional drinkers into the reference group, a possibility which is more likely to have occurred in studies of older cohorts which use current abstainers as the reference group. This study also demonstrates the degree to which observed associations between consumption and mortality are highly dependent on the modeling strategy used and the degree to which efforts are made to minimize confounding and other threats to validity.

"It also examined risk estimates when using occasional drinkers rather than lifetime abstainers as the reference group. The occasional drinker reference group avoids the issue of former drinker misclassification that can affect the abstainer reference group, and may reduce confounding to the extent that occasional drinkers are more like low-volume drinkers than are lifetime abstainers.2,8,132 In the unadjusted and partially adjusted analyses, using occasional drinkers as the reference group resulted in nonsignificant protective associations and lower point estimates for low-volume drinkers compared with significant protective associations and higher point estimates when using lifetime nondrinkers as the reference group. In the fully adjusted models, there were nonsignificant protective associations for low-volume drinkers whether using lifetime abstainers or occasional drinkers as the reference group, though this was only a RR of 0.97 for the latter.

"Across all studies, there were few differences in risk for studies when stratified by median age of enrollment above or below age 56 years in the fully adjusted analyses. However, in the subset of studies who enrolled participants aged 50 years or younger who were followed for at least 10 years, occasional drinkers and medium-volume drinkers had significantly increased risk of mortality and substantially higher risk estimates for high- and higher-volume consumption compared with results from all studies. This is consistent with our previous meta-analysis for CHD,9 in which younger cohorts followed up to older age did not show a significantly beneficial association of low-volume consumption, while older cohorts, with more opportunity for lifetime selection bias, showed marked, significant protective associations.

"Our study also found sex differences in the risk of all-cause mortality. A larger risk of all-cause mortality for women than men was observed when drinking 25 or more grams per day, including a significant increase in risk for medium-level consumption for women that was not observed for men. However, mortality risk for mean consumption up to 25 g per day were very similar for both sexes."

"From 2016–2017 to 2020–2021, the average annual number of U.S. deaths from excessive alcohol use increased by more than 40,000 (29%), from approximately 138,000 per year (2016–2017) to 178,000 per year (2020–2021). This increase translates to an average of approximately 488 deaths each day from excessive drinking during 2020–2021. From 2016–2017 to 2020–2021, the average annual number of deaths from excessive alcohol use increased by more than 25,000 among males and more than 15,000 among females; however, the percentage increase in the number of deaths during this time was larger for females (approximately 35% increase) than for males (approximately 27%). These findings are consistent with another recent study that found a larger increase in fully alcohol-attributable death rates among females compared with males (8).

"Increases in deaths from excessive alcohol use during the study period occurred among all age groups. A recent study found that one in eight total deaths among U.S. adults aged 20–64 years during 2015–2019 resulted from excessive alcohol use (9). Because of the increases in these deaths during 2020–2021, including among adults in the same age group, excessive alcohol use could account for an even higher proportion of total deaths during that 2-year period. In addition, data from Monitoring the Future, an ongoing study of the behaviors, attitudes, and values of U.S. residents from adolescence through adulthood, showed that the prevalence of binge drinking among adults aged 35–50 years was higher in 2022 than in any other year during the past decade§§§; this increase could contribute to future increases in alcohol-attributable deaths. In this study, fewer than one third of deaths from excessive alcohol use were from fully alcohol-attributable causes, highlighting the importance of also assessing partially alcohol-attributable causes to better understand the harms from excessive drinking, including binge drinking.

"The nearly 23% increase in the deaths from excessive alcohol use that occurred from 2018–2019 to 2020–2021 was approximately four times as high as the previous 5% increase that occurred from 2016–2017 to 2018–2019. Increases in the availability of alcohol in many states might have contributed to this disproportionate increase (10). During the peak of the COVID-19 pandemic in 2020–2021, policies were widely implemented to expand alcohol carryout and delivery to homes, and places that sold alcohol for off-premise consumption (e.g., liquor stores) were deemed as essential businesses in many states (and remained open during lockdowns).¶¶¶ General delays in seeking medical attention, including avoidance of emergency departments**** for alcohol-related conditions††††; stress, loneliness, and social isolation; and mental health conditions might also have contributed to the increase in deaths from excessive alcohol use during the COVID-19 pandemic."

"Of the 1,220,143 deaths with involved drugs listed on the death certificate, 130 560 (10.7% of all decedents) were found to have stimulants listed. Among stimulant-involved deaths, 93,689 decedents (71.8%) were men, the median (interquartile range) age was 45 (34-54) years, and 98,635 (75.5%) were White (Table). Of these, 120,803 certificates (92.5%) listed only illicit stimulants, 5544 (4.2%) listed only medical stimulants, and 3524 listed both types (2.7%). Among illicit stimulants, there were 77,013 deaths (61.9%) involving cocaine, 49,602 deaths (39.9%) involving methamphetamine, and 817 deaths (0.7%) involving 3,4-methylenedioxymethamphetamine. Among medical stimulants, there were 8240 deaths (90.9%) involving amphetamine, 295 deaths (0.3%) involving methylphenidate, and 615 deaths (0.7%) involving pseudoephedrine. Among all 3 stimulant groups, the proportion of deaths that also involved opioids was substantial; concomittant use of benzodiazepines and antidepressants was also not uncommon.

"Stimulant mortality has risen rapidly since 2010 (Figure). The mortality rate involving all stimulants rose from 2.913 deaths per 100,000 population in 2010 to 9.690 in 2017. Mortality rates increased among all medical stimulants (ARR, 1.226; 95% CI, 1.202-1.250), amphetamine (ARR, 1.118; 95% CI, 1.082-1.155), cocaine (ARR, 1.234;95% CI, 1.222-1.245), and methamphetamine (ARR, 1.278; 95% CI, 1.261-1.295)."

"The estimates presented in this article find important evidence of the potential consequences of the rapid expansion of the MA supply in Ohio, which can help inform the public health consequences of a similar expansion across the US. We find that relatively more MA detected by crime labs is either unrelated to or associated with a small, but measurable decrease in the overall risk of unintentional overdose death. This is not to say that MA is safe or cannot cause overdose deaths. Our findings are not that the combination of MA and fentanyl is in fact safer than fentanyl on its own. As our estimates are only showing averages, it could certainly be the case that an increase in MA availability makes illicit drug consumption more deadly for some people or at particular dose levels. Rather, given the context of extremely dangerous synthetic opioids, our estimates should be interpreted as showing that a relative increase in the availability of less deadly drugs, especially if they are replacing synthetic opioids, may reduce the overall number of overdose deaths, at least in the short-run. Furthermore, we do not investigate the substantial, non-fatal health consequences of MA use such as psychosis and cardiovascular disease, which may be increasing even if deaths decline.

"The exact mechanism linking MA to overdose deaths is not clear. Is it that MA use directly reduces the risk of overdose when used concurrently with opioids? If the animal data are applicable to humans, is MA co–use with fentanyl reducing opioid overdose risk at some doses and increasing it at others? Is it that MA use allows people to lengthen the duration between opioid use or substitute away from opioids entirely? This is supported by recent research showing that some people find MA helpful for managing opioid withdrawal (Ondocsin et al., 2023). Or is MA supply simply correlated with a reduction in overdose death, and we are missing a key unobservable omitted variable, such as greater migration to substance use treatment, that is positively correlated with MA supply?"

• "After annual increases of 7% or less between 2000 and 2018, the overall age-adjusted rate of alcohol-induced deaths increased 26%, from 10.4 per 100,000 in 2019 to 13.1 in 2020 (Figure 1).
   
• "Rates of alcohol-induced deaths for males were stable from 2000 to 2009, increased 30% from 2009 (11.3) to 2018 (14.7), and increased 26% from 2019 (15.2) to 2020 (19.2).
   
• "Rates of alcohol-induced deaths for females increased over the entire period, with the largest annual increase (27%) occurring between 2019 (5.9) and 2020 (7.5).
   
• "Differences in rates between males and females decreased over the study period, from 3.6 times higher for males than females in 2000 (11.4 and 3.2, respectively), to 2.6 times higher in 2020 (19.2 and 7.5, respectively)."

"• Age-adjusted rates of alcohol-induced deaths among all persons aged 25 and over were stable from 2000 to 2006 at about 10.7 per 100,000, then increased 43% to 15.3 in 2018 (Figure 1).

"• For males aged 25 and over, rates were stable from 2000 to 2005, then increased 34% from 2005 through 2018, from 16.9 to 22.6.

"• For females aged 25 and over, rates increased 76% from 2000 through 2018, from 4.9 to 8.6.

"• For each year, rates of alcohol-induced deaths for males aged 25 and over were higher than for females."

"In 2014, alcohols, including ethanol and isopropyl alcohol, were involved in 15% of all drug overdose deaths and 17% of the drug overdose deaths that mentioned involvement of at least one specific drug. Table E shows the frequency of alcohol involvement among drug overdose deaths involving specific drugs.

"• Alcohol involvement was mentioned in 12%–22% of the drug overdose deaths involving fentanyl, heroin, hydrocodone, morphine, oxycodone, alprazolam, diazepam, or cocaine.

"• Alcohol involvement was mentioned in less than 10% of the drug overdose deaths involving methadone and methamphetamine."

• "In 2019 and 2020, alcoholic liver disease was the most frequent cause of alcohol-induced death, followed by mental and behavioral disorders due to use of alcohol (Figure 5).
   
• "From 2019 to 2020, the largest increases in rates were from alcohol-induced acute pancreatitis (50%), from 0.1 per 100,000 to 0.2, followed by mental and behavioral disorders due to use of alcohol (33%), from 3.0 to 4.0.
   
• "Deaths from alcoholic liver disease increased 23%, from 6.4 in 2019 to 7.9 in 2020, and deaths from accidental poisoning of alcohol increased 14%, from 0.7 in 2019 to 0.8 in 2020.
   
• "No change was seen in rates of death from alcoholic cardiomyopathy or from other alcohol-induced causes of death from 2019 to 2020."

"The 2014 Surgeon General's report estimates that cigarette smoking causes more than 480,000 deaths each year in the United States.¹ This widely cited estimate of the mortality burden of smoking may be an underestimate, because it considers deaths only from the 21 diseases that have been formally established as caused by smoking (12 types of cancer, 6 categories of cardiovascular disease, diabetes, chronic obstructive pulmonary disease [COPD], and pneumonia including influenza). Associations between smoking and the 30 most common causes of death in the United Kingdom in the Million Women Study suggest that the excess mortality observed among current smokers cannot be fully explained by these 21 diseases.²

"Our results suggest that the Surgeon General's recent estimate of smoking-attributable mortality may have been an underestimate. The Surgeon General's estimate, which took into account only the 21 diseases formally established as caused by smoking, was that approximately 437,000 deaths among adults are caused each year by active smoking (not including secondhand smoke). However, the Surgeon General’s report presents an alternative estimate of 556,000 deaths among adults on the basis of the excess mortality from all causes. The difference between these two estimates is nearly 120,000 deaths.¹ If, as suggested by the results in our cohort, at least half of this difference is due to associations of smoking with diseases that are causal but are not yet formally established as such, then at least 60,000 additional deaths each year among U.S. men and women may be caused by cigarette smoking."

"From 2006 through 2010, excessive alcohol consumption accounted for nearly 1 in 10 deaths and over 1 in 10 years of potential life lost among working-age adults in the United States. Furthermore, an average of 2 out of 3 AAD and 8 out of 10 alcohol-attributable YPLL involved working-age adults. Although AAD rates varied by state, the national annual average AAD rate of 27.9 deaths per 100,000 population was higher than the average annual death rate for 10 of the 15 leading causes of deaths from 2006 through 2010 (12). The majority of the average annual AAD involved males (71%); over half of AAD and two-thirds of YPLL resulted from acute causes of death, all of which were by definition attributable to binge drinking. About 5% of all average annual AAD and 10% of average annual YPLL involved those under age 21 years, most of which were due to acute conditions."

"In 2011, 5,188 opioid-analgesic poisoning deaths also involved benzodiazepines (sedatives used to treat anxiety, insomnia, and seizures), up from 527 such deaths in 1999 (Figure 3). From 2006 through 2011, the number of opioid-analgesic poisoning deaths involving benzodiazepines increased 14% on average each year, while the number of opioid-analgesic poisoning deaths not involving benzodiazepines did not change significantly."

"Opioids were frequently implicated in overdose deaths involving other pharmaceuticals. They were involved in the majority of deaths involving benzodiazepines (77.2%), antiepileptic and antiparkinsonism drugs (65.5%), antipsychotic and neuroleptic drugs (58.0%), antidepressants (57.6%), other analgesics, antipyretics, and antirheumatics (56.5%), and other psychotropic drugs (54.2%). Among overdose deaths due to psychotherapeutic and central nervous system pharmaceuticals, the proportion involving only a single class of such drugs was highest for opioids (4903/16 651; 29.4%) and lowest for benzodiazepines (239/6497; 3.7%)."

"Of the estimated 585,000 deaths attributed to drug use in 2017, half are attributed to liver cancer, cirrhosis and other chronic liver diseases related to hepatitis C, which remains mostly untreated among PWID. Deaths attributed to drug use disorders (167,000) account for 28 per cent of all deaths resulting from drug use; 110,000 or 66 per cent of those deaths are attributable to opioids. Over the past decade, the total number of deaths attributed to drug use has increased by a quarter, with a major increase in deaths caused by opioid use disorders (71 per cent increase), followed by cirrhosis and other chronic liver diseases (55 per cent increase) and liver cancer (46 per cent) resulting from hepatitis C.

"The comparison of deaths attributed to drug use among men and women over the past decade shows that the number of deaths attributed to drug use disorders, in particular opioid use disorders, has increased disproportionately among women, with a 92 per cent increase in deaths attributed to opioid use disorders among women compared with a 63 per cent increase among men."

"Over the 15-year study period, 335,123 opioid-related deaths in the United States met our inclusion criteria, with an increase of 345% from 9489 in 2001 (33.3 deaths per million population) to 42,245 in 2016 (130.7 deaths per million population). By 2016, men accounted for 67.5% of all opioid-related deaths (n = 28,496), and the median (interquartile range) age at death was 40 (30-52) years. The proportion of deaths attributable to opioids increased over the study period, rising 292% (from 0.4% [1 in 255] to 1.5% [1 in 65]), and increased steadily over time in each age group studied (P < .001 for all age groups) (Figure). The largest absolute increase between 2001 and 2016 was observed among those aged 25 to 34 years (15.8% increase from 4.2% in 2001 to 20.0% in 2016), followed by those aged 15 to 24 years (9.4% increase from 2.9% to 12.4%). However, the largest relative increases occurred among adults aged 55 to 64 years (754% increase from 0.2% to 1.7%) and those aged 65 years and older (635% increase from 0.01% to 0.07%). Despite the fact that confirmed opioid-related deaths represent a small percentage of all deaths in these older age groups, the absolute number of deaths is moderate. In 2016, 18.4% (7762 of 42,245) of all opioid-related deaths in the United States occurred among those aged 55 years and older.

"In our analysis of the burden of early loss of life from opioid overdose, we found that opioid-related deaths were responsible for 1,681,359 YLL [Years of Life Lost] (5.2 YLL per 1000 population) in the United States in 2016 (Table); however, this varied by age and sex. In particular, when stratified by age, adults aged 25 to 34 years and those aged 35 to 44 years experienced the highest burden from opioid-related deaths (12.9 YLL per 1000 population and 9.9 YLL per 1000 population, respectively). We also found that the burden of opioid-related death was higher among men (1,125,711 YLL; 7.0 YLL per 1000 population) compared with women (555,648 YLL; 3.4 YLL per 1000 population). Importantly, among men aged 25 to 34 years, this rate increased to 18.1 YLL per 1000 population, and the total YLL in this population represented nearly one-quarter of all YLL in the United States in 2016 (411,805 of 1,681,359 [24.5%])."

"This analysis confirms the predominant role opioid analgesics play in pharmaceutical overdose deaths, either alone or in combination with other drugs. It also, however, highlights the frequent involvement of drugs typically prescribed for mental health conditions such as benzodiazepines, antidepressants, and antipsychotics in overdose deaths. People with mental health disorders are at increased risk for heavy therapeutic use, nonmedical use, and overdose of opioids.^4-6 Screening, identification, and appropriate management of such disorders is an important part of both behavioral health and chronic pain management."

The White House Council of Economic Advisers [CEA] released its analysis of the economic costs of illegal opioid use, related overdoses, and overdose mortality in November 2017. It reported a dramatically higher estimate than previous analyses, largely due to a change in methodology. Previous analyses had used a person's estimated lifetime earnings to place a dollar value on that person's life. According to the CEA, "We diverge from the previous literature by quantifying the costs of opioid-related overdose deaths based on economic valuations of fatality risk reduction, the “value of a statistical life” (VSL)."

The CEA noted that "According to a recent white paper prepared by the U.S. Environmental Protection Agency’s (EPA) Office of Policy for review by the EPA’s Science Advisory Board (U.S. EPA 2016), the EPA’s current guidance calls for using a VSL estimate of $10.1 million (in 2015 dollars), updated from earlier estimates based on inflation, income growth, and assumed income elasticities. Guidance from the U.S. Department of Health and Human Services (HHS) suggests using the range of estimates from Robinson and Hammitt (2016) referenced earlier, ranging from a low of $4.4 million to a high of $14.3 million with a central value of $9.4 million (in 2015 dollars). The central estimates used by these three agencies, DOT, EPA, and HHS, range from a low of $9.4 million (HHS) to a high of $10.1 million (EPA) (in 2015 dollars)."

In addition, the CEA assumed that the number of opioid-related overdoses in the US in 2015 was significantly under-reported. According to its report, "However, recent research has found that opioids are underreported on death certificates. Ruhm (2017) estimates that in 2014, opioid-involved overdose deaths were 24 percent higher than officially reported.⁴ We apply this adjustment to the 2015 data, resulting in an estimated 41,033 overdose deaths involving opioids. We apply this adjustment uniformly over the age distribution of fatalities."

The combination of that assumption with the methodology change resulted in a dramatically higher cost estimate than previous research had shows. According to the CEA, "CEA’s preferred cost estimate of $504.0 billion far exceeds estimates published elsewhere. Table 3 shows the cost estimates from several past studies of the cost of the opioid crisis, along with the ratio of the CEA estimate to each study’s estimate in 2015 dollars. Compared to the recent Florence et al. (2016) study—which estimated the cost of prescription opioid abuse in 2013—CEA’s preferred estimate is more than six times higher, reported in the table’s last column as the ratio of $504.0 billion to $79.9 billion, which is Florence et al.’s estimate adjusted to 2015 dollars. Even CEA’s low total cost estimate of $293.9 billion is 3.7 times higher than Florence et al.’s estimate."

In contrast, the CEA noted that "Among the most recent (and largest) estimates was that produced by Florence et al. (2016), who estimated that prescription opioid overdose, abuse, and dependence in the United States in 2013 cost $78.5 billion. The authors found that 73 percent of this cost was attributed to nonfatal consequences, including healthcare spending, criminal justice costs and lost productivity due to addiction and incarceration. The remaining 27 percent was attributed to fatality costs consisting almost entirely of lost potential earnings." According to the CDC, there were 25,840 deaths in 2013 related to an opioid overdose.

According to the CEA, "We also present cost estimates under three alternative VSL assumptions without age-adjustment: low ($5.4 million), middle ($9.6 million), and high ($13.4 million), values suggested by the U.S. DOT and similar to those used by HHS. For example, our low fatality cost estimate of $221.6 billion is the product of the adjusted number of fatalities, 41,033, and the VSL assumption of $5.4 million. Our fatality cost estimates thus range from a low of $221.6 billion to a high of $549.8 billion."

"A xylazine-associated death was defined as a positive postmortem xylazine serum toxicology test result in an unintentional, undetermined, or pending intent substance-related death during January 2017–October 2021. Routine postmortem tests were conducted for other substances including fentanyl, fentanyl analogs, cocaine, and naloxone. Xylazine testing is standard in Cook County for suspected drug overdose deaths. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.*

"A total of 236 xylazine-associated deaths were reported during the study period. Xylazine-associated deaths increased throughout the study period; incidence peaked during July 2021 (Figure). The percentage of fentanyl-associated deaths involving xylazine also increased throughout the study period, rising to a peak of 11.4% of fentanyl-related deaths assessed by the Cook County Medical Examiner’s Office during October 2021. Fentanyl or fentanyl analogs were detected on forensic testing in most xylazine-involved deaths (99.2%). Other common co-occurring substances included diphenhydramine (79.7%), cocaine (41.1%), and quinine (37.3%). Naloxone was detected in 32.2% of xylazine-associated deaths."

According to the US Centers for Disease Control, in 2016, there were 63,632 drug overdose deaths in the United States. The CDC further estimates that of those, 42,249 deaths involved any opioid.

The CDC reports that in 2016, 15,469 deaths involved heroin; 14,487 deaths involved natural and semi-synthetic opioids; 3,373 deaths involved methadone; and 19,413 deaths involved synthetic opioids other than methadone, a category which includes fentanyl. The sum of those numbers is greater than the total opioid involved deaths because, as noted by the CDC, "Deaths involving more than one opioid category (e.g., a death involving both methadone and a natural or semisynthetic opioid such as oxycodone) are counted in both categories."

"During 2015, drug overdoses accounted for 52,404 U.S. deaths, including 33,091 (63.1%) that involved an opioid. There has been progress in preventing methadone deaths, and death rates declined by 9.1%. However, rates of deaths involving other opioids, specifically heroin and synthetic opioids other than methadone (likely driven primarily by illicitly manufactured fentanyl) (2,3), increased sharply overall and across many states."

"From 1999 to 2007, the number of U.S. poisoning deaths involving any opioid analgesic (e.g., oxycodone, methadone, or hydrocodone) more than tripled, from 4,041 to 14,459, or 36% of the 40,059 total poisoning deaths in 2007. In 1999, opioid analgesics were involved in 20% of the 19,741 poisoning deaths. During 1999–2007, the number of poisoning deaths involving specified drugs other than opioid analgesics increased from 9,262 to 12,790, and the number involving nonspecified drugs increased from 3,608 to 8,947."

According to the CDC, Human Immunodeficiency Virus (HIV) disease was the ninth leading cause of death in the US among all people aged 25-34, the eighth leading cause of death among males aged 25-34, and the tenth leading cause of death among males aged 35-44.

"The number of accidental drug overdose deaths increased by 622% between 2000 and 2020, and age-standardized mortality rates increased nearly four-fold in both men and women. Age-period-cohort decomposition found rapid increases in mortality since 2012 in men and women, with higher mortality risk in cohorts born after 1990. The fastest increase occurred in Black Americans since 2012, and Americans of all races born after 1975 had significantly higher mortality risk, with mortality risk increasing rapidly in more recent cohorts. The peak of mortality has shifted from the 40–59 age group to the 30–40 year age group in the past decade."

"In 2019, a total of 74,511 persons died of drug-induced causes in the United States (Tables 6, 8, and I– 2). The category of drug-induced causes includes deaths from drug overdose as well as deaths from other medical conditions caused by use of legal or illegal drugs. In 2019, drug-overdose deaths accounted for 94.8% of all drug-induced deaths (Tables 6 and 8). The drug-induced category excludes deaths indirectly related to drug use, as well as newborn deaths due to the mother’s drug use. (For a list of all drug-induced causes including those specifically classified as drug-overdose causes, see Technical Notes.)

"The age-adjusted death rate for drug-induced causes increased 4.6% for the total population from 21.8 in 2018 to 22.8 in 2019 (Table 10). For males in 2019, the age-adjusted death rate for drug-induced causes was 2.1 times the rate for females. T0he rate for males increased by 6.1% in 2019 from 2018.

"Among the major race-ethnicity groups—Age-adjusted rates increased in 2019 from 2018 by 15.0% for the non-Hispanic black population and by 15.5% for the Hispanic population. The age-adjusted death rate for non-Hispanic white males was 9.5% lower than for non-Hispanic black males and 76.1% higher than for Hispanic males. The rate for non-Hispanic white females was 31.7% higher than for non-Hispanic black females and 211.7% higher than for Hispanic females. Rates increased between 2018 and 2019 for non-Hispanic white males (2.3%), non-Hispanic black males (15.3%), non-Hispanic black females (15.4%), Hispanic males (17.1%), and Hispanic females (7.1%) (Tables 5, 10, and I–2). The age-adjusted death rate for druginduced causes did not change significantly in 2019 from 2018 for the total female population, total non-Hispanic white population, and non-Hispanic white females."

"The number of unintentional poisoning deaths increased from 12,186 in 1999 to 20,950 in 2004. The annual age-adjusted rate increased 62.5%, from 4.4 per 100,000 population in 1999 to 7.1 in 2004. The increase among females, from 2.3 to 4.7 per 100,000 population (103.0%), was twice the increase among males, from 6.5 to 9.5 per 100,000 population (47.1%) (Table 1). Among males, rates among whites, American Indians/Alaska Natives, and Asians/Pacific Islanders all increased approximately 50%. Rates among black males were highest in 1999 but did not increase. Among females, rates among whites more than doubled, whereas nonwhites had smaller increases or decreased. Overall, rates increased 75.8% among whites, 55.8% among American Indians/Alaska Natives, 27.4% among Asians/Pacific Islanders, and 11.2% among blacks. Rates among non-Hispanics increased more than rates among Hispanics for both sexes. Among all sex and racial/ethnic groups, the largest increase (136.5%) was among non-Hispanic white females. Among all age groups, the largest increase occurred among persons aged 15--24 years (113.3%). In 2004, the highest rates were among persons aged 35--54 years, who accounted for 59.6% of all poisoning deaths that year.

"From 1999 to 2004, rates increased by less than one third in the Northeast and West but more than doubled in the South and nearly doubled in the Midwest.† Delaware, Maryland, New York, and Rhode Island had decreases in rates, and California had the smallest increase (4.0%) (Figure). States with the largest relative increases were West Virginia (550%), Oklahoma (226%), Maine (210%), Montana (195%), and Arkansas (195%). Increases of 100% or more occurred in 23 states: 11.8% (two of 17) of states§ in the most urban tertile, 41.2% (seven of 17) of those in the middle tertile, and 82.4% (14 of 17) of those in the most rural tertile (extended Mantel-Haenszel chi-square for linear trend across the tertiles = 15.4, p<0.001).

"The increase in poisoning mortality occurred almost exclusively among persons whose deaths were coded as unintentional drug poisoning (X40--X44), for which the rate increased 68.3% (Table 2). The rate for poisoning deaths attributed to other substances (X45--X49) increased 1.3%. By 2004, drug poisoning accounted for 19,838 deaths, 94.7% of all unintentional poisoning deaths. Among types of drug poisoning, the greatest increases were in the "other and unspecified" drug, psychotherapeutic drug, and "narcotic and hallucinogen" drug categories."

"In 2019, a total of 39,043 persons died of alcohol-induced causes in the United States (Tables 6, 8, and I–3). This category includes deaths from dependent and nondependent use of alcohol, and deaths from accidental poisoning by alcohol. It excludes unintentional injuries, homicides, and other causes indirectly related to alcohol use, and deaths due to fetal alcohol syndrome. For a list of alcohol-induced causes, see Technical Notes.

"The age-adjusted death rate for alcohol-induced causes increased 5.1%, from 9.9 in 2018 to 10.4 in 2019 (Tables 5, 10, and I–3). For males in 2019, the age-adjusted death rate for alcohol-induced causes was 2.6 times the rate for females. The rate increased 3.4% for males and 5.4% for females from 2018 to 2019 (Tables 5, 10, and I–3).

"Among the major race-ethnicity groups—Age-adjusted rates increased 4.7% for the non-Hispanic white population, 7.0% for the non-Hispanic black population, and 7.1% for the Hispanic population from 2018 to 2019. In 2019, the ageadjusted death rate for non-Hispanic white males was 32.8% higher than for non-Hispanic black males and 11.2% lower than for Hispanic males. The rate for non-Hispanic white females was 61.9% higher than for non-Hispanic black females and 78.9% higher than for Hispanic females. Rates increased 3.3% for nonHispanic white males, 4.6% for non-Hispanic white females, 6.3% for non-Hispanic black males, and 15.2% for Hispanic females.

"The age-adjusted rate for alcohol-induced death did not change significantly in 2019 from 2018 for non-Hispanic black females and Hispanic males."

According to the CDC, Human Immunodeficiency Virus (HIV) disease was the eighth leading cause of death among Black people in the US aged 20-24, the sixth leading cause among Black people aged 35-44, and the eighth among Black people aged 45-54.

HIV disease was the sixth leading cause of death among Black males in the US aged 20-24, the sixth leading cause among Black males aged 25-34, the eighth leading cause among Black males aged 35-44, and the eighth leading cause among Black males aged 45-54.

HIV disease was the ninth leading cause of death among Black females in the US aged 25-34, the seventh leading cause among Black females aged 35-44, and the tenth leading cause among Black females aged 45-54.

"Hall and Henry (2006) reviewed the medical scenarios and treatment options for physicians dealing with MDMA-related medical emergencies: ‘Hyperpyrexia and multi-organ failure are now relatively well-known, other serious effects have become apparent more recently. Patients with acute MDMA toxicity may present to doctors working in Anaesthesia, Intensive Care, and Emergency Medicine. A broad knowledge of these pathologies and their treatment is necessary for those working in an acute medicine speciality’.

"Despite rapid medical intervention, some disorders are difficult to reverse and deteriorate rapidly, with occasional fatal outcomes (Schifano et al., 2003). In an early report, Henry et al. (1992) described MDMA-induced fatalities in seven young party goers, whose body temperatures at the intensive care unit ranged between 40 C and 43 C. The causes of death include various forms of organ failure. MDMA induces apoptosis, or programmed cell death, in cultured liver cells (Montiel-Duarte et al., 2002), and another form of death is from acute liver failure (Smith et al., 2005). Other fatalities result from cardiac arrest, brain seizure, ‘rhabdomyolysis’ or the destruction of skeletal muscle tissue, and ‘disseminated intravascular coagulation’ or the failure of blood clotting—which results in uncontrollable bleeding through multiple sites (Henry et al., 1992; Hall and Henry, 2006)."

"In summary, this study showed little, if any, effect of marijuana use on non-AIDS mortality in men and on total mortality in women. The increased risk of AIDS mortality in male marijuana users probably did not reflect a causal relationship, but most likely represented uncontrolled confounding by male homosexual behavior. The risk of mortality associated with marijuana use was lower than that associated with tobacco cigarette smoking."

"During 1999–2008, overdose death rates, sales, and substance abuse treatment admissions related to OPR increased in parallel (Figure 2). The overdose death rate in 2008 was nearly four times the rate in 1999. Sales of OPR in 2010 were four times those in 1999."

"Schifano et al. (2010) analysed the government data on recreational stimulant deaths in the UK between 1997 and 2007. Over this period, there were 832 deaths related to amphetamine or methamphetamine and 605 deaths related to Ecstasy/MDMA. Many were related to multiple-drug ingestion or ‘polydrug’ use. However, in the analysis of ‘mono-intoxication’ fatalities, Schifano et al. (2010) found that deaths following Ecstasy use were significantly more represented than deaths following amphetamine/methamphetamine use (p < 0.007)."

"First, factors related to death investigation might affect rate estimates involving specific drugs. At autopsy, the substances tested for, and circumstances under which tests are performed to determine which drugs are present, might vary by jurisdiction and over time. Second, the percentage of deaths with specific drugs identified on the death certificate varies by jurisdiction and over time. Nationally, 19% (in 2014) and 17% (in 2015) of drug overdose death certificates did not include the specific types of drugs involved. Additionally, the percentage of drug overdose deaths with specific drugs identified on the death certificate varies widely by state, ranging from 47.4% to 99%. Variations in reporting across states prevent comparison of rates between states. Third, improvements in testing and reporting of specific drugs might have contributed to some observed increases in opioid-involved death rates. Fourth, because heroin and morphine are metabolized similarly (9), some heroin deaths might have been misclassified as morphine deaths, resulting in underreporting of heroin deaths. Finally the state-specific analyses of opioid deaths are restricted to 28 states, limiting generalizability."

"The lethal dose of alcohol divided by a typical recreational dose (safety ratio) is 10, which places it closer to heroin (6), and GHB (8) in terms of danger from overdose, than MDMA ('Ecstasy' – 16), and considerably more dangerous than LSD (1000) or cannabis (>1000)."

"Assault (homicide), the 16th leading cause of death in 2019, dropped from among the 15 leading causes of death in 2010. In 2019, the age-adjusted rate for homicide did not change significantly from 2018. Homicide remains a major issue for some age groups. Homicide was among the 15 leading causes of death in 2019 for age groups under 1 year (13th), 1–4 (4th), 5–14 (5th), 15–24 (3rd), 25–34 (3rd), 35–44 (5th), 45–54 (12th), and 55–64 (15th) (10)."

"Excessive alcohol use* accounted for an estimated average of 80,000 deaths and 2.3 million years of potential life lost (YPLL) in the United States each year during 2001–2005, and an estimated $223.5 billion in economic costs in 2006. Binge drinking accounted for more than half of those deaths, two thirds of the YPLL, and three quarters of the economic costs."

* Excessive alcohol use includes binge drinking (defined by CDC as consuming four or more drinks per occasion for women or five or more drinks per occasion for men), heavy drinking (defined as consuming more than one drink per day on average for women or more than two drinks per day on average for men), any alcohol consumption by pregnant women, and any alcohol consumption by youths aged less than 21 years.

"Indeed, epidemiological data indicate that in the general population marijuana use is not associated with increased mortality."

"Although the mean annual opioid analgesic overdose mortality rate was lower in states with medical cannabis laws compared with states without such laws, the findings of our secondary analyses deserve further consideration. State-specific characteristics, such as trends in attitudes or health behaviors, may explain variation in medical cannabis laws and opioid analgesic overdose mortality, and we found some evidence that differences in these characteristics contributed to our findings. When including state-specific linear time trends in regression models, which are used to adjust for hard-to-measure confounders that change over time, the association between laws and opioid analgesic overdose mortality weakened. In contrast, we did not find evidence that states that passed medical cannabis laws had different overdose mortality rates in years prior to law passage, providing a temporal link between laws and changes in opioid analgesic overdose mortality. In addition, we did not find evidence that laws were associated with differences in mortality rates for unrelated conditions (heart disease and septicemia), suggesting that differences in opioid analgesic overdose mortality cannot be explained by broader changes in health. In summary, although we found a lower mean annual rate of opioid analgesic mortality in states with medical cannabis laws, a direct causal link cannot be established."

"Overall, we found that alcohol use accounted for approximately 3.5% of all cancer deaths, or about 19 500 persons, in 2009. It was a prominent cause of premature loss of life, with each alcohol-attributable cancer death resulting in about 18 years of potential life lost. Although cancer risks were greater and alcohol-attributable cancer deaths more common among persons who consumed an average of more than 40 grams of alcohol per day (‡ 3 drinks), approximately 30% of alcohol-attributable cancer deaths occurred among persons who consumed 20 grams or less of alcohol per day. About 15% of breast cancer deaths among women in the United States were attributable to alcohol consumption."

"Our estimate of 19,500 alcohol-related cancer deaths is greater than the total number of deaths from some types of cancer that receive much more prominent attention, such as melanoma or ovarian cancer,³⁶ and it amounted to more than two thirds of all prostate cancer deaths in 2009.³⁶ Reducing alcohol consumption is an important and underemphasized cancer prevention strategy, yet receives surprisingly little attention among public health, medical, cancer, advocacy, and other organizations in the United States, especially when compared with efforts related to other cancer prevention topics such as screening, genetics, tobacco, and obesity."

"Other leading causes of death that showed significant decreases in 2019 from 2018 were Chronic lower respiratory diseases (3.8%), Alzheimer disease (2.3%), kidney disease (1.6%), Influenza and pneumonia (17.4%), suicide (2.1%), Septicemia (6.9%), and Pneumonitis due to solids and liquids (2.1%)."

"On average, 6 people died every day from alcohol poisoning in the US from 2010 to 2012. Alcohol poisoning is caused by drinking large quantities of alcohol in a short period of time. Very high levels of alcohol in the body can shutdown critical areas of the brain that control breathing, heart rate, and body temperature, resulting in death. Alcohol poisoning deaths affect people of all ages but are most common among middle-aged adults and men."

"3. The most obvious concern when dealing with drug safety is the possibility of lethal effects. Can the drug cause death?

"4. Nearly all medicines have toxic, potentially lethal effects. But marijuana is not such a substance. There is no record in the extensive medical literature describing a proven, documented cannabis-induced fatality.

"5. This is a remarkable statement. First, the record on marijuana encompasses 5,000 years of human experience. Second, marijuana is now used daily by enormous numbers of people throughout the world. Estimates suggest that from twenty million to fifty million Americans routinely, albeit illegally, smoke marijuana without the benefit of direct medical supervision. Yet, despite this long history of use and the extraordinarily high numbers of social smokers, there are simply no credible medical reports to suggest that consuming marijuana has caused a single death.

"6. By contrast aspirin, a commonly used, over-the-counter medicine, causes hundreds of deaths each year.

"7. Drugs used in medicine are routinely given what is called an LD-50. The LD-50 rating indicates at what dosage fifty percent of test animals receiving a drug will die as a result of drug induced toxicity. A number of researchers have attempted to determine marijuana's LD-50 rating in test animals, without success. Simply stated, researchers have been unable to give animals enough marijuana to induce death.

"8. At present it is estimated that marijuana's LD-50 is around 1:20,000 or 1:40,000. In layman terms this means that in order to induce death a marijuana smoker would have to consume 20,000 to 40,000 times as much marijuana as is contained in one marijuana cigarette. NIDA-supplied marijuana cigarettes weigh approximately .9 grams. A smoker would theoretically have to consume nearly 1,500 pounds of marijuana within about fifteen minutes to induce a lethal response.

"9. In practical terms, marijuana cannot induce a lethal response as a result of drug-related toxicity."

"Our study revealed that experiencing an ADR [Adverse Drug Reaction] while hospitalized substantially increased the risk of death (1971 excess deaths, OR 1.208, 95% CI 1.184-1.234). This finding reflects about a 20% increase in mortality associated with an ADR in hospitalized patients. Extrapolating this finding to all patients suggests that 2976 Medicare patients/year and 8336 total patients/year die in U.S. hospitals as a direct result of ADRs; this translates to approximately 1.5 patients/hospital/year."

In 1997 it was estimated that "Each year, use of NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) accounts for an estimated 7,600 deaths and 76,000 hospitalizations in the United States."

(NB: NSAIDs include aspirin, ibuprofen, naproxen, diclofenac, ketoprofen, and tiaprofenic acid.)

"The most toxic recreational drugs, such as GHB (gamma-hydroxybutyrate) and heroin, have a lethal dose less than 10 times their typical effective dose. The largest cluster of substances has a lethal dose that is 10 to 20 times the effective dose: These include cocaine, MDMA (methylenedioxymethamphetamine, often called 'ecstasy') and alcohol. A less toxic group of substances, requiring 20 to 80 times the effective dose to cause death, include Rohypnol (flunitrazepam or 'roofies') and mescaline (peyote cactus). The least physiologically toxic substances, those requiring 100 to 1,000 times the effective dose to cause death, include psilocybin mushrooms and marijuana, when ingested. I’ve found no published cases in the English language that document deaths from smoked marijuana, so the actual lethal dose is a mystery."

"Data on 27,338 overdose deaths that occurred during July 2016–December 2017 were entered into SUDORS, and 152 (0.56%) of these decedents tested positive for kratom on postmortem toxicology (kratom-positive). Postmortem toxicology testing protocols were not documented and varied among and within states. Kratom was determined to be a cause of death (i.e., kratom-involved) by a medical examiner or coroner for 91 (59.9%) of the 152 kratom-positive decedents, including seven for whom kratom was the only substance to test positive on postmortem toxicology, although the presence of additional substances cannot be ruled out (4).

"In approximately 80% of kratom-positive and kratom-involved deaths in this analysis, the decedents had a history of substance misuse, and approximately 90% had no evidence that they were currently receiving medically supervised treatment for pain. Postmortem toxicology testing detected multiple substances for almost all decedents (Table). Fentanyl and fentanyl analogs were the most frequently identified co-occurring substances; any fentanyl was listed as a cause of death for 65.1% of kratom-positive decedents and 56.0% of kratom-involved decedents. Heroin was the second most frequent substance listed as a cause of death (32.9% of kratom-positive decedents), followed by benzodiazepines (22.4%), prescription opioids (19.7%),** and cocaine (18.4%)."