Which Medications Are Most Involved in Overdose Suicides?

Antidepressants, prescription opioids, and benzodiazepines consistently rank as the three drug categories most frequently detected in overdose suicides in the United States and other high-income countries.¹ That ranking, though, hides enormous variation in how dangerous individual drugs within each class actually are. A bottle of one antidepressant can be many times more lethal in overdose than a bottle of another, and a drug’s frequency in suicide statistics often reflects how commonly it is prescribed as much as how toxic it is at high doses.

Antidepressants and the Wide Gap Between Old and New

Antidepressants show up in overdose suicides more than any other prescription drug class. Emergency department data from one Canadian study found antidepressants involved in roughly 37% of prescription-drug suicide attempts, more than anxiolytics and opioids combined.² But “antidepressant” is a broad label. The difference in overdose lethality between the older tricyclic antidepressants and the newer SSRIs is staggering.

A large UK analysis found that the case fatality rate for tricyclics was about 28 times higher than for SSRIs. Tricyclics had a case fatality rate ratio of 13.8, compared with just 0.5 for SSRIs. In between sat venlafaxine at 2.5 and mirtazapine at 1.9.³ In practical terms, someone who takes a large overdose of a tricyclic like amitriptyline faces a dramatically higher chance of dying than someone who takes the same relative overdose of fluoxetine or sertraline. Tricyclics can cause fatal cardiac arrhythmias and seizures at doses not far above the therapeutic range. SSRIs, while not harmless in overdose, have a much wider margin of safety. Overdose with venlafaxine and SSRIs was also less likely to cause coma, and SSRIs were less likely to prolong the heart’s QRS interval, a marker of dangerous cardiac toxicity.⁴

This gap is one reason that prescribing patterns have shifted so dramatically over the past three decades. Doctors prescribe tricyclics far less frequently now, partly because SSRIs and SNRIs work about as well for most people and partly because the overdose risk with tricyclics is well recognized. In Australian data examining fatal toxicity per million prescriptions dispensed, antidepressants still had some of the highest “dispensed medicine” proportions in poisoning suicides, meaning the person who died had recently been prescribed the drug themselves, at a rate of about 86%.⁵ That figure underscores something important: in most cases, the medication used in a suicide was the person’s own prescription.

Opioids and Benzodiazepines

Prescription opioids have long been a major factor in overdose suicides, though the picture has shifted as prescribing practices and the broader drug supply have changed. In U.S. data spanning 1999 to 2022, prescription opioids were one of the three leading drug categories among intentional overdose deaths, along with antidepressants and benzodiazepines.¹ Opioids kill in overdose primarily by depressing breathing. The margin between a therapeutic dose and a lethal one varies enormously by drug: methadone and oxycodone are more dangerous per dose than hydrocodone, for instance. One county-level analysis of accidental overdose deaths found that hydrocodone, despite accounting for the majority of prescribed pills, had the lowest fatal toxicity index among the drugs studied, at about 0.5 deaths per million pills dispensed. Fentanyl, by contrast, had an index of roughly 36, and methadone about 9.⁶ Those figures are from accidental deaths rather than suicides specifically, but the underlying pharmacology holds: fentanyl and methadone are simply more dangerous at any given excess dose.

Australian suicide data paint a similar picture. Oxycodone and morphine ranked among the medicines with the highest fatal toxicity indices in confirmed poisoning suicides, at roughly 365 and 241 deaths per million years of use respectively.⁵ Yet only about half of the opioid-related suicide deaths involved a drug the person had been recently dispensed. The rest involved opioids obtained through other channels, a pattern less common with antidepressants.

Benzodiazepines occupy an interesting position. Taken alone, most benzodiazepines are surprisingly difficult to die from, because the gap between a sedating dose and a lethal one is relatively wide. When combined with opioids or alcohol, however, the risk multiplies. U.S. data from 2000 to 2019 showed that when benzodiazepines were involved in an overdose death alongside opioids, only about 8.5% of those deaths were classified as suicides, because the combination is so commonly lethal even in accidental circumstances. But when benzodiazepines were involved without opioids, the suicide proportion jumped to about 36%.⁷ That gap likely reflects the fact that intentionally taking a large amount of benzodiazepines alone, while rarely fatal, signals deliberate intent more clearly than a mixed-substance overdose where the cause of death could easily be accidental.

Not all benzodiazepines carry the same risk. Clonazepam topped the Australian fatal toxicity list with the highest index of any medicine studied, at roughly 1,592 deaths per million years of use, though only about 16% of those deaths involved a recently dispensed prescription for clonazepam, suggesting many people obtained it through other means.⁵

Antipsychotics, Anticonvulsants, and Other Prescription Drugs

Beyond the big three classes, several other prescription categories appear regularly in overdose suicide data. Quetiapine, an antipsychotic frequently prescribed for insomnia and mood disorders in addition to psychosis, had one of the higher fatal toxicity indices in the Australian study, at about 268 deaths per million years of use. Chlorpromazine, an older antipsychotic, also appeared on the list. Antipsychotics as a class had a high “dispensed medicine” proportion of around 77%, meaning the person who died had usually been prescribed the drug themselves.⁵ Quetiapine in particular has become more concerning as its prescribing has expanded well beyond psychosis into off-label uses for sleep and anxiety, putting more bottles into more medicine cabinets.

Anticonvulsants accounted for about 9% of prescription drug overdose attempts in one emergency department study.² Antiepileptic drugs as a group had a dispensed-medicine proportion of about 61% in Australian suicide data.⁵ Within this class, phenobarbitone (an older barbiturate still used for seizures in some settings) carried a high fatal toxicity index. Gabapentin, a newer anticonvulsant widely prescribed for nerve pain, was long considered extremely safe in overdose because of its limited absorption at high doses, and fatalities attributed solely to gabapentin have been rare enough that a single published case report was considered notable.

Cardiovascular medications get less attention, but certain ones are remarkably dangerous in overdose. Among beta blockers, propranolol stands out. A review of over 52,000 beta blocker exposures reported to U.S. poison control centers found that propranolol was responsible for about 44% of all exposures but 71% of deaths where a beta blocker was the primary cause.⁸ Propranolol’s danger comes from its ability to block sodium channels in the heart at high doses, a property most other beta blockers do not share. Calcium channel blockers, particularly verapamil and diltiazem, are similarly dangerous in overdose but appear less often in suicide statistics because they are prescribed to a narrower population.

Over-the-Counter Medications, Especially Acetaminophen

Among drugs you can buy without a prescription, acetaminophen (paracetamol in most of the world) dominates overdose statistics. In the Montreal emergency department study, acetaminophen accounted for about 30% of all over-the-counter drug suicide attempts.² The drug is everywhere, inexpensive, and most people do not think of it as dangerous, which is part of why it is so commonly chosen.

Acetaminophen overdose is an unusual case, though, because the experience of taking it does not resemble what most people imagine a fatal overdose looks like. There is often no immediate loss of consciousness. Instead, the drug quietly destroys the liver over the course of days. People who take intentional overdoses tend to arrive at the hospital relatively quickly and receive the antidote, N-acetylcysteine, before severe damage sets in. One large review found that the death rate from acetaminophen overdose was under 1%, and the liver transplant rate was about 1.5%.⁹ Paradoxically, accidental overdoses, where people take too much over multiple days for pain without realizing they are poisoning themselves, are actually more likely to cause liver failure and death. In one study, peak drug levels were higher in the intentional group, but severe liver damage and death were significantly more common in the accidental group, because those patients did not seek help until their livers had been under assault for much longer.¹⁰

This does not mean acetaminophen overdose is harmless. A “failed” suicide attempt with acetaminophen can still result in days of miserable hospitalization, liver damage, and the need for ongoing medical monitoring. And the sheer volume of attempts means that even a low fatality rate translates into a meaningful number of deaths.

Availability Matters More Than Most People Realize

One of the most consistent findings in the research is that the drugs people use in overdose suicides are heavily influenced by what is available in their medicine cabinet. A large Belgian study examining intentional drug overdoses over five years concluded that the availability of medication through prescriptions plays an important role in determining which drug a person takes during a self-harm act.¹¹ The Australian data reinforce this: the “dispensed medicine” proportion, meaning the percentage of deaths where the person had recently been prescribed the drug themselves, was highest for antidepressants at about 86% and antipsychotics at 77%.⁵

This means the drugs that show up most often in overdose suicides are not necessarily the “deadliest” per pill. They are the ones sitting in the greatest number of homes belonging to people at elevated risk. Antidepressants lead the statistics partly because they are prescribed to tens of millions of people, including people experiencing exactly the mental health conditions that raise suicide risk. The same logic applies to benzodiazepines and opioids prescribed for chronic pain: the prescription itself puts the means within reach.

Gender Patterns in Drug Overdose

Drug overdose as a method of suicide is more common among women than men. Research consistently shows that women tend to choose overdose and self-cutting, while men more frequently choose hanging and asphyxiation. One study found statistically significant differences, with women choosing pharmacological drug overdose at higher rates and men choosing hanging and asphyxiation at higher rates.¹² Women also tended to use a greater number of different methods across attempts.

Because men are more likely to choose highly lethal methods like firearms and hanging, overall completed suicide rates are higher among men in most countries, even though women attempt suicide more often. Drug overdose, while dangerous, has a lower case fatality rate than many other methods. This pattern has practical implications: reducing access to large quantities of medications may disproportionately protect women, who are the group most likely to reach for a pill bottle during a crisis.

What Happens When You Restrict Access to Medications

The strongest evidence that availability drives overdose suicides comes from the United Kingdom’s 1998 legislation limiting pack sizes of acetaminophen and aspirin. Before the law, you could walk into a UK shop and buy a hundred paracetamol tablets at once. After the law, non-pharmacy outlets could sell no more than 16 tablets per pack, and pharmacies were limited to 32. The results were striking: deaths from paracetamol poisoning dropped by about 21% in the first year, and deaths from salicylate poisoning (aspirin and related drugs) fell by nearly half. Liver transplants due to paracetamol toxicity dropped by about two-thirds.¹³

A follow-up analysis confirmed that these benefits persisted for at least three years. Suicidal deaths from paracetamol and salicylates remained about 22% lower than before the law. Large overdoses, defined by the number of tablets taken, dropped by about 20% for paracetamol and 39% for salicylates. Liver unit admissions and transplants remained down by about 30% over four years.¹⁴

The key question skeptics raise about any means-restriction strategy is substitution: if you make one method harder, do people just switch to another? The evidence suggests that substitution is limited, particularly for impulsive attempts. Reviews of the literature have found that many people have a strong preference for a specific method and that suicidal crises are often brief, driven by impulsiveness and ambivalence. When access to a preferred method is restricted, most people do not simply pick up an alternative. Any shift that does occur tends to be partial and delayed.¹⁵ The UK paracetamol data support this: the reduction in paracetamol deaths was not offset by increases in deaths from other methods.

Prescription Drug Monitoring Programs

In the United States, the main policy response to prescription drug overdose deaths has been prescription drug monitoring programs, electronic databases that track controlled substance dispensing and allow prescribers to check a patient’s history. Every U.S. state now has one. The evidence for their effectiveness is surprisingly mixed. An early national analysis found that these programs were not significantly associated with lower rates of drug overdose mortality overall, though three states that required special prescription forms (California, New York, and Texas) did see slower growth in overdose death rates.¹⁶

More recent research has raised additional concerns. A study examining “must-query” mandates, which require prescribers to check the database before writing certain prescriptions, found that these mandates were actually associated with increases in overdose deaths across all racial and ethnic groups. The increase was largest among Hispanic and Black populations, with relative risks of about 1.32 and 1.23 respectively, compared with about 1.14 for white populations.¹⁷ One interpretation is that restricting prescription opioid access without providing alternative pain management or addiction treatment pushes people toward more dangerous illicit supplies. The contrast with the UK pack-size legislation is instructive: that law succeeded partly because there was no illicit paracetamol market to absorb displaced demand.

How Toxicity Indices Work and Why They Matter

When researchers want to rank how dangerous a specific drug is in overdose, they often calculate a fatal toxicity index rather than just counting deaths. A raw death count tells you little, because a drug that kills 100 people out of 50 million prescriptions is far safer per exposure than one that kills 20 out of 100,000 prescriptions. Fatal toxicity indices adjust for how widely a drug is prescribed, producing a figure like “deaths per million prescriptions” or “deaths per million pills dispensed” that allows apples-to-apples comparison.

In the Australian study, this approach revealed that some drugs relatively uncommon in raw death counts were actually extremely dangerous per prescription. Phenobarbitone, an old barbiturate rarely prescribed today, had the second-highest fatal toxicity index after clonazepam, even though it contributed fewer total deaths than oxycodone.⁵ Similarly, in U.S. county-level data, chlordiazepoxide (the original benzodiazepine, marketed as Librium) had the highest fatal toxicity index of the scheduled drugs examined, at about 40 deaths per million pills dispensed, despite being prescribed far less commonly than hydrocodone.⁶

These indices matter because they help clinicians make prescribing decisions for patients at elevated suicide risk. When two medications might work equally well for a condition, the one with the lower fatal toxicity index is the safer bet. This thinking already drove the shift from tricyclics to SSRIs as first-line antidepressants, and it informs decisions about pain management, where choosing a less dangerous opioid or a non-opioid alternative can reduce the odds that a bottle in someone’s home becomes the instrument of a crisis.

Predicting Risk Before It Becomes a Crisis

A growing area of research involves using electronic health records and machine learning to identify patients at elevated risk before they reach a crisis point. One model trained on records of patients with post-traumatic stress disorder who received opioid prescriptions was able to predict suicide-related outcomes with a balanced accuracy of about 86%, flagging roughly two-thirds of patients who went on to have a suicide-related event during follow-up.¹⁸ Models like these are being tested for integration into clinical decision support systems, where they could prompt a pharmacist or prescriber to reduce the quantity dispensed, recommend more frequent follow-up, or discuss safe storage and disposal of unused medications.

The practical challenge is precision. That same model’s positive predictive value was only about 27%, meaning roughly three-quarters of the patients it flagged did not go on to have a suicide-related outcome. In a clinical setting, that false-positive rate creates tension between caution and the risk of stigmatizing patients or restricting access to needed medication. Still, the research signals where things are heading: toward a future where the combination of which drug a person is prescribed, their mental health history, and dozens of other variables might prompt a targeted intervention rather than a one-size-fits-all restriction.