On its own, tramadol is fairly gentle. Millions of people have taken it and serious problems are rare, and at normal doses it barely suppresses breathing — which is what sets it apart from the proper opioids.

The usual complaints are drowsiness, dizziness, headache, dry mouth and constipation.

Two things to be careful about. It has triggered seizures in over 280 people, so avoid it in anyone with epilepsy or another neurological condition. And although it is safe at normal doses, an overdose can kill — especially alongside anything else that slows the brain down.

The dangerous combinations all come from how it works. Tramadol is only weakly opioid; mostly it stops nerves reabsorbing noradrenaline and serotonin.

• Block noradrenaline reuptake, and adding an MAOI can send the blood pressure through the roof. That combination is absolutely forbidden.
• Block serotonin reuptake, and adding an SSRI, SNRI or tricyclic can cause serotonin syndrome.
• Alcohol and benzodiazepines make its sedating effects much stronger.

The same mechanism explains something else: naloxone only partly reverses tramadol, because most of what tramadol does is not opioid at all.

That combination is not just "be careful" — tramadol should not be combined with alcohol or benzodiazepines at all.

Methadone carries two serious warnings, and they are different kinds of danger.

The heart. It stretches out the QT interval, which can tip into a fatal rhythm called torsades de pointes. That has happened at doses of 65 mg a day and above.

• Be very careful — or do not use it at all — in anyone who already has a long QT, has long QT syndrome in the family, or takes other drugs that stretch the QT.
• Do an ECG at the start, again later, and then every year.
• If the QT goes above 500 ms, think about stopping it or lowering the dose.

The breathing. Methadone can suppress breathing severely enough to kill. That is why patients must be told two things very plainly: never take more than prescribed, and stay away from anything else that slows the brain — benzodiazepines, alcohol, and other opioids.

Three kinds of drug, and the order matters more than the names.

• Methadone and buprenorphine are given before someone goes through withdrawal. They stand in for the opioid the person is using, so they can stop the chaos without stopping the drug.
• Naltrexone is given after supervised withdrawal is finished. It blocks the receptors, so going back to opioids achieves nothing.

Get that order backwards and you cause harm: give a blocker to someone still dependent and you throw them into withdrawal.

Who is allowed to prescribe them differs, and that shapes who gets treated:

• Methadone for maintenance can only come from a certified opioid treatment programme, approved by the state.
• Buprenorphine can be prescribed in ordinary primary care by any clinician — including a nurse practitioner — who has done the training and registered.

The details worth memorising: methadone is a full opioid agonist, schedule II, taken once daily. Buprenorphine is an agonist-antagonist, schedule III, taken once daily under the tongue.

Most people who end up misusing opioids started outside medicine, not with a prescription. Only a small minority of people given opioids for pain go on to compulsive use.

There is one striking exception: healthcare staff — doctors, nurses and pharmacists — misuse opioids more than other people with similar education. The reason is simply that they can get hold of them.

The famous "rush" after injecting heroin lasts about 45 seconds. But it is not why people keep using — the long, calm euphoria that follows is.

Tolerance is selective, and that is what makes opioids dangerous:

• The body gets used to the euphoria, the slowed breathing, and the nausea.
• It does not get used to constipation or to pinpoint pupils — those stay.
• Because tolerance to slowed breathing keeps pace with tolerance to the high, taking more to feel the same does not make breathing worse.

Two important limits. Someone tolerant to one opioid is tolerant to others — but that does not extend to alcohol or benzodiazepines, which is why mixing them still kills. And the highest risk of dying is in someone who has not built up tolerance at all.

Two more: most opioids are schedule II controlled substances. And the group that tolerance does not carry over to is barbiturates, benzodiazepines and alcohol — barbiturates included.

This is about balance, not banning. People in long-term pain that is not cancer do get real benefit from opioids — less pain, better mood, more able to function — and they still have a right to have their pain treated.

The guidelines exist to hold both things at once: their right to relief, and your responsibility not to cause harm.

• Reach for an opioid only after non-opioid painkillers and more conservative approaches have failed.
• Talk through the benefits and risks of long-term opioids with the person.

The CDC issued its pain guidelines in 2016; pain-medicine bodies had issued their own before that.

On top of all that sits your state's law, which is where the specifics live. Most states cap how much you can prescribe at once, particularly the first time. Many also require you to educate the patient, check the prescription monitoring database, and do extra training yourself. It differs state by state, so the national guideline is only half the answer.

The single most important thing about naloxone: it wears off before the opioid does. One dose is not the treatment.

It has to be given again every few hours until the opioid has dropped to a safe level, and that can take days. People have died after being brought round with naloxone because nobody gave them another dose. Waking up is not the same as being out of danger.

• Nasal spray — one spray into one nostril, giving 4 to 8 mg. If nothing happens, repeat every 2 to 3 minutes until the ambulance arrives.
• Prefilled syringe (Zimhi) — one dose into the muscle or skin of the outer thigh, with a fresh syringe every 2 to 3 minutes if needed.

It only became easy to get quite recently: an outpatient version in 2014, a nasal one in 2015, and by 2017 every state had passed a law to widen access — though the rules differ from state to state.

For the record: naloxone is the classic pure opioid antagonist, blocking both μ and κ receptors, and its main job is reversing the slowed breathing and drowsiness of an opioid overdose.

The active ingredient is THC, an oily substance that dissolves in fat. It is strongest in the flowering tops of female plants and weakest in the seeds. Hashish — the dried resin from those flowers — is a good deal stronger than marijuana itself.

How much it takes to cause problems varies enormously between people. Some are fine on very large amounts; others get side effects at ordinary ones.

Two things happen with long-term use:

• Amotivational syndrome — apathy, dullness, not looking after yourself, losing interest in achieving anything. Worth being careful here: nobody has established that marijuana actually causes it, and the evidence does not point to brain damage.
• Cannabinoid hyperemesis syndrome — repeated bouts of nausea and vomiting that are strangely relieved by hot showers or baths. It was first described in 2004 and became familiar as legalisation spread. The only treatment is stopping.

That second one is genuinely odd, and worth remembering for exactly that reason: a lot of people use cannabis to stop feeling sick.

A few specifics: THC stands for delta-9-tetrahydrocannabinol, and the plant is Cannabis sativa, the Indian hemp plant. The psychoactive compounds are present in both male and female plants — the female flowering tops are simply where they are most concentrated.

For scale: in 2021, 2.7 million American adolescents aged 12–17 had used marijuana in the past year, and more than 52 million Americans reported using it.