: Why is it that psychoactive drugs tend to be dangerous? I'm personally not a big fan of recreational drugs, illicit or otherwise, but there's an interesting medical question buried in their use. Why is it that substances

Question: Why is it that psychoactive ("feel good") drugs tend to be dangerous?

The question implies that psychoactive drugs are 1) dangerous and that 2) the reason is in their low therapeutic indices.

Answer: Psychoactive drugs make one feel good, which, for some people, is addictive, so they start to overuse them. Overuse can result in increased tolerance and this in further overuse and overdose, which is the main reason why these drugs tend to be dangerous.

DANGERS

ACUTE DANGERS

Overdose can result in acute sickness, for example, gastric ischemia with cocaine overdose, or death, mainly due to opioids (130/day in US), but also alcohol (6/day in US).

Street drugs can be adulterated with other dangerous drugs: heroin can be laced with fentanyl, which can cause fatal respiratory depression; ecstasy with "bath salts, which can dangerously increase blood pressure

Emergency room visits due to psychoactive drugs use in the US in 2011 (ussc.gov):

V = ER visits/year ; RR = risk ratio (total users/ER visits)

- V RR
- PCP (phencyclidine) 75,538 2.9
- Heroin 258,224 0.92
- Oxycodone/oxycontin 151,218 0.39
- Cocaine 505,224 0.37
- Methamphetamine 102,961 0.23
- MDMA (Ecstasy) 22,498 0.04
- Marijuana 445,668 0.03
- LSD 4,819 0.03

Road accidents

In one 2004 study in Netherlands, the risk of road trauma was strongly associated with a single use of benzodiazepines (5.1), alcohol (5.5), combination of drugs (6.1) and combination of drugs and alcohol (112.2). The values in brackets are adjusted odd ratios.

CHRONIC DANGERS

Examples of chronic physical damage due to psychoactive drugs, usually after years of overuse:

Tobacco smoking: chronic bronchitis, arteriosclerosis (ischemic heart disease, peripheral vascular diseases), throat and lung cancer
Alcohol: liver cirrhosis, alcoholic neuropathy, Wernicke-Korsakoff syndrome, fetal alcohol syndrome
Cocaine: brain damage
Methamphetamine: brain damage, tooth decay (meth mouth)

Withdrawal

Abrupt withdrawal after prolonged use of certain drugs can be deadly:

Alcohol withdrawal can be deadly due to seizures or arrhythmia.
Opiate withdrawal can also be deadly.

Withdrawal symptoms can be expected after prolonged use of drugs that cause physical dependence: alcohol, nicotine, caffeine, opioids, benzodiazepines, GHB and hypnotics (barbiturates, zopiclone, zolpidem).

THERAPEUTIC INDEX

Psychoactive drug overdose is dangerous only if a drug has a low enough therapeutic index.

Therapeutic index is the ratio between the dose that is Toxic for 50% of population and the dose that is Effective (therapeutic or "feel good") for 50% of population, so a TI = TD50/ED50.

Examples of psychoactive drugs with low therapeutic indices: alcohol, amphetamines, barbiturates, some benzodiazepines, cocaine, some opioids (especially heroin), and phenylpropanolamine.

When psychoactive drugs are not used for therapy, we can't speak about therapeutic indices, so comparable indices, such as "margin of exposure" and "safety ratio" have been developed for these cases.

Margin of exposure (MOE) is the ratio between the lowest dose found to harm health and estimated drug intake in humans.

Picture: Margin of exposure for daily drug use estimated using probabilistic analysis; red bar = average user ; error bar = standard deviation ; gray bar = tolerant user (Image source: Scientific Reports, Nature.com, Open Access)

Image explanation:

For individual exposure the four substances alcohol, nicotine, cocaine
and heroin fall into the “high risk” category with MOE < 10, the rest
of the compounds except THC fall into the “risk” category with MOE <
100.

Another source: RS Gable, Addiction, 2004 (pdf) mentions "safety ratio" that "was computed for each substance for reported acute lethal dose with the dose most commonly used for non-medical purposes."

- Heroin: 6
- Gamma hydroxybutyrate (GHB): 8
- Isobutyl nitrite: 8
- Methamphetamine: 10
- Alcohol: 10
- Cocaine: 15
- MDMA (ecstasy): 16
- Codeine: 20
- Methadone: 20
- Mescaline (peyote cactus): 24
- Flunitrazepam (a benzodiazepin): 30
- Ketamine: 38
- Dimethyltryptamine: 50
- Fluoxetine (Prozac): 100
- Nitrous oxide: >150
- LSD: 1,000
- Psilocybin (mushrooms): 1,000
- Marijuana: >1,000

In conclusion, psychoactive drugs can become dangerous when they are overused or overdosed. The danger of a drug can be sometimes explained by its low "margin of exposure" or "safety ratio," but long-term dependence on a drug can be harmful on its own.

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the illicit drug supply chain has an incentive to make drugs addictive but safe, as a dead client is a bad client

Theoretically yes, however, safety is a cost factor. Everything from packaging to quality assurance has a price tag on it. It would make the drug trade unprofitable. Illegal trade comes with the benefit of being unregulated as well.

Some of these drugs may actually not be safe for everyone to use. Being in a profitable unregulated business, you would not want to lose valuable customers.

Then there is the problem that the substances themselves do not require improving. The therapeutic indices of practically all recreational drugs are nothing out of the ordinary. They are safe enough for medical purposes as long as they are produced and used in a correct and supervised manner in which they even can be used to treat the addiction to them.

Their safety value drops exponentially when put into a recreational setting. You can compare that with motor vehicles. Not unlike drugs, their safety is significantly lower when used recreationally.

That said, lack of safety is not a particular characteristic of psychoactive substances. Notable examples are caffeine (coffee, tea) and theobromine (chocolate) and even some opioids.

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