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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 that make you feel good tend to be dangerous? The most effective "feel good" drugs — opioids, benzodiazepines, amphetamines, cocaine in all its forms, MDMA, and of course, alcohol — tend to be very dangerous from a medical perspective, with fairly low therapeutic indices and numerous means of causing harm.

Sources:

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    You mentioned opioids and benzodiazepines as very dangerous from a medical perspective, yet they are prescribed for medical problems. Can you please provide some articles to back the claim that "the most effective 'feel good' drugs tend to be very dangerous from a medical perspective"? – Chris Rogers Sep 20 '19 at 16:22
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    The evidence is in their therapeutic indices, which indicate ratio between lethal dose and effective dose. The lower the index, the closer those two doses are, and the easier to overdose. The therapeutic index for acetaminophen is tiny with a few times the recommended dose associated with liver failure, while that of Vitamin B12 is in the millions or higher, making it very difficult to overdose – TheEnvironmentalist Sep 20 '19 at 18:34
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    Do you have a list of drugs with their therapeutic indices? I think you need to support your assertion that psychoactive drugs have lower TIs. – Carey Gregory Sep 20 '19 at 20:31
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    @CareyGregory OP presents a leading question that is unclear and broad. 'Most psychoactives' are not 'dangerous' (number of dead for LSD?)… – The Q is framed in a way that taken at face value doesn't result in reasonable As. The scope needs reduction, 'dangerous' & 'psychoactives' definition, etc. In its present form I'd challenge a lot of basic assumptions informing this Q. – LаngLаngС Sep 22 '19 at 8:58
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    @Jan It's not a hypothesis; it's an assertion of fact with no supporting reference. The question lacks prior research and you doing it for him in an answer doesn't change that. If you want to edit the question and add that information that's fine. That's how it should be handled. Answering non-compliant questions puts mods in the position of choosing between closing good answers or being inconsistent about enforcing the guidelines. The next person whose question gets closed for lack of prior research can point to this question as proof there is no such requirement. – Carey Gregory Sep 24 '19 at 18:52
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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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    I'd like to point out that an overdose is not equivalent to "effective dose". For instance, diamorphine has an LD50 of ~21mg/kg IV while a typical dose is at 5-10mg every four hours. I would strongly suggest to put this whole discussion into a medical context. References derived from law enforcement agencies distort the picture as they lack the above-mentioned medical perspective. As "danger" is always relative, studies comparing psychoactive drugs with other psychoactive drugs isn't helpful to assess their danger (as compared to non-psychoactive drugs) either. – life-on-mars Sep 25 '19 at 8:57
  • The concept of let's say heroin is also different in a law-enforcement context as it includes everything that the user or the law-enforcement agency thinks is heroin, which usually is a cocktail of varying substances of which diamorphine is just the main ingredient. – life-on-mars Sep 25 '19 at 9:02
  • "The therapeutic indices of practically all recreational drugs are nothing out of the ordinary." You are saying this without any evidence. Alcohol (ethanol), cocaine, heroin and barbiturates have been all used for medical treatment in the past but no longer (except barbiturates) because of their low therapeutic indices. Most opioids (prescribed or not) have low therapeutic indices and many people die due to their overuse. No drug, when sitting on a shelf, is dangerous, but can become dangerous when someone uses it. – Jan Sep 25 '19 at 9:15
  • @Jan Please see the link I provided. It would also be helpful to define "low TI" before turning this into a discussion. – life-on-mars Sep 25 '19 at 9:18
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    Let us continue this discussion in chat. – life-on-mars Sep 25 '19 at 9:37
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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:

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.

enter image description here

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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    I don't think you understood the question. You're simply restating the adverse effects of known drugs. The question asks why can't there be a psychoactive drug with no adverse effects. – stackzebra Sep 21 '19 at 19:18
  • No, the question does not ask that. It's clear as it is: "Why psychoactive drugs tend to be dangerous?" So, this is what I answered: They are dangerous because of circumstances (overdose, overuse, withdrawal, addiction) and not necessary because they are inherently dangerous. To answer your question: There are psychoactive drugs without adverse effects, for example, alcohol in a certain dose. – Jan Sep 23 '19 at 6:34
  • The circumstances include prohibition, quality control, miseductaion, disinformation, political abuse and political crimes, like prohibition, other crimes within legislation like 3-strike-rule. And that is what you misunderstand: "tend to be" 'assumes medically inherent qualities' 911-call "I'm dying; ate cookie" is no sign of danger, even if an ERvisit follows, not even if a court orders PT. The main dangers are purely from conservative criminals that poured their insanity into law. Unless this is clearly separately analysed and compared in perspective, answer is incomplete. – LаngLаngС Sep 23 '19 at 8:56
  • We have to shed light on the 'morals' side, as that is one major root cause of many of the 'dangers' you list. Intentional overdose is one thing, but popping a pill with unknown ingredients & strength, just because it's illegal? How much violence is 'associated' with hemp, kath, coca-leaves chewing, mushrooms, GHB or poppers? Correctly dosed clean MDMA is by far not dangerous on its own enough to outlaw it. The dangers of dancing or driving or working as roofer or overdosing water? How much alc 'danger' on car-less islands? Death in Thailand ('justice') is worse than any substance. – LаngLаngС Sep 23 '19 at 9:34
  • @LangLang: To clear the confusion: I do not make an emphasis on "illicit" but on "feel good" drugs, so I included alcohol, benzodiazepines, opioids and I could include the entire group of painkillers, most of which are perfectly legal. A lot of things that makes you "feel good," including certain foods, can become "dangerous" if you overuse them. Eating too much chocolate can easily make you overweight. I don't see inherent dangers in chocolate, but I do see dangers in obesity. I totally don't see anything moralistic in discussing obvious physical and other harms of overuse. – Jan Sep 23 '19 at 10:14
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According to https://www.sciencedaily.com/terms/psychoactive_drug.htm :

"Many of these substances (especially the stimulants and depressants) can be habit-forming, causing chemical dependency and may lead to substance abuse."

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