**Question:** Why is it that psychoactive or "feel good" drugs tend to be dangerous? **Answer, in short:** They *tend* to be dangerous because people *tend* to **overuse** and **overdose** them. The focus is on "feel good" and not specifically on "illicit" psychoactive drugs. Some psychoactive drugs have **a low [therapeutic index][1],** which is the ratio between the dose that is **T**oxic for 50% of population and the dose that is **E**ffective (therapeutic) for 50% of population, so a TI = TD50/ED50. Examples of psychoactive drugs with a low therapeutic index: [alcohol][2] (TI =10), [amphetamines][3], [barbiturates][4], [some benzodiazepines][5], [cocaine][6], [some opioids][7], especially [heroin][8], and [phenylpropanolamine][9]. Another evaluation of drug danger is **margin of exposure (MOE)**, which is the ratio between the lowest dose found to harm health and estimated drug intake in humans. [![enter image description here][10]][10] *Image source: [Scientific Reports, Nature.com][11], Open Access (red bar = average user ; error bar = standard deviation ; gray bar = tolerant user)* 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. Most dangers of psychoactive drugs stem from overuse: **1) Overdose** Opioids, such as heroin, in high doses can cause [respiratory depression][12]. According to [Drugabuse.gov][13]: "Every day, more than 130 people in the United States die after overdosing on opioids" and "Roughly 21 to 29 percent of patients *prescribed* opioids for chronic pain misuse them." **2) Addiction** Moderate alcohol drinking (1-2 drinks/day) does not likely make you addicted, but higher amounts drunk for several months/years can. [Alcohol dependence and withdrawal][14]. **3) Withdrawal** - Withdrawal from moderate or short-term excessive **alcohol** drinking is usually not dangerous, but [withdrawal from long-term excessive drinking][15] can be deadly, for example, due to seizures or arrhythmia. - [**Opiate** withdrawal][16] can also be deadly. - **Benzodiazepines** withdrawal can result in [rebound insomnia and rebound anxiety][17]. **4) Organ damage** Physical complications after prolonged use (years): - Alcohol: [liver cirrhosis][18], [alcoholic neuropathy][19], [Wernicke-Korsakoff syndrome][20] - Cocaine: [brain damage][21] (acute effect can be [gastric ischemia][22]) - Methamphetamine: [brain damage, tooth decay (meth mouth)][23] In conclusion, many "feel good" psychoactive drugs are dangerous mainly because they can be easily overdosed. Most of them have a "narrow [therapeutic index][24]:" alcohol, [benzodiazepines][5], cocaine, [opioids][7]. **"Emergency room visits due to "feel good" drugs** Emergency room visits ratios in the US, 2011 ([ussc.gov][25]): *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 ```` If you evaluate *danger* by ER visits, the relative risks (RR) may not appear high, but number of ER visits does. **Road accidents associated with "feel good" drugs** > The risk for road trauma was increased for single use of > **benzodiazepines** (adjusted OR 5.1 (95% Cl: 1.8-14.0)) and **alcohol** (blood alcohol concentrations of 0.50-0.79 g/l, adjusted OR 5.5 (95% Cl: 1.3-23.2) and >or=0.8 g/l, adjusted OR 15.5 (95% Cl: > 7.1-33.9)). High relative risks were estimated for drivers using **combinations of drugs** (adjusted OR 6.1 (95% Cl: 2.6-14.1)) and those using **a combination of drugs and alcohol** (OR 112.2 (95% Cl: > 14.1-892)). Increased risks, although not statistically significantly, were assessed for drivers using amphetamines, cocaine, or opiates. No > increased risk for road trauma was found for drivers exposed to > cannabis. [1]: https://toxtutor.nlm.nih.gov/02-005.html [2]: https://web.cgu.edu/faculty/gabler/drug_toxicity.htm [3]: https://www.mdedge.com/clinicianreviews/article/72259/addiction-medicine/teen-prescription-drug-abuse-national-epidemic/page/0/2 [4]: https://www.ncbi.nlm.nih.gov/pubmed/9255991 [5]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896864/ [6]: https://books.google.com/books?id=utVOHYuhxioC&pg=PA246&lpg=PA246&dq=%22low%20therapeutic%20index%22%20cocaine&source=bl&ots=woQnRCtF5b&sig=ACfU3U28E1U-mvPfFx1gMh1q32yMdc-SzQ&hl=sl&sa=X&ved=2ahUKEwi-5aXo--bkAhUNElAKHXrKCJUQ6AEwDnoECAkQAQ#v=onepage&q=%22low%20therapeutic%20index%22%20cocaine&f=false [7]: https://www.ncbi.nlm.nih.gov/pubmed/21999760 [8]: https://www.ncbi.nlm.nih.gov/books/NBK441876/ [9]: https://jamanetwork.com/journals/jama/article-abstract/394687 [10]: https://i.sstatic.net/JmgJw.jpg [11]: https://www.nature.com/articles/srep08126 [12]: https://www.ncbi.nlm.nih.gov/pubmed/30735692 [13]: https://www.drugabuse.gov/drugs-abuse/opioids/opioid-overdose-crisis [14]: https://www.drinkaware.co.uk/alcohol-facts/health-effects-of-alcohol/mental-health/alcohol-dependence/ [15]: https://www.drugfoundation.org.nz/matters-of-substance/november-2011/mythbusters-death-by-withdrawal/ [16]: https://ndarc.med.unsw.edu.au/blog/yes-people-can-die-opiate-withdrawal [17]: https://www.ncbi.nlm.nih.gov/pubmed/6132413 [18]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513682/ [19]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370340/ [20]: https://rarediseases.org/rare-diseases/wernicke-korsakoff-syndrome/ [21]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943678/ [22]: https://medcraveonline.com/IJRRT/IJRRT-05-00125.php [23]: https://www.drugabuse.gov/publications/research-reports/methamphetamine/what-are-long-term-effects-methamphetamine-misuse [24]: https://en.wikipedia.org/wiki/Therapeutic_index [25]: https://www.ussc.gov/sites/default/files/pdf/amendment-process/public-comment/20170807/FPD.pdf