**Question:** Why is it that psychoactive or "feel good" drugs tend to be dangerous? **Answer, in short:** Some of these drugs *tend* to be dangerous because people commonly **overuse** and **overdose** them. The focus is on "feel good" and not specifically on "illicit" psychoactive drugs. Low therapeutic index - 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]. Low margin of exposure - 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] 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][11], 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. Low safety ratio - Another source [Comparison of acute lethal toxicity of commonly abused psychoactive substances (RS Gable, Addiction, 2004)][12] mentions **"safety ratio"** (equivalent of therapeutic index) 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 ```` Evidence of actual dangers - **1) Death by Overdose** According to [Drugabuse.gov][13], every day, more than 130 people in the United States die after overdosing on opioids. **2) Death by Withdrawal** - Withdrawal from moderate or short-term excessive **alcohol** drinking is usually not dangerous, but [withdrawal from long-term excessive drinking][14] can be deadly, for example, due to seizures or arrhythmia. - [**Opiate** withdrawal][15] can also be deadly. **3) Organ damage** Examples of physical complications after prolonged drug use (years): - Alcohol: [liver cirrhosis][16], [alcoholic neuropathy][17], [Wernicke-Korsakoff syndrome][18] - Cocaine: [brain damage][19] (acute effect can be [gastric ischemia][20]) - Methamphetamine: [brain damage, tooth decay (meth mouth)][21] **4) Emergency room visits in the US** ([ussc.gov, 2011][22]): *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 ```` **5) Road accidents** > 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. **6) Dependence** Drug dependence by itself is harmful, because it takes control over someone's life and prolongs the eventual physical harm of a drug. Psychoactive drugs that can cause [physical dependence][23]: alcohol, nicotine, [caffeine][24], opioids, barbiturates, benzodiazepines, GHB, hypnotics (zopiclone, zolpidem). Physical dependence means that stopping using a drug causes withdrawal symptoms ([Drugabuse.gov][25]). **In summary,** the dangers of psychoactive drugs stem from overdose and overuse; examples of drugs with low safety ratios are: opioids, isobutyl nitrite (poppers), gamma hydroxybutyrate (GHB), methamphetamine, alcohol, cocaine, methamphetamine, ecstasy and nicotine. [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://onlinelibrary.wiley.com/doi/full/10.1111/j.1360-0443.2004.00744.x?sid=nlm%3Apubmed [13]: https://www.drugabuse.gov/drugs-abuse/opioids/opioid-overdose-crisis [14]: https://www.drugfoundation.org.nz/matters-of-substance/november-2011/mythbusters-death-by-withdrawal/ [15]: https://ndarc.med.unsw.edu.au/blog/yes-people-can-die-opiate-withdrawal [16]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513682/ [17]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370340/ [18]: https://rarediseases.org/rare-diseases/wernicke-korsakoff-syndrome/ [19]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943678/ [20]: https://medcraveonline.com/IJRRT/IJRRT-05-00125.php [21]: https://www.drugabuse.gov/publications/research-reports/methamphetamine/what-are-long-term-effects-methamphetamine-misuse [22]: https://www.ussc.gov/sites/default/files/pdf/amendment-process/public-comment/20170807/FPD.pdf [23]: https://en.wikipedia.org/wiki/Physical_dependence [24]: https://www.ncbi.nlm.nih.gov/pubmed/3131789 [25]: https://www.drugabuse.gov/publications/principles-drug-addiction-treatment-research-based-guide-third-edition/frequently-asked-questions/there-difference-between-physical-dependence