**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