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**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][6], [cocaine][7], [some opioids][8], especially [heroin][9], and [phenylpropanolamine][10].

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][11]][11]

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][12], 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)][13] 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."

````
 - Alcohol: 10
 - Cocaine: 15
 - Codeine: 20
 - Dimethyltryptamine: 50
 - Gamma hydroxybutyrate (GHB): 8
 - Heroin: 6
 - Isobutyl nitrite: 8
 - Ketamine: 38
 - LSD: 1,000
 - Marijuana: >1,000
 - MDMA (ecstasy): 16
 - Mescaline (peyote cactus): 24
 - Methadone: 20
 - Methamphetamine: 10
 - Nitrous oxide: >150
 - Phenobarbital: 50
 - Fluoxetine (Prozac): 100
 - Psilocybin (mushrooms): 1,000
 - Flunitrazepam (benzodiazepin): 30
````

Dangers stem from overuse
-

**1) Overdose** 

Opioids, such as heroin, in high doses can cause [respiratory depression][14]. According to [Drugabuse.gov][15]: "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][16].

**3) Withdrawal**

 - Withdrawal from moderate or short-term excessive **alcohol** drinking is usually not dangerous, but [withdrawal from long-term excessive drinking][17] can be deadly, for example, due to seizures or arrhythmia.
 - [**Opiate** withdrawal][18] can also be deadly.
 - **Benzodiazepines** withdrawal can result in [rebound insomnia and rebound anxiety][19].

**4) Organ damage**

Physical complications after prolonged use (years):

 - Alcohol: [liver cirrhosis][20], [alcoholic neuropathy][21], [Wernicke-Korsakoff syndrome][22]
 - Cocaine: [brain damage][23] (acute effect can be [gastric ischemia][24])
 - Methamphetamine: [brain damage, tooth decay (meth mouth)][25]

In conclusion, many "feel good" psychoactive drugs are dangerous mainly because they can be easily overdosed. Most of them have a "narrow [therapeutic index][26]:" alcohol, [benzodiazepines][6], cocaine, [opioids][8].

Evidence of actual dangers
-

**Emergency room visits ratios in the US, 2011** ([ussc.gov][27]):

*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**

> 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.

**In summary,** psychoactive drugs with the lowest safety ratios (<20) are: heroin, (and other opiates, such as codeine and methadone), isobutyl nitrite (poppers), gamma hydroxybutyrate (GHB), methamphetamine, alcohol, cocaine and methamphetamine.

  [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.researchgate.net/figure/Therapeutic-Index-values-of-some-drugs_tbl7_265996548
  [6]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896864/
  [7]: 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
  [8]: https://www.ncbi.nlm.nih.gov/pubmed/21999760
  [9]: https://www.ncbi.nlm.nih.gov/books/NBK441876/
  [10]: https://jamanetwork.com/journals/jama/article-abstract/394687
  [11]: https://i.sstatic.net/JmgJw.jpg
  [12]: https://www.nature.com/articles/srep08126
  [13]: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1360-0443.2004.00744.x?sid=nlm%3Apubmed
  [14]: https://www.ncbi.nlm.nih.gov/pubmed/30735692
  [15]: https://www.drugabuse.gov/drugs-abuse/opioids/opioid-overdose-crisis
  [16]: https://www.drinkaware.co.uk/alcohol-facts/health-effects-of-alcohol/mental-health/alcohol-dependence/
  [17]: https://www.drugfoundation.org.nz/matters-of-substance/november-2011/mythbusters-death-by-withdrawal/
  [18]: https://ndarc.med.unsw.edu.au/blog/yes-people-can-die-opiate-withdrawal
  [19]: https://www.ncbi.nlm.nih.gov/pubmed/6132413
  [20]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513682/
  [21]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370340/
  [22]: https://rarediseases.org/rare-diseases/wernicke-korsakoff-syndrome/
  [23]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943678/
  [24]: https://medcraveonline.com/IJRRT/IJRRT-05-00125.php
  [25]: https://www.drugabuse.gov/publications/research-reports/methamphetamine/what-are-long-term-effects-methamphetamine-misuse
  [26]: https://en.wikipedia.org/wiki/Therapeutic_index
  [27]: https://www.ussc.gov/sites/default/files/pdf/amendment-process/public-comment/20170807/FPD.pdf