Depressants

Drugs that lower central nervous excitability and produce sedation. Most families here reach it through GABA: positive modulation at GABA-A (benzodiazepines, thienodiazepines, z-drugs, barbiturates, carbamates, quinazolinones), GABA-B agonism (GHB and its prodrugs, and phenibut), and ethanol, which does the first and antagonises NMDA besides. Some do not — gabapentinoids bind a calcium-channel subunit, kavalactones act on ion channels, and the α₂ agonists sedate through adrenergic autoreceptors with no GABA involvement at all, which is why neither flumazenil nor naloxone touches them.

The two class facts are in the line above. Depressant effects add, so two of them at amounts each survivable alone can stop someone breathing, and the combination with an opioid is where this subject does most of its killing. And the GABA-A depressants are cross-tolerant, so tolerance built on one carries to the others — while withdrawal after sustained heavy use of any of them can produce seizures and end in death.