| 3-Cl-PCP | Dangerous | Both cause respiratory depression and unconsciousness; vomiting while dissociated risks aspiration |
| 3-HO-PCE | Dangerous | Both cause respiratory depression and unconsciousness; vomiting while dissociated risks aspiration |
| 3-HO-PCP | Dangerous | Both cause respiratory depression and unconsciousness; vomiting while dissociated risks aspiration |
| 3-MeO-PCE | Dangerous | Both cause respiratory depression and unconsciousness; vomiting while dissociated risks aspiration |
| 3-MeO-PCMo | Dangerous | Both cause respiratory depression and unconsciousness; vomiting while dissociated risks aspiration |
| 3-MeO-PCP | Dangerous | Both cause respiratory depression and unconsciousness; vomiting while dissociated risks aspiration |
| 4-MeO-PCP | Dangerous | Both cause respiratory depression and unconsciousness; vomiting while dissociated risks aspiration |
| Alcohol | Dangerous | — |
| Atropa belladonna | Dangerous | Compounding CNS depression with anticholinergic effects; risk of cardiac events and respiratory failure |
| Benzodiazepines | Dangerous | — |
| Cake | Dangerous | Severe respiratory depression risk; leading cause of polydrug overdose |
| Datura | Dangerous | Compounding CNS depression with anticholinergic effects; risk of cardiac events and respiratory failure |
| Deschloroetizolam | Dangerous | Severe respiratory depression; this combination is the leading cause of prescription drug overdose deaths |
| Deschloroketamine | Dangerous | Both cause respiratory depression and unconsciousness; vomiting while dissociated risks aspiration |
| Desomorphine | Dangerous | Compounding respiratory depression and overdose risk |
| Diclazepam | Dangerous | Severe respiratory depression; this combination is the leading cause of prescription drug overdose deaths |
| Diphenhydramine | Dangerous | Compounding CNS depression with anticholinergic effects; risk of cardiac events and respiratory failure |
| Diphenidine | Dangerous | Both cause respiratory depression and unconsciousness; vomiting while dissociated risks aspiration |
| Ephenidine | Dangerous | Both cause respiratory depression and unconsciousness; vomiting while dissociated risks aspiration |
| Eszopiclone | Dangerous | Severe respiratory depression risk; leading cause of polydrug overdose |
| Etizolam | Dangerous | Severe respiratory depression; this combination is the leading cause of prescription drug overdose deaths |
| Flubromazepam | Dangerous | Severe respiratory depression; this combination is the leading cause of prescription drug overdose deaths |
| Flubromazolam | Dangerous | Severe respiratory depression; this combination is the leading cause of prescription drug overdose deaths |
| Flunitrazepam | Dangerous | Severe respiratory depression; this combination is the leading cause of prescription drug overdose deaths |
| Flunitrazolam | Dangerous | Severe respiratory depression; this combination is the leading cause of prescription drug overdose deaths |
| Gaboxadol | Dangerous | Severe respiratory depression risk; leading cause of polydrug overdose |
| GBL | Dangerous | — |
| GHB | Dangerous | — |
| Harmala alkaloid | Dangerous | Risk of serotonin syndrome and severe respiratory depression; potentially fatal |
| HXE | Dangerous | Both cause respiratory depression and unconsciousness; vomiting while dissociated risks aspiration |
| Inhalants | Dangerous | Both cause respiratory depression and unconsciousness; vomiting while dissociated risks aspiration |
| Ketamine | Dangerous | — |
| Lorazepam | Dangerous | Severe respiratory depression; this combination is the leading cause of prescription drug overdose deaths |
| Memantine | Dangerous | Both cause respiratory depression and unconsciousness; vomiting while dissociated risks aspiration |
| Mephenaqualone | Dangerous | Severe respiratory depression risk; leading cause of polydrug overdose |
| Metizolam | Dangerous | Severe respiratory depression; this combination is the leading cause of prescription drug overdose deaths |
| Midazolam | Dangerous | Severe respiratory depression; this combination is the leading cause of prescription drug overdose deaths |
| MXiPr | Dangerous | Both cause respiratory depression and unconsciousness; vomiting while dissociated risks aspiration |
| Naloxone | Dangerous | Compounding respiratory depression and overdose risk |
| Nicotine | Dangerous | Severe respiratory depression risk; leading cause of polydrug overdose |
| Nifoxipam | Dangerous | Severe respiratory depression risk; leading cause of polydrug overdose |
| O-PCE | Dangerous | Both cause respiratory depression and unconsciousness; vomiting while dissociated risks aspiration |
| PCE | Dangerous | Both cause respiratory depression and unconsciousness; vomiting while dissociated risks aspiration |
| Peganum harmala | Dangerous | Risk of serotonin syndrome and severe respiratory depression; potentially fatal |
| Pentobarbital | Dangerous | Severe respiratory depression risk; leading cause of polydrug overdose |
| Phenobarbital | Dangerous | Severe respiratory depression risk; leading cause of polydrug overdose |
| SAMe | Dangerous | Severe respiratory depression risk; leading cause of polydrug overdose |
| 3-FMA | Caution | Stimulants mask opioid sedation, increasing overdose risk when the stimulant wears off |
| 4-MMC | Caution | Stimulants mask opioid sedation, increasing overdose risk when the stimulant wears off |
| 8-Chlorotheophylline | Caution | Stimulants mask opioid sedation, increasing overdose risk when the stimulant wears off |
| Adrafinil | Caution | Stimulants mask opioid sedation, increasing overdose risk when the stimulant wears off |
| Benzydamine | Caution | Stimulants mask opioid sedation, increasing overdose risk when the stimulant wears off |
| Bromantane | Caution | Stimulants mask opioid sedation, increasing overdose risk when the stimulant wears off |
| Dichloropane | Caution | Stimulants mask opioid sedation, increasing overdose risk when the stimulant wears off |
| Ephedrine | Caution | Stimulants mask opioid sedation, increasing overdose risk when the stimulant wears off |
| Hexedrone | Caution | Stimulants mask opioid sedation, increasing overdose risk when the stimulant wears off |
| Methcathinone | Caution | Stimulants mask opioid sedation, increasing overdose risk when the stimulant wears off |
| Oxiracetam | Caution | Stimulants mask opioid sedation, increasing overdose risk when the stimulant wears off |
| Phenylpiracetam | Caution | Stimulants mask opioid sedation, increasing overdose risk when the stimulant wears off |
| Rhodiola Rosea | Caution | Stimulants mask opioid sedation, increasing overdose risk when the stimulant wears off |
| Nitrous | Uncertain | — |
| Psilocybin Mushrooms | Low Risk & No Synergy | No significant pharmacological interaction; opioids may slightly dull the psychedelic experience |