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Depressants (1,4-Butanediol, 2M2B, alcohol, benzodiazepines, barbiturates, GHB/GBL, methaqualone, opioids) - Combining these substances amplifies their muscle-relaxing, memory-impairing, sedative, and respiratory-depressant effects. At higher doses, it can result in sudden loss of consciousness and dangerously reduced breathing. There is also an elevated risk of suffocation from vomiting while unconscious. If nausea or vomiting occurs before losing consciousness, individuals should try to sleep in the recovery position or be moved into it by a friend.

Dissociatives - Mixing these substances can unpredictably enhance the memory impairment, sedation, loss of motor control, and delusions they induce individually. It may also lead to sudden loss of consciousness coupled with severe respiratory depression. If nausea or vomiting happens before losing consciousness, individuals should aim to sleep in the recovery position or be helped into it by a companion.

Stimulants - Stimulants conceal the sedative effects of depressants, which are often the primary indicators of intoxication levels. Once the stimulant effects diminish, the depressant effects significantly escalate, causing intensified lack of inhibition, loss of motor control, and potentially hazardous blackout episodes. This combination can also lead to severe dehydration if fluid intake is not carefully monitored. If opting for this combination, individuals should adhere strictly to a predetermined dosing schedule, limiting intake to a specified amount per hour until reaching a maximum threshold.