Speedball (also referred to as powerballing) is a term commonly referring to the (sometimes intravenous) use of cocaine with heroin or morphine (if intravenously, in the same syringe). Some also use it with two syringes, one in each arm. The speedball can also be taken by insufflation. The original speedball used cocaine hydrochloride mixed with morphine sulfate, as opposed to heroin. The term can also be applied to use of pharmaceutical opioids, benzodiazepines or barbiturates along with stimulants. However, since opioids and sedative-hypnotics have different objective and subjective effects, stimulant-depressant mixtures are known by the slang term "set up"  A cocktail of drugs containing an opioid can cause a strong physical dependence and withdrawal symptoms.
These mixtures are often more than the sum of the parts, through drug synergy; and this is an effect which can and has been used clinically, such as Brompton cocktail, the caffeine content of many codeine and dihydrocodeine combination drugs, and the use of stimulants both to potentiate the opioid and combat somnolence caused by high and rapidly escalating doses. 
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Cocaine acts as a stimulant, whereas heroin/morphine acts as a depressant. Co-administration is meant to provide an intense rush of euphoria with a high that is supposed to combine the effects of both drugs, while hoping to reduce the negative effects, such as anxiety, hypertension, palpitations and other common side effects of stimulants and sedation/drowsiness from the depressant. While this is somewhat effective, as one drug (the CNS stimulant) triggers the sympathetic nervous system and the other (the CNS depressant) triggers the parasympathetic nervous system, the two systems that regulate the fight-or-flight and rest-and-digest responses, respectively, and simultaneous activity of the two pathways is what normally keeps one's body in natural homeostasis, there is an imperfect overlap in the effects of stimulants and depressants. Additionally, by suppressing the typical negative side-effects of the two drugs, the user may falsely believe they have a higher tolerance, or that they are less intoxicated than they actually are. This can cause users to misjudge the intake of one or both of the drugs, sometimes fatally.
Because the stimulant effects of cocaine wear off far more quickly than the depressant effects of heroin or morphine, fatal respiratory depression often occurs when the full effects of a heroin or morphine overdosage are felt in isolation. Due to the countering effect of the cocaine, a fatally high opioid dose can be unwittingly administered without immediate incapacitation, thus providing a false sense of tolerance until it is too late. This form of delayed opioid overdose is believed to be the most common mechanism of death in speedball overdoses.
Notable deaths attributed to speedball use
- Jean-Michel Basquiat, though some sources list his death as heroin overdose only.
- John Belushi
- Ken Caminiti
- Chris Farley, died of cocaine and morphine sulfate overdose.
- Pete Farndon
- Zac Foley
- Lowell George
- Trevor Goddard
- Mitch Hedberg
- Philip Seymour Hoffman, died of cocaine, heroin, benzodiazepines, and amphetamines overdose.
- Sebastian Horsley
- Chris Kelly
- Brent Mydland
- River Phoenix
- DJ Rashad
- Eric Show
- Judee Sill
- Layne Staley
- Joey Stefano, died of cocaine, morphine, heroin and ketamine overdose.
- Hillel Slovak
Circa 1900, Harry Kendall Thaw was an early user of the speedball. In 1996, Dave Gahan suffered a heart attack following a speedball overdose, but survived. Steven Adler had a stroke after taking a speedball, leaving him with a permanent speech impediment.
Among celebrities who admitted using speedballs are Chet Baker (in the documentary film Let's Get Lost), Megadeth front man Dave Mustaine, and bassist David Ellefson (in the documentary Behind The Music), Cream bassist Jack Bruce (as stated in an interview with Daily Record in 2009), Nikki Sixx (in The Heroin Diaries: A Year in the Life of a Shattered Rock Star and The Dirt), Anthony Kiedis (in his autobiography Scar Tissue), Kurt Cobain (in his biography Heavier Than Heaven), David Crosby (in his autobiography Long Time Gone), Jerry Garcia, Miles Davis, and Slash (in his autobiography Slash). Slash experienced cardiac arrest for 8 minutes, but was revived. In Season 9, episode 207 of The Late Late Show, comedian Craig Ferguson admitted to using speedballs, but refused along with musician/actress Courtney Love (who said she had "done both parts" but "not together") to tell the audience what drugs are in speedballs, for "legal reasons".
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