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THE HIGHER THE DOSE, THE FASTER THE DEATH
Nakamura conducted a study in which he "..selected for toxicologic analyses seven cases of heroin fatalities in Los Angeles County, all of whom had a common history of what appeared to be sudden death. ...The blood level of morphine ranged from 0.2 to 1.0 mcg/ml." (0.2 to 1 mg per litre, ed.). "Blood morphine levels in most acute heroin-involved deaths range from 0.1 to 1.0 mcg/ml (0.1 to 1.0 mg per litre, ed.)...Blood levels of morphine also appear to be regulated by dosage." (63). Only one case in the 7 case study by Nakamura had a blood morphine level in Cobain's range, at 1.8 mg per litre, and the next closest was 0.9 mg per litre. The rest were 0.5 mg per litre and lower, with levels as low as 0.1 mg per litre causing immediate death. Nakamara also refers to his related 1974 doctoral thesis from the School of Criminology at the University of California, Berkely, where he "...examined blood specimens from 64 fatalities...whose survival time could be estimated." The highest blood morphine level was 0.8 mg per litre, and there was a clear indication that the higher the dose, the faster the death.

3.) OTHER FACTORS ENSURED OVERDOSE LETHALITY:

COMPENSATING FOR BODY WEIGHT - A blood morphine level of 1.52 mg/L indicates a heroin intake of approximately 225 mg - 240 mg. Thus, despite suggestions that Cobain may have simply been incapacitated by a normal, large dose fit for an addict, it must be noted that his body weight was at highest 130 lbs., and he was listed as being 115 lbs. in late 1993. This would generally increase his susceptibility to overdose by as much as 20%, since toxicity data is based on a 150 lb. adult.

COMPENSATING FOR ADULTERATION - Heroin purity has been shown to vary widely, with samples containing as little as 1% heroin. Mexican black tar is usually no higher than 40% pure, but is not uncommonly up to 80% pure, while highest recorded purity level for Mexican black tar heroin is 93% pure (89). If the heroin used in this case was indeed Mexican black tar heroin, and it was in the range of the highest potency recorded, i.e. 93% purity, then the dose required to reach a blood morphine level of 1.52 mg per litre would be approximately 245 mg to 260 mg. Whatever the physical source of heroin was, it does not really matter; the only thing that makes one type of heroin stronger than another is concentration of dose, so it was approximately 225 mg to 240 mg of some type of heroin. If the purity was 40%, a more common figure, then the lethal dose, including adulterants, would have been around 600 mg. Thus there is a definite chance of up to 350 mg of procaineor acetyl procaine as an adulterant. Note that procaine is commonly found in samples of Mexican black tar heroin. Regarding the potential toxicity of procaine, it should be noted that procaine levels would likely be undetectable in Cobain's blood due to the fact that the body was found at least three days after death. Still, the importance of procaine's potential toxicity is emphasized by Nakamura, who says "Nearly all the contraband heroin in the western areas is obtained from Mexico and contains an appreciable amount of procaine, or acetyl-procaine, as a filler material. ...The potential danger of a large concentration of this dilutent in street heroin needs to be better understood. (63).

THE SIGNIFICANCE OF DIAZEPAM PRESENCE - Diazepam is generally synonymous with the more well-known drug Valium, and sometimes the term diazepam refers to the generic category of drugs known as benzodiazepines. This class of drugs is regarded as sedative-hypnotic, and is not cross-tolerant to opioids. That means addicts can use diazepam and similar drugs in the same way that non-addicts use them. Conversely, even a heroin addict will experience toxicity to benzodiazepines in the same manner as a non-addict. A junkie is not immune to the toxic effects of a benzodiazepine overdose simply because he or she can handle a big dose of heroin. Cassidy, et. al. report "as both drugs cause respiratory depression...the likelihood of death resulting as a consequence...is greater than if either drug were taken alone." (10). Oldendorf reports on the effect of relaxation as increasing heroin absorption in the brain (67), a factor which addicts often attempt to manipulate, eg. by using heroin with a relaxant such as a benzodiazepine.

BENZODIAZEPINES & HEROIN COMMON PARTNERS IN DEATHS - Diazepam poisoning in particular, and benzodiazepine poisoning in general, is rare in isolation, but not at all uncommon in combination with other similar drugs, notably heroin. Several current studies from sources as disparate as the USA, Australia, Denmark, and the U.K., show that benzodiazepine abuse frequently occurs with heroin abuse, and that resultant death is a serious, growing concern. The two drugs have a definite added effect, increasing the likelihood of respiratory failure associated with heroin overdose by a very significant amount, which has now been relatively well quantified. The lethality of the combined use of heroin and diazepam are discussed by Nakamura, who mentions them in reference to occasional problems with finding a postmortem blood morphine level. The lethality of the heroin is so greatly increased that very small doses kill, meaning that "...the interaction of drugs in eliciting acute responses and causing deaths even when sublethal amounts of two or more drugs are present in postmortem specimens from the same cadaver may be a factor." (63).

THE POSSIBILITY OF FAST-ACTING BENZODIAZEPINES
The previous relative safety of benzodiazepines has become especially challenged lately with the misuse and abuse of related drugs such as Halcion and Xanax. Notably, these newer ultra-short acting benzodiazepines have a much shorter half-lives. This means that they clear out of the body very fast. Also, they have been considered the sole cause of death in recent forensic cases. Their potential lethality is especially increased when injected, and is the most common form of benzodiazepine-related respiratory failure. While diazepam is effective at a dose of 5 mg, the effective dose of Xanax is merely 250 mcg, with a half-life of 10-20 hours. Thus Xanax works as well as Diazepam at one-twentieth of the dose. Diazepam works in 30 minutes, while Xanax works immediately, and has a half-life of 10-20 hours. That means that 10-20 hours after taking it, half of it has been rendered useless. When injected, benzodiazepines in general are twice as potent. Thus a significantly toxic oral dose of 30 mg of diazepam would be easily achieved by an approximate equivalent of 500 mcg to 750 mcg of intravenously administered Xanax. Diazepam is measured usually by its secondary metabolites in the liver, and the metabolites for Xanax and Diazepam and Valium are all very similar, so often no differentiation is made during testing, which is often only conducted to determine presence, not quantity. If the benzodiazepine in Cobain's blood was indeed a fast-acting one, then it very likely played a major role in making the massive dose of heroin even more deadly.

SOME DEATHS INVOLVING HEROIN & DIAZEPAM
Gottschalk and Cravey, in their large compilation of deaths involving psychotropic drugs, found 129 cases where morphine, predominantly intravenous heroin, was determined to be the primary cause of death. Three of these cases involved diazepam and intravenous heroin or morphine (33). The first and second cases both involved oral diazepam plus intravenous heroin and/or morphine. The first case showed a blood morphine level of only 0.13 mg/L and diazepam at 1.4 mg/L, and the body was discovered approximately nine hours after death. Case 2 showed 0.3 mg/L blood morphine and 6 mg/L diazepam, and was discovered about seven hours after death. Case 3 included the possibility that the diazepam might have been injected with the morphine, and the blood levels were 0.02 mg/L morphine and 0.3 mg/L diazepam, with the body discovered about 24 hours after death. The third case in particular shows an extremely low blood morphine level can be lethal when combined with a low dose of diazepam.

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Appendix A - Appendix B - References 1 / 2