Cocaine Overdose Mortality Increased During Hot Days

It was recently reported that deaths from cocaine overdose are higher on hot days. "High ambient temperature is associated with a significant increase in mortality from cocaine overdose. Based on our comparison groups, the increase is not explained by changes in cocaine use among the general population. Although cocaine use is dangerous on all days, it appears to be even more dangerous on hot days." J. Am. Med. Assoc. 1998; 279: 1795-1800. My work may explain this. I suggest the reason cocaine is abused is to increase the supply of the major adrenal hormone, dehydroepiandrosterone (DHEA) for the brain. No one else has considered a connection of cocaine and DHEA, but a number of investigators have examined the connection of cocaine and cortisol, the second major adrenal hormone. The effects of cortisol and DHEA may explain the JAMA findings.

I suggest a person who produces sufficient DHEA to maintain a DHEA response to cocaine use will not be prone to death during hot days. DHEA is proven to protect animals from heat stress. Rats "reared from day 21 of life at temperatures of 23, 34 or 37 degrees C. While the rats survived for unlimited periods at 23 and 34 degrees C, the animals reared at 37 degrees C succumbed within 5 days to heat stress. [37 degrees C is normal human temperature.] The latter group, when injected s.c. or i.p. with 50 mg dehydroepiandrosterone (DHA)/kg/day were no longer affected by the heat." (J. Endocrinol. 1975; 67: 99). What this means is that DHEA is higher in some people, and some cocaine users, than in others. It is well known that heat stress in humans occurs mainly in the young and the very old. DHEA is at low levels in the young and the very old. I suggest it is the low DHEA in these two groups that makes them vulnerable to heat and why some cocaine users are vulnerable on hot days. The mechanism involves the negative effects of the other adrenal hormone, cortisol.

In 1985, I copyrighted my explanation of how the "fight or flight" mechanism works. Based on my hypothesis that all tissues rely on DHEA for proper growth and development and maintenance in adult tissues, I concluded that the known negative effects of cortisol evolved to counteract the effects of DHEA. Since I think DHEA is necessary for proper brain function, then DHEA is involved in motivation. When an animal confronts another, DHEA is involved in this brain function. If two animals are properly motivated, a fight usually ensues with death or damage most likely occurring. This would soon remove the most fierce animals; they would not leave many offspring. Since the stress hormone is known to be cortisol, I deduced that this evolved to counteract the motivation. Some animals will still fight for the "alpha male" position, but most conflicts end before, or early into, the fight. I suggest this is due to the ratio of DHEA to cortisol. High DHEA types will engage in the high stress activity, they will fight; high cortisol types will refrain. (A study of first time parachutists discovered that these individuals, who can jump out of an airplane, actually experience an increase in DHEA, compared to cortisol. (J. Endocrinol. Invest. 1998; 21: 148). I suggest most risk seekers are of this type.) Many more males who refrain from fighting to the death produce more offspring than the few who will. This is why and how I think the DHEA - cortisol ratio became a part of us. The problem is that prolonged, or excess, cortisol will also negatively affect every tissue as DHEA will positively affect every tissue.

DHEA and cortisol are usually produced in a combination; in the parachutists mentioned above, cortisol and DHEA were both produced during the jump. The hormone ACTH stimulates both DHEA and cortisol. It is known that cocaine stimulates ACTH. "ACTH increases were significantly correlated with increases in plasma cocaine levels." (J. Clin. Endocrinol. Metab. 1998; 83: 966) As would be expected, another study demonstrated that cocaine increased both ACTH and cortisol. "In summary, cocaine stimulated the pulsatile ACTH and cortisol release by increasing the amplitude of secretory episodes in behaviorally responsive monkeys." (J. Pharmacol. Exp. Ther. 1996; 277: 225) Cocaine increases levels of norepinephrine (NE) and epinephrine (E) and exaggerates these levels during exercise (Metabolism 1991; 40: 1043). Very hot exercise increases both catecholamines (NE and E) and cortisol (Int. J. Sports. Med. 1998; 19: 130). Heat and cocaine produce similar stress responses, i.e., increases in catecholamines and cortisol.

"Many of the known actions of cortisol and catecholamines are atherogenic, cardiotoxic and arrhythmogenic. Emotional stress can produce sudden cardiac death in experimental animals, as can the administration of exogenous catecholamines. Previous studies have found that emotional stress is a common precursor to sudden cardiac death." (J. Am. Coll. Cardiol. 1985; 5 (6 Suppl): 95B). Since it is known, from above, that DHEA increases resistance to heat stress, and that "DHEAS [the serum precursor of DHEA] at physiological concentration of human serum significantly inhibited the release of NE..." (Neurosci. Lett. 1996; 204: 181), sufficient levels of DHEA may reduce the impact of cocaine-induced stimulation of catecholamines and cortisol. I suggest the reason that "High ambient temperature is associated with a significant increase in mortality from cocaine overdose." is due to a low DHEA to cortisol ratio in these individuals. Now, this could happen in new users of cocaine or in those who have exhausted their DHEA supply due to repeated use of cocaine.

New Support:

Neuropsychopharmacology. 2006 Jan 18

DHEA, a Neurosteroid, Decreases Cocaine Self-Administration and Reinstatement of Cocaine-Seeking Behavior in Rats.

Doron R, Fridman L, Gispan-Herman I, Maayan R, Weizman A, Yadid G.

1Faculty of Life Sciences and The Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel.

Dehydroepiandrosterone (DHEA), which can act as a potential antidepressant in both animals and humans, appears to lower distress involved with cocaine withdrawal. In fact, a role for neurosteroids in modulation of substance-seeking behavior is becoming increasingly clear. Therefore, we tested the effects of DHEA on the self-administration of cocaine (1 mg/kg/infusion) by rats. At maintenance, a relatively low dose of exogenous DHEA (2 mg/kg; i.p.) attenuated cocaine self-administration after several days of chronic treatment. More than 2 weeks (19 days) of daily DHEA injections were required to decrease the cocaine-seeking behavior of rats to less than 20% of their maintenance levels. DHEA does not seem to decrease cocaine self-administration by increasing the reinforcing properties of the drug, as indicated by a cocaine dose-response determination. After being subjected to extinction conditions in the presence of DHEA, rats demonstrated a minimal response to acute exposure to cocaine (10 mg/kg), which indicated a protective effect of DHEA on relapse to cocaine usage. Our results suggest a potential role for the neurosteroid DHEA in controlling cocaine-seeking behavior, by reducing both the desire for cocaine usage and the incidence of relapse.Neuropsychopharmacology advance online publication, 18 January 2006; doi:10.1038/sj.npp.1301013.