When heroin is injected, it is metabolised to morphine in the brain. Until now, the prevailing perception has been that morphine causes the rush and heroin addiction is thus a form of morphine addiction. Morphine stimulates the µ-opioid receptors in the brain. When these receptors are affected in certain areas of the brain it leads to a sense of euphoria – the “rush” - and further to the development of addiction.
Euphoria caused by 6-MAM
Research at the Department of Drug Abuse Research at the Norwegian Institute of Public Health, has previously questioned the notion that heroin addiction is caused by morphine. Fernando Boix and colleagues confirm that it is not primarily morphine, but the metabolite 6-monoacetylmorphine (6-MAM), that provides the euphoria and intoxication after heroin intake. This opens up new avenues in the treatment of addiction.
- What happens when heroin is injected?
“Heroin is converted rapidly to 6-MAM in the blood. The concentration becomes high and it quickly crosses the blood-brain barrier. In the brain, 6-MAM binds to µ-opioid receptors and provides the rush. In addition, some 6-MAM is metabolised to morphine. Morphine also binds to µ-opioid receptors, but this only gives a supplementary effect. Essentially it is 6-MAM that produces the effects," said Fernando Boix.
– Does this mean that heroin itself does not have any intoxicant effect?
“Heroin is a peculiar substance. It has a very strong effect and is one of the most addictive drugs we know. But when heroin is tested directly on brain cells, it has very little effect. Previously it was believed that heroin quickly entered the brain and it was the conversion to morphine there that caused the euphoria. An earlier report by my colleague Jannike M. Andersen as first author showed that the rush effect is primarily due to 6-MAM - at least in mice. We believe that the same is true in humans.”
Boix made calculations using advanced pharmacokinetic modelling. He calculated the mathematical values that describe the rates of metabolism, excretion and the transfer between blood and brain of heroin and its metabolites. These processes determine the distribution of the substances in blood and brain.
The calculations confirm that very little heroin reaches the brain, because heroin is metabolised so rapidly to 6-MAM in the blood. The new report shows that 6-MAM moves then to the brain and gives the strong rush effect of heroin.
Need to change perception
These results mean that the international scientific community should review their understanding on how heroin affects the brain. To date, researchers have assumed that heroin is converted to morphine.
The research not only provides a new understanding of the powerful addiction potential of heroin, but also opens up new gateways for treatment.
Vaccine may be possible
– Could a vaccine against 6-MAM be effective against heroin addiction?
“There is a possibility. A vaccine against heroin is unlikely to work because heroin is converted so quickly," said Boix, adding that it is a long time before a 6-MAM vaccine becomes a reality.
The research team is now looking closely at whether the rapid metabolism to 6-MAM applies to all methods of heroin administration. Boix also emphasises that the research has been performed on mice. The next step is to verify that the metabolism of 6-MAM is as fast and as extensive in humans, and also how this metabolism takes place by different routes of administration - intravenous, smoking or other means. For ethical reasons this cannot be tested directly in humans, but experiments must be set up in vitro with blood and various cell types in the laboratory.
Boix F, Andersen JM og Mørland J. Pharmacokinetic modelling of subcutaneous heroin and its metabolites in blood and brain of mice. Addiction Biology, 2010.