NEXT time you drink up or if you’re crazy enough to spliff up or shoot up, be prepared for some unwelcome bodily changes. And we’re not talking constipation, freaky hallucinations, or the midnight munchies here. Evidence is mounting that certain illicit and recreational drugs like heroin, alcohol and marijuana subvert the body’s natural defence mechanisms, opening the flood gates to disease.
But all is not doom and gloom for the drug abuser, casual or otherwise. There are hints that cocaine, the traditional bane of New York stockbrokers and Washington mayors, might actually strengthen the body’s defences. The impact on the immune system of ecstasy, the youth drug of the nineties, is a largely unasked question.
Circumstantial evidence that drugs and alcohol harm the body’s ability to fight off disease has been around for ever. Intravenous drug abusers, for instance, are prone to tuberculosis and pneumonia. These infections are transmitted through the air, rather than through infected needles, and usually only strike people with weak immune systems. Drug injectors also suffer more than their fair share of food poisoning and intestinal upsets caused by bacteria like Salmonella typhimurium and Listeria monocytogenes. Alcoholics are prone to hepatitis, tuberculosis and other infections. And young marijuana users have a higher than normal incidence of head and neck cancers that cannot be accounted for by the tobacco in spliffs.
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Crazy cells
It was tantalising, but about as far from proof as you could get because of the difficulty of disentangling the effects of the drugs from those of the sex and rock and roll. Did addicts get sick because the drugs were messing with their immune systems, or because food, hygiene and medical care took second place to scoring the next fix?
“People thought drug users got ill and died just because of this bad lifestyle,” says Alan Leshner, director of the US National Institute on Drug Abuse (NIDA) in Rockville, Maryland. That changed when a small group of immunologists decided to test their gut instinct that drugs were disrupting the body’s immune defences.
It’s now pretty well established that the brain exerts some direct control over the immune system, so it was an obvious first place to look for any immunosuppressive effects of drugs like heroin. And in 1993, Barbara Bayer and her colleagues at Georgetown University in Washington DC injected morphine, heroin’s breakdown product in the body and its laboratory stand-in, into the brains of rats. Within 30 minutes, the rats’ T cells, which kill infected cells and ensure that different parts of the immune system work together, had lost their punch. When they were removed from the animals and treated with a chemical that usually makes them divide like crazy, they divided at 80 per cent less than the normal rate.
Bayer’s first thought was that the morphine had set off a chain of command from the hypothalamus to the adrenal gland via the pituitary, stimulating the release of corticosteroids into the blood. These hormones can suppress the immune system. But when she removed the rats’ adrenal glands or pituitary glands and repeated the experiment, she got exactly the same result, suggesting that morphine affects T cells through another as yet mysterious brain mechanism.
But it is the ability of morphine to act at a local level, by latching onto immune cells that excites the most interest. One of the first hints that this is possible came in 1994 when George Stefano of the State University of New York at Stony Brook showed that morphine binds directly to human granulocytes. These cells are found in pus; they gobble up everything from cancerous cells to bits of viruses and make chemicals such as histamine that increase blood flow to areas of tissue damage.
In the past three years, other research teams have shown that various types of human T cells and B cells (which make antibodies), as well as the granulocytes, turn on genes for the m receptor—the same receptor the brain uses for morphine and heroin and the body’s own painkilling and anti-stress opiates.
But the evidence has not convinced everyone that heroin-like drugs can have a direct impact on immune cells. They say that just because the m genes in immune cells produce messenger RNA—the molecular intermediary between genes and proteins—doesn’t mean that the cells actually have functioning m receptors. “It’s not enough just to find mRNA,” says Henry “Skip” Francis, the head of the NIDA’s clinical medicine branch. “That’s just the smoking gun.” Now, immunologists like Toby Eisenstein and her colleagues at Temple University in Philadelphia have evidence that morphine directly damages immune cells. For example, when mB cells are taken out of mice and treated with morphine they make only half as much antibody as usual.
But the pièce de résistance is an experiment that Eisenstein and her colleagues reported in the Journal of Infectious Diseases in July (vol 176, p 183). They found that mice that had been given morphine for two days, at doses roughly equivalent to those a heroin addict would use, tended to die of blood poisoning. When they opened up the mice, they found that bacteria had migrated from the intestine, where they normally live, into other organs such as the liver and spleen. Animals that received naltrexone, a chemical that blocks morphine’s action, remained healthy, so it looks as though the morphine causes the fatal migration of the bacteria.
If a similar thing happens in heroin addicts, it would certainly help to explain why they are susceptible to salmonella and listeria infections. Eisenstein points out that morphine and heroin are known to slow gut peristalsis and cause constipation. Perhaps, she says, “something happens to the integrity of the gut and the balance of organisms in there, so the gut wall becomes more permeable”.
For heroin, the message is clear: it douses immunity. The same cannot be said of cocaine.
At the annual meeting of the American Society for Microbiology in Miami Beach in May, Stan Lefkowitz and Ken Grattendick, both of the Texas Tech University in Lubbock, unveiled some curious findings about cocaine and macrophages— immune cells that digest things like bacteria and damaged cells, and help T cells recognise microbial invaders. They showed that adding cocaine, at levels similar to the amount coke addicts would have in their blood, to cultured mouse macrophages boosts their production of interferon by about one third. Interferons carry messages between different parts of the immune system and help stop viruses infecting healthy cells.
In addition, cocaine slows the replication of hepatitis viruses in cultured mouse macrophages, says Lefkowitz. And the effect is dose-dependent: viral replication falls as more cocaine is added. Finally, macrophages from mice injected with cocaine are as much as 90 per cent better at digesting and killing Escherichia coli bacteria than those from other mice. This autumn, the researchers plan to see if mice on cocaine are more resistant than normal to the human influenza virus.
“All the effects we demonstrate last [from] just a few hours up to a day after administration of cocaine,” says Lefkowitz. And the beneficial response doesn’t diminish with each new hit.
But there have been some negative findings as well. David Ou and his colleagues at the University of Illinois at Chicago have found that in mice cocaine kills thymocytes, cells that migrate to the thymus, where they mature into T cells. And Ronald Watson of the University of Arizona at Tucson has shown that the numbers of two types of T cells, CD4 and CD8 cells, fall more rapidly in mice infected with the mouse version of AIDS if they are given cocaine. “It’s a mixed bag, and it’s hard to say whether [cocaine] is good or bad,” says Lefkowitz.
At first blush, the evidence from real-life coke addicts suggests that the drug is anything but good for your health—cokeheads are vulnerable to stomach upsets and diarrhoea, and infections like syphilis. But the official numbers should be taken with a pinch of salt, says Francis. Addicts who make the health statistics are likely to be down-and-outs already at high risk of catching infections. Affluent addicts tend not to get scooped off the streets and charged, so they are rarely counted, he says.
And what if cocaine really does boost immunity in humans? “If we find that drugs of abuse boost the immune system, we will find non-abusable analogues,” says Leshner.
There is no direct evidence for cocaine docking sites on any immune cells, but T cells do have receptors for the main mind-bending components of marijuana—the cannabinoids. The most psychoactive cannabinoid, delta-9-tetrahydrocannabinol (THC), also seems to have the most potent effect on immunity.
At the ASM, Herman Friedman of the University of South Florida in Tampa reported that mice become far more susceptible to the bacteria that cause Legionnaire’s disease if they are injected with THC (the mice get visibly stoned) than with the milder cannabidiol and cannabinol. They also harboured twice as many live bacteria in their livers and spleens, and produced abnormally high levels of certain cytokines. The overproduction of cytokines stoked up the immune system to attack the animals’ own tissue, triggering toxic shock, and killing many of them.
In the test tube, THC dramatically reduces antibody production by B cells from mice, as well as the capacity of T cells and “natural killer cells” to slay infected or cancerous cells. The ability of immune cells like macrophages to gobble up microorganisms also takes a hit, and the cells make inactive forms of tumour necrosis factor—one of the immune system’s key chemical messengers.
Ecstasy priority
But once again, evidence from real-life drug abuse seems to contradict the lab evidence. Marijuana is one of the few recreational drugs not associated with chronic bad health, with the exception that marijuana users between 25 and 40 years have slightly more head and neck cancers.
Of all the recreational drugs, the one least is known about is 3,4-methylenedioxymethamphetamine—or ecstasy. In a rare study, Robert House and colleagues at the IIT Research Institute in Chicago, Illinois, found that ecstasy levels one hundredth those in the blood of a typical user boosted production of interleukin-2 by mouse T cells in a test tube. Interleukin-2 is a cytokine that stimulates production of other T cells. Ecstasy also boosted the activity of mouse natural killer cells in culture. On the other hand, very high concentrations of ecstasy—well above the levels that are lethal to people—suppressed the proliferation of the type of mouse T cells that kill infected cells. Ecstasy use among young people in Britain and the US is booming, so further studies on ecstasy and immunity are a priority.
In fact, experts on drug addiction and its health consequences want more studies across the board. The crucial next step, says Leshner, is to study animals given drugs over long periods—heroin addicts may stay strung out for decades, and dope smokers and coke snorters typically indulge on and off for years. “We need to create animal models of the actual phenomenon, and that means turning animals into real junkies,” he says.
There is also an urgent need to find out which medicines are most effective in immunosuppressed drug addicts, says Leshner. “Drug use is now the major vector for transmission of HIV, hepatitis and TB, and some of it has to do with the immunosuppressive effects,” he says. And better medical care for drug addicts would reap benefits for everyone, by stifling infectious diseases before they spread to the population at large.
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What’s your poison?
So you thought alcohol was a safe drug? Not so, according to studies of people and laboratory animals.
Under the influence, the thymus produces fewer “activated” T cells—immune cells primed to kill specific invaders. Tiddly T cells produce less migration inhibition factor, a chemical that stops immune cells like macrophages from deserting the sites of infection and cancer. And inebriated macrophages are less efficient at gobbling up infected or damaged cells.
Meanwhile, acetaldehyde—an alcohol breakdown product—binds to proteins on the surface of liver cells forming “adducts”. The immune system sees these as dangerous, and picks a fight with otherwise healthy liver cells.
Little wonder that alcoholics are prone to a long list of ills, including tuberculosis; gut-invading bacteria like Salmonella typhimurium and Listeria monocytogenes; head, neck and laryngeal cancers (although that could be the heavy smoking that often accompanies alcoholism); and liver damage caused by hepatitis B and C and the adduct-induced inflammatory responses.
So if you’re still thinking of going out for a few pints tonight, don’t overdo it. “What we are talking about is heavy drinking,” says Thomas Jerrell, who studies alcohol and immunosuppression at Washington State University in Pullman. “A beer or two a day is not going to hurt you.”