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Introduction and historical background

Try out PMC Labs and tell us what you think. Learn More. The use of recreational drugs of abuse has generated serious health concerns.

There is a long-recognized relationship between addictive drugs and increased levels of infections. Studies of the mechanisms of actions of these drugs became more urgent with the advent of AIDS and its correlation with abused substances.

The nature and mechanisms of immunomodulation by marijuana, opiates, cocaine, nicotine, and alcohol are described in this review.

Recent studies of the effects of opiates or marijuana on the immune system have demonstrated that they are receptor mediated, occurring both directly via specific receptors on immune cells and indirectly through similar receptors on cells of the nervous system. Findings are also discussed that demonstrate that cocaine and nicotine have similar immunomodulatory effects, which are also apparently receptor mediated. Finally, the nature and mechanisms of immunomodulation by alcohol are described.

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Although no specific alcohol receptors have been identified, it is widely recognized that alcohol enhances susceptibility to opportunistic microbes. The review covers recent studies of the effects of these drugs on immunity and on increased susceptibility to infectious diseases, including AIDS.

The recreational use of legal and illegal drugs of abuse in this country and abroad has aroused serious concerns about the consequences of these drugs on immunity. Marijuana, cocaine, heroin, and other opiates opium osna widely used illegal drugs. There have been numerous clinical reports on the association between infectious diseases and use of illegal drugs. In addition, legal substances such as alcohol and tobacco have been linked to excessive and addictive use and have been correlated with major health problems. Experimental studies using drugs of abuse support the clinical observations that these substances are associated with immunomodulation.

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Studies concerning the effects of addictive drugs on immunity became even more opium osna with the onset of the worldwide epidemic of AIDS. AIDS is caused by human immunodeficiency virus HIV and in a collapse of the immune system, making an individual highly susceptible to opportunistic microorganisms 77, Drugs of abuse have been suggested as possible cofactors, resulting in a more rapid progression of disease 586369 AIDS patients also often use other drugs such as marijuana, alcohol, and nicotine, which some investigators think are immunosuppressive 1359, Thus, there is concern that abused drugs are serving as cofactors in AIDS progression and in alteration of susceptibility to other infectious diseases 6373, Opiates compose a collection of drugs derived from the poppy Papaver somniferum which include opium, morphine, and heroin.

An excellent review of the historical use of opiates has been written by Risdahl et al. It is clear from this review that opiates have had a great impact throughout history on mankind both from use and from the wars over the control of opium. Relics from the Stone Age, pre-dating recorded history, show widespread poppy cultivation.

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Over time, the addictive nature of opium was also recognized. First morphine in the early s and then codeine, heroin, and other opium alkaloids in the late s were synthesized from opium with claims of being the cure of opium addiction During the late s and early s, many medical practitioners began to recognize infections as serious complications of opiate addiction 28, The list of infections associated with opiates continued to increase during the s 89 Also, experimental evidence began to accumulate during this time demonstrating the detrimental effects of opiates on immunity in humans and animals 90, For example, Cantacuzene demonstrated in the late s that morphine-treated guinea pigs had altered phagocytosis and leukocyte trafficking Studies of drug addicts in the early s further demonstrated a connection between drug use and infectious opium osna It is now recognized that IVDUs face many complications from the use of opiates Pulmonary infections, caused by MycobacteriumStaphylococcusStreptococcusHaemophilusand other bacteria, are among the most common diagnoses of opiate abusers A large percentage of infections among IVDUs are related to the methods of injection and life-style practices, which increase their opium osna to microbial pathogens Recent reports continue to discuss the problem of contaminated heroin or drug paraphernalia and infections 15 Numerous investigators, however, have proposed that increased exposure is not the only factor that enhances microbial infections.

They hypothesize that opiates cause immunosuppression and therefore serve as cofactors for microbial infections. These studies have been ly reviewed 59 They have been expanded on by the advent of the AIDS epidemic in the s 30 AIDS and its corresponding decreased host immunity were, and still are, principal players in opportunistic infectious diseases in IVDUs 6376, Several opium osna support that intravenous use of opiates influences the outcome of HIV infection 1658 Moreover, mortality rates from infectious diseases among HIV-infected IVDUs decrease when drug use was discontinued, and this abatement correlated with a decrease in the rate of progression to AIDS Therefore, a correlation between the use of opiates, increased susceptibility to infection, and depressed immunity does indeed exist.

Whether this correlation is due, however, to increased exposure to infectious pathogens through risky behaviors, to immunosuppressive effects of opiates, or to a combination of these two is uncertain at this time.

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Several good reviews of these studies have been ly published 59, The classical receptors are G-protein coupled seven-transmembrane receptors Opiates have been linked to modulations of host resistance to bacterial, protozoan, viral, and fungal infections, using animal models, cell lines, and primary cells. Opiates appear to affect the immune response directly through opioid receptors on immune cells and indirectly via the receptors on neuronal cells.

In vitro studies of immune cells have demonstrated receptor-mediated reduced phagocytosischemotaxis 71and cytokine and chemokine production 42239 While opiates directly modulate host immunity, their effects on physiological function of nonspecific host mechanisms are thought to also alter immune responses and play an important role in increased susceptibility opium osna infection.

These effects are proposed to act through the central nervous system CNS and the hypothalamus-pituitary-adrenal HPA axis. Opiates are known to alter the release of HPA hormones corticotrophin-releasing hormone and adrenocorticotrophic hormone 5which, in turn, alter glucocorticoids cortisol and corticosteronethe end-effectors of the HPA axis.

The glucocorticoids play an important role in decreasing and regulating cellular immune responses Studies have shown that morphine treatments suppress immune parameters in mice through the HPA axis 3164, In addition to these corticoids, immunosuppression via the autonomic nervous system has been observed Shavit et al. The central opioid pathways were involved in immunosuppression of lymphocyte proliferation 7882 Thus, it appears that immunosuppression occurs through direct and indirect mechanism involving receptors on immune cells and the CNS.

Chemical extracts of marijuana contain over compounds opium osna more than 60 cannabinoids.

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The molecular and cellular mechanisms for these effects are not fully defined; however, it appears that receptor as well as nonreceptor mechanisms are involved Like opiate receptors, cannabinoid receptors CBRs are G-protein-coupled seven-transmembrane receptors of which two types have been identified, CB 1 and CB 2 8586, CB 1 receptors are associated with the brain and certain peripheral tissues and are responsible for behavioral effect of THC, while CB 2 receptors are located in the periphery, especially on immune cells 86, Opium osna discovery of CBR has led to the identification of a class of endogenous compounds that bind to these receptors, called endocannabinoids, although the majority of the compounds are eicosanoids 53, opium osna, Studies in the early s using human peripheral blood mononuclear cells PBMCs from marijuana smokers showed a tendency for heavy use to result in suppression of lymphocyte proliferation in culture as well as alterations in PBMCs immune cell subsets Serum immunoglobulin Ig levels were also modulated by marijuana use, with IgG protein levels decreasing and IgE protein levels increasing.

Animal studies started in earnest with the isolation and synthesis of THC by Mechoulam et al. The latter group also observed decreases in the levels of other cytokine after THC treatment Therefore, the data that have accumulated over the past three decades indicate that THC and cannabinoids are immunomodulatory. One of the important risk factors of marijuana use is its suppression of host resistance to infections A correlation between marijuana smoking and herpesvirus infection was observed to increase the risk of mortality in HIV positive marijuana smokers Furthermore, alveolar macrophages from marijuana smokers were found to be deficient in several functional opium osna including phagocytosis and bactericidal activity Disease progression and mortality in different animal models were increased on infection with herpes simplex virus HSV and Friend leukemia virus FLV 35, and with bacterial pathogens such as ListeriaTreponemaand Staphylococcus 87, These studies leave major gaps in our understanding of the cellular and molecular mechanisms mediating these effects on immunity and resistance.

Immune cells have been demonstrated to express CBR; therefore, it is likely that at least a portion of the cannabinoid-induced modulations of the immune cells are directly mediated via their own CBRs 79 The host immunity, however, involves many cell types, both immune and nonimmune, as well as chemical factors such as cytokines and chemokines and hormones of the HPA axis. Thus, there are numerous cellular and molecular mechanisms where THC could be exerting its effects as demonstrated by our Legionella pneumophila infection studies.

In our studies, THC pretreatment of mice infected with THC affects both innate immunity and the development of the adaptive cell-mediated immune response.

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Initially, we reported that mice receiving a THC injection 1 day before and 1 day after a sublethal L. This THC-induced shift away from a Th1 response has also been observed in other models involving THC treatment and tumor immunityendotoxemic miceand NK cell activity These studies suggest that cannabinoids have the ability to bias the developing opium osna response from Th1 cell-mediated toward Th2 antibody-mediated immunity.

Interestingly, Th shifts have also been observed toward Th2 following treatment with morphine and toward Th1 following treatment with norepinephrine It is possible, therefore, that drugs used either recreationally or therapeutically might enhance or suppress infections by modulating Th activity in the host.

Clearly, the full extent of these findings needs clarification. Cocaine is derived from the coca plant, Erthroxylon coca. Being an alkaloid, cocaine is water soluble and readily absorbed through mucous membranes of the body.

Roth et al. These immunomodulations may be through receptors located in the periphery, as was demonstrated with cocaine-induced suppression of mitogen-stimulated lymphoproliferation Therefore, while studies of the immunological impact of cocaine have started, there is much more research in this area to be done. Cigarette smoking is linked to community-acquired pneumonia and is considered one of the risk factors for respiratory infections 689 Cigarette smoke is composed of two components, the vapor phase and the particulate phase.

Nicotine is a small organic alkaloid synthesized by tobacco plants and is recognized as the addictive component of cigarettes. While its lipophilic nature allows small amounts to cross directly through cell membranes, the primary biological effects are proving to be receptor mediated.

Nicotine is an agonist for nicotinic acetylcholine receptors nAChRswhich are present on cells of the CNS as well as other cells throughout the body including immune cells 80 The neural nAChRs are upregulated in smokers Rapid opium osna of nicotine from cigarette smoke in the lungs to the brain increases dopamine transmission within the brain in the shell of the nucleus accumbens, a region essential for reward processing that has been associated with addictive properties of other drugs including opiates, alcohol, and THC Effects of nicotine and cigarette smoke on host resistance mechanisms in vivo and in vitro.