Cell‐Mediated Immune Response in MDMA Users After Repeated Dose Administration

Abstract

Acute administration of 3,4‐methylenedioxymethamphetamine (MDMA, “ecstasy”) produces time‐dependent immune dysfunction in humans. Recreational use of MDMA generally includes repeated drug consumption, often in association with other drugs, such as alcohol and cannabis. In the laboratory setting, repeated MDMA administration to healthy MDMA consumers produced a time‐dependent immune dysfunction similar to that observed with the ingestion of a single dose, and the first of the two administrations paralleled the time‐course of MDMA‐induced cortisol stimulation kinetics and MDMA plasma concentrations. A significant decrease in CD4 T‐helper cells with simultaneous increase in natural killer (NK) cell and a decrease in functional responsiveness of lymphocytes to mitogenic stimulation was observed. Response to the second dose was either long‐lasting compared with the first dose or disproportionate and did not show any parallelism with cortisol and MDMA plasma concentrations. This circumstance extended the critical period during which immunocompetence is highly impaired as a result of MDMA use. Accumulation of MDMA in the body of a poor metabolizer induced higher immunomodulatory effects with statistically significant differences in NK cell function compared with extensive metabolizers. When basal values of lymphocyte subsets were examined in a population of recreational MDMA users participating in different clinical trials, alterations in several immunological parameters were observed. The absolute number of lymphocytes, in particular T lymphocytes and CD4 T‐helper cell subsets, showed a trend toward reduced values, although cell counts were within normal limits. By contrast, NK cells in MDMA consumers were reduced to one‐third of those from healthy persons. A statistically significant decrease in affected immune parameters was recorded during a 2‐year observation period in a subgroup of recreational MDMA users. These permanent alterations in immunologic homeostasis may result in impairment of general health and subsequent increased susceptibility to infection and immune‐related disorders.

Plasma Drug Concentrations and Physiological Measures in ‘Dance Party’ Participants

“…A decrease in plasma urea and lymphocytes were seen with an increase in neutrophils. It is of interest that a number of studies have indicated that MDMA may have an influence in suppressing immune function in humans due to depression of lymphocyte cell subsets such as T-helper cells and CD4 T-helper cells (Pacifici et al, 1999(Pacifici et al, , 2002. The biological significance of the deceased urea is unclear and is contrary to what would be predicted from case studies demonstrating rhabdomyolysis and renal failure.…”

“…In particular, there are no data available regarding plasma levels of MDMA in recreational 'ecstasy' consumers who do not develop medical complications (or are not apprehended by authorities). There have been several studies in which MDMA was administered to humans in a controlled laboratory setting and in which plasma pharmacokinetics of MDMA were measured (Helmlin et al, 1996;de la Torre et al, 2000de la Torre et al, , 2004Pacifici et al, 2001Pacifici et al, , 2002. However, these studies necessarily involved a limited dose range that was well below that reported by some MDMA users (Parrott, 2005).…”

Mephedrone-Related Fatalities in the United Kingdom: Contextual, Clinical and Practical Issues

“…Anecdotally, it appears that alcohol is taken in association with stimulants to get a stronger/better 'high'. Similarly, other stimulants such as MDMA/ecstasy, whilst in the presence of alcohol, show more significant physiopathological effects (Pacifici et al, 2002;Schifano et al, 2003a). In 15 cases mephedrone was ingested with stimulants.…”

A mechanistic insight into 3,4-methylenedioxymethamphetamine (“ecstasy”)-mediated hepatotoxicity

“…MDMA-mediated depression of the innate and adaptative immunity has been demonstrated in humans (Pacifici et al , 2002 as well as laboratory animals (Connor et al 2000(Connor et al , 2005. Despite the in vivo evidence, several in vitro studies have only presented a modest influence or even failed to show a significant MDMA-mediated immunosuppression (House et al 1995;Connor et al 2000;Camarasa et al 2010).…”

“…Although this observed immunosuppression is in agreement with the results from in vivo studies, it appears to contradict the increased MDMA-induced cytotoxicity we observed in our HepG2/PBMC co-culture. In relation to these immunosuppressive effects, it has been suggested that MDMA could probably be the cause of a greater susceptibility to infectious diseases through a reduction of pro-inflammatory events (Pacifici et al 2002;Boyle and Connor 2010;Carvalho et al 2010). …”