Nevertheless, several lines of research suggest that individuals with substance use disorders, including MA users , have higher densities of D3 receptor levels in striatal and extrastriatal brain regions than those who do not frequently abuse drugs . Thus, it seems probable that the lower [18F]fally pride BPND among MA users primarily reflects lower D2 receptor availability in this group compared to controls. An additional limitation includes the possibility of competition with endogenous dopamine influencing [18F]fally pride BPND . That IQ was not assessed is also a limitation, because IQ has been found to be significantly correlated with delay discounting , and a group difference in the former could therefore overshadow the true group difference in the latter. There are also some caveats that should be considered when interpreting the results of this study. First, the MCQ has limited ability to provide precise estimates of discount rates for individuals who discount very steeply. That is, the choice items only probe preference up to a maximum k-equivalence value of 0.25, and this value was assigned as a conservative estimate of discount rate to individuals whose calculated k value was predicted to exceed this value . Second, BPND values were highly correlated across all VOIs examined in both groups of participants, which limits the ability to draw conclusions regarding the relative importance of D2 /D3 receptor availability in specific brain regions to discount rate. Finally, as there is some evidence that abstinence from drugs can increase temporal discounting among addicted individuals , it is possible that abstinence from MA may have amplified the difference in discount rate between MA users and controls. The results of this study may help to explain why low striatal D2 /D3 receptor availability is associated with poor treatment response among individuals with MA dependence and cocaine dependence . This view seems reasonable given that steep temporal discounting has also been linked with poor treatment response among cocainedependent individuals , and predicts relapse among smokers .
The present results lend empirical support to a theoretical model in which Trifilieff and Martinez propose that,cannabis dry rack “low D2 receptor levels and dopamine transmission in the ventral striatum lead to impulsive behavior, including the choice for smaller, immediate rewards over larger, but delayed or more effortful, rewards, which may represent an underlying behavioral pattern in addiction.” Consistent with this model, we found evidence of a negative correlation between discount rate and D2 / D3 receptor availability in the limbic striatal subdivision . The correlation in the limbic striatum did not reach statistical significance, possibly due to the high D3 /D2 receptor ratio in this region and partial volume effects. An important question for future research is to determine whether interventions that increase D2 /D3 receptor availability can reduce temporal discounting, at least among those with low D2 /D3 receptor availability. Pharmacological interventions could prove useful to this end. For example, varenicline increases striatal D2 /D3 receptor availability in rats , and in a study of human smokers, males treated with varenicline showed lower temporal discounting than placebo-treated controls . This finding is compelling considering that dorsal striatal D2 /D3 receptor availability is lower in male smokers compared to nonsmoker controls . There also is evidence that rimonabant increases striatal D2 /D3 receptor availability , and can decrease discounting of delayed rewards in rats . Nonpharmacological approaches may be useful as well, as there is preliminary evidence that intensive exercise can increase striatal D2 /D3 receptor availability in MA-dependent individuals and patients with early-stage Parkinson’s disease . Similarly, in a mouse model of Parkinson’s disease, higher striatal D2 /D3 receptor availability and D2 receptor expression was noted among those exposed to high-intensity exercise relative to non-exercising controls . Establishing a causal link between D2 /D3 receptor availability and temporal discounting is likely to have significant clinical implications.
This is because there is evidence that interventions that reduce temporal discounting are useful for treating disorders that are associated with both steep discounting and low striatal D2 /D3 receptor availability. For instance, contingency management decreases discounting among cocaine-dependent individuals and smokers , and methylphenidate decreases discounting in children with attention-deficit hyperactivity disorder . More importantly, greater reductions in discounting predict a greater likelihood of protracted abstinence among cocaine users and smokers . Thus, if a causative link between D2 /D3 receptor availability and temporal discounting is established, it may lead to the development of novel D2 /D3 -targeted interventions which could be used to more effectively treat a variety of disorders. In conclusion, the results of this study indicate that low D2 / D3 receptor availability is associated with steep temporal discounting. This link may explain why some individuals choose to continue using drugs despite knowledge of their future negative consequences, and could help to guide strategies for treating substance abuse and other psychiatric disorders.To date, this is the largest SC case series describing MABCHMINACA toxicity. In the fall of 2014, MAB-CHMINACA was responsible for more than 125 patients seeking hospital care in Baton Rouge, LA.It is a highly potent SC, which was just recently added to the Schedule 1 Controlled Substance Act in late 2015.The clinical manifestations observed in these patients appear similar to those described with other SC toxicities.The exact mechanism of MAB-CHMINACA toxicity is unknown. Affinities of SCs and their metabolites are multi-fold higher at the CB1 and CB2 receptors than that of Δ-9 THC and are thought responsible for such severe clinical manifestations.CB1 receptors are mostly located in the brain and regulate the central nervous system effects of Δ-9 THC and other cannabinoids; they are also expressed peripherally in adipocytes and skeletal muscle.The identification of CB1 receptors presynaptically on GABA and glutamatergic terminals with increased excitatory and decreased inhibitory tone may be responsible.Other postulated mechanisms include activation of non-cannabinoid receptors and drug-drug synergistic effects.Some patients demonstrated stimulant and serotonergic agent use as detected by comprehensive urine drug LC/ MS testing that could have contributed to their clinical presentation, such as sympathomimetic or serotonergic toxidromes. However, this was not universal and would not explain the fairly consistent clinical presentation of all of these patients.
Further, the relative concentrations of MABCHMINACA do not necessarily correlate with toxicity and may demonstrate the potential lipophilic distribution of the drug to tissue at the time of blood draw. For example, patient #11 had a relatively low concentration, yet expired. Interestingly, post-mortem analysis of a patient who died from MAB-CHMINACA toxicity demonstrated a relatively low amount in the adipose tissue, atypical of other SCs. The authors hypothesized the compound may require time to distribute to that tissue, and that may have been the salient issue regarding patient #11 given the length of time from medical attention.Limitations in real-time detection by routine toxicologic immunoassay screening appear to be a factor in SC use.The reasons for the abrupt, recent increase in exposures, however, remain unclear. The celebration of “4/20” correlated with this surge and might have influenced users. Management of the SC-intoxicated patient centers on meticulous supportive care, as no specific antidote currently exists. Decontamination is of little value. Given their beneficial pharmacokinetic profile, administration of benzodiazepines titrated to clinical effect can control agitation, delirium,hyperthermia and seizures. Cooling measures without antipyretic administration can also be implemented for hyperthermic patients.Endotracheal intubation may be required for the severely intoxicated patient.Serotonin plays a crucial role in emotional processes. A considerable number of imaging studies involving pictures of emotional faces show that changes in serotonergic function are associated with changes in amygdala reactivity when viewing negative facial expressions: Acute tryptophan depletion, which reduces central serotonin synthesis,planting racks leads to higher amygdala activity when processing negative face expressions . Several studies have found that acute/subacute SSRI intervention leads to a decrease in amygdala activation . Further, when the cerebral serotonin level is pharmacologically enhanced by a three-week intervention with a selective serotonin reuptake inhibitor , the ensuing decreased cerebral [11C]SB207145- PET binding in response to pharmacologically increased brain serotonin levels is associated with lower threat-related amygdala reactivity . Whereas it is relatively clear that induction of acute and subacute changes in serotonin neurotransmission leads to changes in emotional processing, less is known about how the neural processing of emotional information is affected by chronic cerebral serotonin depletion. Ecstasy, or 3,4-methylene-dioxymethamphetamine is a widely used recreational drug that has immediate effects in terms of improved mood and feelings of empathy . In this paper, we will use the term “ecstasy” when referring to the recreational human, and “MDMA” when referring to experimental human/animal studies. MDMA exerts its primary effects on the serotonin neurotransmitter system, in particular by reversing normal serotonin transporter function and hence releasing serotonin from the storage vesicles into the synaptic cleft . Animal studies show that repeated exposure to moderate and high doses of MDMA is associated with a reduction in cerebral serotonin levels and a decreased number of SERT binding sites. In humans, prolonged recreational use of ecstasy is also associated with reductions in SERT in both cortical and sub-cortical brain areas .
Most , although not all , molecular imaging studies show that the accumulated lifetime intake of ecstasy correlates negatively with SERT binding, supporting a dose-dependent relationship between recreational ecstasy use and reductions in SERT binding. Thus, it also seems plausible that in humans, an ecstasy-associated reduction in SERT is associated with reduced cerebral serotonin levels, and that the SERT changes may even result from chronically reduced serotonin levels. Additional support for serotonin depletion in recreational ecstasy use comes from the finding of increased levels of the post-synaptic serotonin 2A receptor in most , although not all , studies where ecstasy users have had their serotonin 2A receptors measured. Importantly, lowering brain serotonin levels in preclinical models leads to low SERT combined with high serotonin 2A receptor levels, and low SERT has also been found to be associated with high serotonin 2A receptor levels in humans . The reduction in subcortical SERT binding in ecstasy users seems to be reversible, since a positive correlation with time of abstinence from ecstasy intake has been observed . Taken together, data from these preclinical and clinical studies indicate that there is a causal relationship between ecstasy intake and effects on the serotonergic system. Reduced SERT and serotonin after MDMA/ecstasy exposure in combination with the observed correlation between serotonin depletion and reduced SERT binding in animal studies makes it plausible that SERT binding can be regarded as a representation of the extent of chronic—but most likely reversible—serotonin depletion in long-term ecstasy users. With MDMA being an interesting and promising candidate as adjunct to psychotherapy for treatment of post-traumatic stress disorder and possibly other conditions as well , it is important to explore the possible long-term impact of this drug on serotonergic neurotransmission, as well as the functional consequences of this. Although the multiple and not always pure MDMA doses used recreationally differ from the only few—and pure—doses employed in therapy, recreational use of MDMA/ ecstasy can serve as a model for the long-term effect of repeated doses. In the present study, we used functional magnetic resonance imaging to investigate the functional effects of long-term recreational ecstasy use, representing a model of long-term serotonin depletion, on the neural basis of emotional responses in the amygdala. We hypothesized that amygdala engagement to aversive stimuli would show a positive correlation with accumulated lifetime ecstasy use; a negative correlation with SERT binding, as assessed with positron emission tomography imaging, in the amygdala; and a negative correlation with time since last use of ecstasy, suggesting recovery of amygdala response. The degree of serotonin depletion as reflected by cerebral SERT binding was assessed with PET and the selective SERT radioligand, 11C-DASB, as described in more detail by Erritzoe et al. . In short, PET data were acquired on a GE-Advance scanner as a dynamic 90-minute emission recording after intravenous injection of the radiotracer, 11C-DASB. There was maximum of 1.6 months between the 11C-DASB PET and the fMRI experiment ; approximately half of the group had PET before MRI, and vice versa. The vast majority was scanned within one to two weeks; only two were scanned with an interval of more than a month. For each participant, a mean SERT binding value from the amygdala was calculated.