Long Term Effects Of Ecstasy On The Brain – Preliminary results on the long-term effects of dextromethorphan on MDMA-mediated serotonergic deficiency and volumetric changes in primates based on 4-[18F]-ADAM PET/MRI

Changes in the serotonergic system due to the consumption of 3,4-methylenedioxymethamphetamine (MDMA) (ecstasy) have been widely documented. However, knowledge of the reversibility of these neurotoxic effects based on in vivo assessments of serotonin transport (SERT) availability remains limited. This study aimed to evaluate the long-term neurotoxicity of MDMA after 66 months of abstinence and explored whether dextromethorphan, a non-competitive N-methyl-D-aspartate (NMDA) receptor, could attenuate MDMA-induced neurotoxicity using 4- [

Long Term Effects Of Ecstasy On The Brain

Long Term Effects Of Ecstasy On The Brain

F]-ADAM, an imaging ligand that selectively targets SERT, with positron emission tomography (PET) technology. Nine monkeys (Macaca cyclopis) were used in this study: control, MDMA and DM + MDMA. Static 4-[

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F]-ADAM PET was performed 60 and 66 months after drug treatment. The availability of serotonin transport (SERT) was presented as the specific absorption rates (SURs) of 4-[

F]-ADAM in brain regions. Voxel-based region-specific SERT availability was calculated to generate 3D PET/MR images. Volumetric structural magnetic resonance imaging (MRI) analysis was also performed at 60 months. Decreased significantly 4-[

F]-ADAM SURs were observed in the striatum and thalamus of the MDMA group at 60 and 66 months compared to controls; midbrain and frontal cortex SURs were similar at 60 and 66 months in the MDMA and control groups. All eleven brain regions showed significantly lower self-recovery rates (~13%) over time; the occipital cortex and cingulate recovered to baseline within 66 months. DM attenuated MDMA-induced SERT deficiency on average by ∼8 and ∼1% at 60 and 66 months, respectively; while significant differences were observed between the thalamus and amygdala of the MDMA and DM + MDMA groups at 66 months. Compared to controls, the MDMA group exhibited significantly increased gray matter volumes (~6.6%) in the frontal cortex, occipital cortex, caudate nucleus, hippocampus, midbrain, and amygdala. Furthermore, gray matter volumes of the occipital cortex, hippocampus, and amygdala were negatively correlated with 4-[

F]-ADAM SURs from the same regions. DM (n = 2) did not appear to affect the volumetric changes induced by MDMA. The 4-[

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F]-ADAM SURs, lower self-recovery rate, and increased volumetric values ​​indicate that the occipital cortex, hippocampus, and amygdala still exhibit MDMA-induced neurotoxicity after 66 months of abstinence. Furthermore, DM may prevent MDMA-induced serotonergic deficiency, as indicated by increased 4-[

3,4-methylenedioxymethamphetamine (MDMA), commonly known as ecstasy or molly, is a synthetic drug that acts as a stimulant, hallucinogen, and entactogen. MDMA is used recreationally for its hallucinogenic and mild stimulant properties, as well as its ability to increase emotional closeness (Lyles and Cadet, 2003). However, studies have also demonstrated that the effectiveness of MDMA may serve as a potential treatment for anxiety in people with post-traumatic stress disorder (PTSD) and terminal illnesses (Morgan, 2020).

3,4-methylenedioxymethamphetamine increases the activity of three neurotransmitters: dopamine, serotonin (Schmidt et al., 1987; Gough et al., 1991), and norepinephrine (Rothman et al., 2001). The drug increases the synaptic release of these neurotransmitters (Sabol and Seiden, 1998) and/or blocks their reuptake (Berger et al., 1992; Verrico et al., 2008), resulting in increased levels of neurotransmitters within the synaptic cleft, which by in turn, it affects mood, energy levels, appetite, confidence, sexual activity, emotions and sleep. MDMA also carries serious risks, including hyperthermia, cardiovascular effects, mental disability, risky behavior, and fatal overdose (Bolla et al., 1998).

Long Term Effects Of Ecstasy On The Brain

Although the recreational effects of MDMA generally last about 3 to 6 hours, the half-life of MDMA is 8 to 9 hours (Freye, 2009). De La Torre et al. (2000) found that the maximum effects of MDMA are observed in the first 1 and 2 hours and decrease approximately 4 to 6 hours after ingestion of the drug (De La Torre et al., 2000). Research in rodents has shown that repeated administration of moderate to high doses of MDMA induces long-lasting sensitization of noradrenergic and serotonergic neurons, which correlates with behavioral sensitization (Kirilly, 2010) and selective ablation of serotonergic axon terminals in the forebrain (O’hearn and others, 1988). MDMA-induced 5-HT neural injury in nonhuman primates lasted at least 7 years and may well be permanent (Hatzidimitriou et al., 1999). Several factors are known to influence the recovery of 5-HT axons after MDMA administration, including the distance between the terminal field of the affected axon and the rostral raphe nuclei, the degree of initial 5-HT axonal injury, and possibly the proximity of the damaged location. 5-HT axons to myelinated fiber tracts ( Hatzidimitriou et al., 1999 ; Chiu et al., 2015 ; Vegting et al., 2016 ).

Long Term Effects Of “ecstasy” Use On Serotonin Transporters Of The Brain Investigated By Pet

SERT functional imaging has been employed in vivo using single photon emission computed tomography (SPECT) or positron emission tomography (PET) to further explore the effects of MDMA on the serotonergic system (Skye and Hwang, 2016). Using [

C]-(+)-McN5652 PET, Mccann et al. (2005) observed decreased global and local SERT binding in 23 previous ecstasy users compared to 19 non-MDMA controls (Mccann et al., 2005). Semple et al. (1999) used [

I]-β-CIT) SPECT and detected a cortical reduction in brain SERTs in long-term MDMA users compared to MDMA-naïve individuals using other drugs (Semple et al., 1999). Buchert et al. (2003) demonstrated that distribution volume ratios (DVR) in the midbrain and thalamus were significantly lower in current ecstasy users compared to drug-naïve control subjects, and concluded that prolonged ecstasy-induced changes in the serotonergic system brain cells last several weeks (Buchert et al., 2003).

Dextromethorphan (DM, 3-methoxy-17-methylmorphinan), a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has been widely used as an antitussive agent. It has been suggested that DM reduces neuronal damage and modulates pain sensations through non-competitive antagonism of excitatory amino acids (EAAs) (Siu and Drachtman, 2007). Excitotoxicity is a phenomenon that describes the toxic actions of excessive excitatory neurotransmitters, mainly EAA glutamate, which lead to exacerbated or prolonged activation of receptors, which initiates a cascade of neurotoxicity that ultimately leads to loss of neuronal function and to cell death (Armada-Moreira et al., 2020; Suzuki et al., 2021). In addition to its therapeutic effects in terms of antitussive activity (Craviso and Musacchio, 1983), cancer pain relief (Weinbroum et al., 2000) and methotrexate toxicity (Kishi et al., 2000), DM has also been used as a neuroprotective. agent for seizures (Schmitt et al., 1994), cerebral ischemia (Lo and Steinberg, 1991), and Parkinson’s disease (Liu et al., 2019).

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As described above, over the past two decades, several SERT imaging agents have become available for human SPECT or PET studies, and some of these agents labeled with

F-labeled radioligands can be transported off site if a cyclotron is not available. The most important advantages of PET imaging are its much higher sensitivity and better contrast and spatial resolution compared to SPECT (Rahmim and Zaidi, 2008). Therefore, a series of

F]fluoromethyl)-(+)-McN5652 has been studied in humans and shown to be suitable for in vivo quantification of SERT with PET (Hesse et al., 2012), and 4-[

Long Term Effects Of Ecstasy On The Brain

The F]F-ADAM developed by our group was synthesized and evaluated in translational studies of its specificity for SERT in rodents (Ma et al., 2009) and primates (Huang et al., 2010). Furthermore, the safety and high specificity of 4-[

Ecstasy Addiction: Signs, Effects & Treatment

F]-ADAM PET, we also reported that MDMA induced neurite damage and neuron death in serotonergic neurons in vitro (Li et al., 2016). MDMA-treated rats exhibited reduced SERT availability in the midbrain and thalamus within 2 weeks, and these changes were associated with depressive behaviors ( Shih et al., 2016 ).

F]-ADAM, In order to investigate the topic of MDMA-induced SERT deficiency and explore whether DM exerts a neuroprotective effect, we performed SERT imaging using [

I]-ADAM SPECT in the primate brain (Ma et al., 2009). We observed that the MDMA-induced decrease in central SERT levels persisted for more than 4 years. O [

I]-ADAM signals were significantly lower in the brains of the MDMA group than in the control group, indicating that the MDMA-treated monkeys had lower levels of SERT in the brain. We also reported that DM exerts a protective effect against serotonergic aberrations induced by MDMA (Ma et al., 2016).

Methylenedioxymethamphetamine (mdma): Serotonergic And Dopaminergic Mechanisms Related To Its Use And Misuse

F]-4-ADAM PET/CT/MR, we further evaluated the availability of SERT, rate of self-recovery and volumetric changes in various brain regions of primates exposed to MDMA 6.5 years after drug administration and also evaluated the neuroprotective effects of Teacher. To extend our previous [

I]-ADAM SPECT, the motivation for this study was (1) to gain a better understanding of prolonged post-MDMA SERT deficiency up to 66 months; (2) emphasize certain specific regions; that is, post-MDMA 3D region-specific SERT PET images are superior to SPECT images; and (3) highlight that current state-of-the-art PET and MRI scanners can benefit greatly from improvements in innovative image reconstruction algorithms; that is, MDMA-induced changes in MRI structural volumetric analysis versus PET SERT functional activity.

F]-ADAM, a SERT-specific radioligand, was synthesized using an automated synthesis device as previously reported (Peng et al., 2008). In summary, the 4-[ precursor

Long Term Effects Of Ecstasy On The Brain

. Purification by high-performance liquid chromatography yielded the desired compound with approximately 3% radiochemical yield at end of synthesis (EOS) in a 120 min synthesis period. The EOS of 4-[

Addiction And Dopamine Neurotransmitters: How Addiction Works

F]-ADAM can be increased to approximately 15% using a different precursor and manual synthesis (Huang et al., 2009). Chemical and radiochemical purities were >95% and specific activity was >3 Ci μmol

Nine Formosan rock monkeys (Macaca cyclopis) aged 4 to 6 years were evaluated in this study (Table 1). The animals were housed separately in

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