Alt er farlig hvis du vil det skal være.

Om antioksidanter er en del av argumentasjonen nødvendig for å erklære substans X for farlig, er det ufarlig i min bok. (Dog det er verdt å nevne at det er jeg som er idioten her. Hva vet vel jeg)

Ikke mine data.

5. MDMA’s long-term effects and reversibility

After the acute 5-HT release, TPH2, SERT, 5-HIAA, 5-HT2A receptor and 5-HT it self are all found to be long-term reduced, dependent on different durations of abstinence time after the MDMA treatment. The extents of these markers decrease and whether there is non-, partial or complete recovery is an extensively studied part of MDMA research, and might suggest an irreversible neurotoxicty. MDMA shows brain regional differences in its effects on these parameters. However, cortex is the most studied region [36], it has the highest density of 5-HT2A receptors [39] and appear generally to be most sensitive to long-term MDMA induced changes [41]. Therefore, this section will focus on cortical effects, while changes in other brain regions will only be discussed if exceptional. For SERT and 5-HT2A human studies are included in addition to rat studies, and therefore its important to have in mind that humans are thought to generally be more sensitive than rats to MDMA [42]. Also, a normal MDMA dose of 1-2 tablets–à 80–150 mg [4] for a human recreational user correspond to 5 mg/kg dose to a rat [1]. The rat studies are all postmortem studies.

5-HIAA and 5-HT levels:
5-HIAA is the main 5-HT metabolite, and is rapidly produced from the 5-HT degradation product 5-HIAL by the enzyme aldehyde dehydrogenase (ALDH). 5-HIAL has much shorter half-life than 5-HIAA [9], and 5-HIAA is therefore the most frequently assessed 5-HT metabolite [9]. Due to the putative neurotoxic effects of MDMA, it is important to evaluate levels of 5-HT and its metabolites after MDMA usage.

In rats 5-HT was already 3 hours after MDMA treatment substantially depleted [18, 22, 36, 43-45], which was followed by a gradual recovery after 6 hours [18, 22, 44, 46] going toward [22, 44] or reaching control values 24 hours post treatment (Table A1) [18]. From here there is a new phase of 5-HT depletion, seen some days after MDMA administration [18, 20, 22, 29, 31, 35, 36, 41, 43, 44, 47-52]. The 5-HT depletion is seen after 3 days, and does not even recover to pre-MDMA levels after a year in some cortical areas [46, 49, 50]. Though incomplete, there is often a pronounced and steady recovery from one week to about 6 months after MDMA [20, 22, 49, 50], which levels out during 7-12 months after MDMA treatment (Fig. 2) [49, 50]. In spite of this, the 5-HT depletion in one case lasted for at least 4 weeks without any recovery [46], and specific brain regions such as parietal, prefrontal, frontal and occipital cortex actually showed small reductions in 5-HT levels even 7-12 months after MDMA use [49, 50]. In contrast, striatum [20, 49], hypothalamus [41, 49, 50] and hippocampus [50] showed complete recovery, and recovery was seen as early as 8 weeks for striatum [50], and hyper-regulation for hypothalamus after a year [41]. 5-HIAA levels show generally the same long-term trends as 5-HT levels both regarding depletion and reversibility (Table A2) [1, 20, 22, 35, 36, 44, 46, 48, 50-53], although might lag behind [22, 53]. For both 5-HIAA and 5-HT levels the recovery was highly dose dependent, where high doses [1, 18, 22, 29, 44, 53] and doses given several of times with short intervals gave the largest depletions (Fig. 3) [29, 48]. Despite this, the length of the inter-dose intervals seems to have a larger influence than the dose size, possibly be due to exhaustion of the system with repeated dosing [48].


TPH2 levels:
Measuring the levels of TPH2 differs from the other serotonergic markers in two ways. Firstly, in addition to be measured by the protein level directly by antibodies, the TPH2 activity is also measured, determined by 5-HTP level, [14C]CO2 trapping [22-24] or the 5-HT synthesis ratio [20]. Secondly, TPH2 is located in all neuronal compartments, so it can also be measured in the 5-HT soma in rostal raphe nuclei [2]. The rostal raphe nucleus is where the serotonergic nerves arise and project fibers to various sites of the forebrain [54]. There is a reduction of TPH2 from 15 minutes post MDMA treatment as mentioned earlier, continuing after 3 hours and from here the decrease is still persisting (Table A3) [20, 22-24, 36]. Similar declines can also be seen when measuring the TPH2 protein levels after 1 and 2 weeks in cortex [54] and dorsal raphe nucleus [2], respectively. There are tendencies of a slow recovery lasting half a year before reaching control values [20] and starting one [23] or two [20] weeks after MDMA administration. The mRNA expression of TPH was hyper regulated in the dorsal raphe nucleus two weeks post treatment with MDMA, that either may be compensation for some kind of irreversible binding or axonal loss [2]. Synthesis of new enzymes is in conflict with the fact that the TPH2 protein synthesis inhibitor cyclohexamide did not prevent the return of enzymatic activity after MDMA treatment [24].


SERT levels:

Rats: