Just a few questions before I put some any effort into making some suggestions, personally after many years of experimentation I tend to gravitate towards the pharmaceutical solution to physiological problems, rather then naturopathic supplements and the like. Though there are a minority of effective supplements out there.
I would be extremely interested in hearing about any pharmaceuticals that have the potential to address this kind of damage. Both out of sheer curiosity about neural regeneration in general, but also because this question comes up a lot here, and in the threads I linked to we seem to be collecting progressively better answers. And I have several friends who have ranged between single and excessive constant use of MDMA, some of whom are noticing cognitive deficits and trying to recover mental faculties to varying degrees.
My suggestion of withanolide's axonal regeneration capability is unproven in vivo, but in my research about neuroregenerative agents I haven't come across any others with this specific ability (does an increase in neurotrophic factors in general have any effect on this type of damage, do you think?). I for one would be extremely grateful for your opinion on the matter.
Here's a few of the imaging studies jama mentioned. I was unaware of some of the research from the past 5 years (esp. the NeXT study), which is quite compelling.
J Psychopharmacol. 2010 Feb;24(2):187-201. Epub 2009 Mar 20.
MDMA (ecstasy) use is associated with reduced BOLD signal change during semantic recognition in abstinent human polydrug users: a preliminary fMRI study.
Raj V, Liang HC, Woodward ND, Bauernfeind AL, Lee J, Dietrich MS, Park S, Cowan RL.
During semantic recognition, lifetime MDMA use was associated with decreased activation in left BA 9, 18 and 21/22 but not 45. This was partly influenced by contributions from cannabis and cocaine use. MDMA exposure was not associated with accuracy or response time during the semantic recognition task. During semantic recognition, MDMA exposure was associated with reduced regional brain activation in regions mediating verbal memory.
Drug Alcohol Depend. 2003 Dec 11;72(3):225-35.
Reduced cortical gray matter density in human MDMA (Ecstasy) users: a voxel-based morphometry study.
Cowan RL, Lyoo IK, Sung SM, Ahn KH, Kim MJ, Hwang J, Haga E, Vimal RL, Lukas SE, Renshaw PF.
Structural magnetic resonance imaging (MRI) scans of 31 MDMA polydrug users versus 29 non-MDMA users were compared using voxel-based morphometry (VBM) to assess regional brain gray and white matter concentration. VBM employs gray/white matter segmentation and statistical parametric mapping (SPM) analysis to calculate a voxel-wise comparison of regional gray or white matter concentration. Using this method, we consistently found several brain regions having decreased gray matter concentration in MDMA polydrug users. These regions were localized to neocortex in bilateral Brodmann area (BA) 18, left BA 21, and left BA 45, as well as bilateral cerebellum, and midline brainstem. Overall, these preliminary findings suggest that MDMA polydrug users have multiple regions of gray matter reduction, potentially accounting for previously reported neuropsychiatric impairments in MDMA users.
Brain. 2008 Nov;131(Pt 11):2936-45. Epub 2008 Oct 7.
Sustained effects of ecstasy on the human brain: a prospective neuroimaging study in novel users.
de Win MM, Jager G, Booij J, Reneman L, Schilt T, Lavini C, Olabarriaga SD, den Heeten GJ, van den Brink W.
Decreased FA and increased ADC in the thalamus may reflect ecstasy-induced axonal damage, because axonal cell membranes are known to be responsible for most of the restriction of water diffusion and axonal damage lead to decreased FA and increased ADC. This finding of ecstasy-induced brain pathology in the thalamus corroborates findings from previous studies showing decreased thalamic SERT densities in (heavy) ecstasy users, most probably reflecting damage to terminals of serotonergic axons...As the thalamus is important for neurocognitive processes, one can speculate that ecstasy-induced thalamic damage is (partly) responsible for decreased verbal memory performance frequently reported in heavy ecstasy users and recently also shown in the current prospective cohort of low-dose ecstasy users (Schilt et al., 2007).
...
In line with this, a previous study showed a positive relation between mean FA and age in young adults up to 39.5 years, suggesting that structural changes in the brain continue in normal young adults, especially in areas with low anisotropy (Yoshiura et al., 2005). Therefore, we speculate that this normal maturation did occur in the persistent ecstasy-naives; whereas, this failed to occur in the group of novel ecstasy users.
Br J Psychiatry. 2008 Oct;193(4):289-96.
Neurotoxic effects of ecstasy on the thalamus.
de Win MM, Jager G, Booij J, Reneman L, Schilt T, Lavini C, Olabarriaga SD, Ramsey NF, Heeten GJ, van den Brink W.
The most interesting finding is that different imaging techniques all showed a specific effect of ecstasy on the thalamus. Even after adjustment for amphetamine, cocaine, cannabis and other relevant potential confounders, a significant effect of ecstasy, and no effects of any of the other drugs, was found on [123I]β-CIT binding (reduced), fractional anisotropy (reduced) and rrCBV (increased) in the thalamus. As [123I]β-CIT SPECT was previously validated to assess in vivo binding to serotonin transporters, the finding of decreased [123I]β-CIT binding probably reflects lower serotonin transporter densities in ecstasy users. Moreover, the thalamus is a serotonin transporter-rich area and previous studies showed that [123I]β-CIT binding in the thalamus is mainly related to transporter binding, although the thalamus also contains noradrenaline transporters. Diffusion tensor imaging measures diffusional motion of water molecules in the brain which is normally restricted in amplitude and direction by cellular structures such as axons. When axons are damaged, extracellular water content increases and fractional anisotropy decreases. Therefore, it is likely that the observed decreased fractional anisotropy is related to ecstasy-induced axonal injury.
...
Taken together, it seems that these measurements in the thalamus converge in the direction of decreased serotonergic function, with decreased serotonin transporter binding and decreased fractional anisotropy values probably reflecting damage to serotonergic axons and increased rrCBV due to decreased vasoconstriction caused by depletion of serotonin. Previous studies in animals also showed ecstasy-induced axonal damage to the serotonergic axons of the thalamus, although signs of re-innervation after a period of recovery were also observed. As the thalamus plays a key role in awareness, attention and neurocognitive processes such as memory and language, one can speculate that ecstasy-induced serotonergic damage to the thalamus is (partly) responsible for reduced verbal memory performance frequently reported in ecstasy users.
And some cognition studies (though in this context I think addressing the neurological damage should have greater priority than trying to improve verbal memory directly, unless some agent specifically obviates deficits caused by damage to the regions mentioned above):
Arch Gen Psychiatry. 2007 Jun;64(6):728-36.
Cognition in novice ecstasy users with minimal exposure to other drugs: a prospective cohort study.
Schilt T, de Win MM, Koeter M, Jager G, Korf DJ, van den Brink W, Schmand B.
At the initial examination, there were no statistically significant differences in any of the neuropsychological test scores between persistent Ecstasy-naive subjects and future Ecstasy users. However, at follow-up, change scores on immediate and delayed verbal recall and verbal recognition were significantly lower in the group of incident Ecstasy users compared with persistent Ecstasy-naive subjects. There were no significant differences on other test scores. CONCLUSIONS: Our findings suggest that even a first low cumulative dose of Ecstasy is associated with decline in verbal memory. Although the performance of the group of incident Ecstasy users is still within the normal range and the immediate clinical relevance of the observed deficits is limited, long-term negative consequences cannot be excluded.
Psychopharmacology (Berl). 2010 Jan;207(4):583-91. Epub 2009 Oct 13.
Long-term neuropsychological effects of ecstasy in middle-aged ecstasy/polydrug users.
Schilt T, Koeter MW, Smal JP, Gouwetor MN, van den Brink W, Schmand B.
Moderate to heavy ecstasy/polydrug users performed significantly worse on a verbal memory task than none or very mild ecstasy using polydrug users and drug naives. Moderate and heavy ecstasy/polydrug users also differed significantly from drug-naives on measures of depression, sensation-seeking and impulsivity but not from none or very mild ecstasy-using polydrug users.
Psychol Med. 2008 Sep;38(9):1309-17. Epub 2007 Nov 8.
Specific effects of ecstasy and other illicit drugs on cognition in poly-substance users.
Schilt T, de Win MM, Jager G, Koeter MW, Ramsey NF, Schmand B, van den Brink W.
Ecstasy use [mean 327 (S.D.=364) tablets in lifetime] had a specific significant dose-related negative effect on verbal delayed recall after adjusting for the use of other drugs.
Neuropsychopharmacology. 2008 Jan;33(2):247-58. Epub 2007 Apr 25.
Assessment of cognitive brain function in ecstasy users and contributions of other drugs of abuse: results from an FMRI study.
Jager G, de Win MM, van der Tweel I, Schilt T, Kahn RS, van den Brink W, van Ree JM, Ramsey NF.
Multiple regression analysis showed that associative memory performance was affected by amphetamine much more than by ecstasy. Both drugs affected associative memory-related brain activity, but the effects were consistently in opposite directions, suggesting that different mechanisms are at play. This could be related to the different neurotransmitter systems these drugs predominantly act upon, that is, serotonin (ecstasy) vs dopamine (amphetamine) systems.
And finally, here's a monkey study which is highly relevant. The
results section of this paper details specific areas and types of 5-HT injury, and the
discussion analyzes factors which may have been involved in the healing which took place over the 7 years. Way too much info to post here, but very technical and highly recommended.
J Neurosci. 1999 Jun 15;19(12):5096-107.
Altered serotonin innervation patterns in the forebrain of monkeys treated with (+/-)3,4-methylenedioxymethamphetamine seven years previously: factors influencing abnormal recovery.
Hatzidimitriou G, McCann UD, Ricaurte GA.
In summary, the present results indicate that MDMA-induced 5-HT neural injury in nonhuman primates lasts for at least 7 years and may well be permanent. In addition, the present results point to several factors that appear to influence axonal recovery after MDMA injury, including the distance of the damaged terminal field from its nerve cell body of origin, the size or severity of the initial lesion, and the proximity of the injured axons to myelinated fiber tracts. Additional studies are needed to assess the relative importance of each of these factors and to identify other variables that may influence recovery of 5-HT axons after MDMA injury. Finally, it will be important to use newly developed positron emission tomography imaging techniques (McCann et al., 1998) to determine whether the present findings generalize to humans with a history of recreational MDMA use.
Edited by chrono, 03 August 2010 - 05:42 PM.
