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The Anhedonia Thread

anhedonia depression attention l-dopa ssre adaptogen quetiapine consummatory anhedonia

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#421 gamesguru

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Posted 23 June 2023 - 08:53 PM

The 5ht2a receptor causes a whole host of symptoms in psychotic disorders. Flat affect is the worst, before flat affect is blunted affect and similar things. Are you sure you're flat and not just the less severe versions?

 

I've found Ginkgo Biloba to be effective against the fatigue and emotional blunting (doesn't fully resolve though it works well) but sadly Ginkgo Biloba is notorious for causing anxiety. I believe it is a 5ht2a antagonist.

 

Okay, so I wasn't able to find conclusive evidence that ginkgo antagonizes 5-HT2A. But let's suppose for a second it does, even though most research generally finds ginkgo to be well-tolerated in schizophrenia.

Perhaps this cumulative anxiety component just speaks to the need to use it—not on a daily basis—but rather as needed?

Ginkgo is one of the few things that led to an immediate and obvious improvement in my anhedonia. I had not used it in nearly a year due to the exact side effect you mentioned—anxiety. But I am hopeful this side effect can be managed or minimized through an infrequent dosing schedule, exercise, or other supplementation.

In reviewing my supplement log and correlating it with my diary/journal, I identified ginkgo as one of the things that was possibly effective in motivating. I obtained a relatively inexpensive bulk order but it seems to be just as effective as before, because my response to treatment was immediate, extensive, and lasting. Ginkgo is a mainstay in any treatment plan for ADHD and depression. I think dopamine plays a pivotal role in anhedonic depression[3], and that ginkgo has unique activity here.

I think any reports of anxiety after long-term treatment with ginkgo may be equally well explained by dopamine/NE depletion, changes in GABA[4] and alpha-2 adrenoreceptor activity, and COMT inhibition. Sometimes I think there is a balance between stimulation and relaxation, people want to be perfectly confident and fluid but never feel any stress and I just don't know if it's realistic. If you turn anxiety down too low you'll have a blank slate, but if you stimulate yourself too much you'll be dragged in 5 different directions and distraught over which way to go.

There are probably ways to knock 5-HT2A down (and GABA up) and counteract anxiety: lower interval dosing (e.g. twice a week), magnesium, tryptophan / 5-HTP, Kava, exercise[2], certain anti-psychotics[1], serotonergic psychedelics, as well as non-psychedelic lysergic acid derivatives (e.g. Methysergide, Lisuride), lithium[5], and bacopa[6].
 

Furthermore, global treatment with a selective 5-HT2AR antagonist (MDL11930) generated an anxiety phenotype. Thus, synaptic recruitment of 5-HT2AR in BLA (basolateral amygdala) neurons may mediate the anxiolytic effects of exercise.

 

Here, we report an increase in basal [5-HT]ext in the ventral hippocampus of BDNF+/- mice, which is normalized in response to fish oil-enriched diet. Interestingly, evidence indicated that an abnormally elevated 5-HT tone favors anxiety through the activation of specific post-synaptic 5-HT receptors including the 5HT1A, 5-HT2A/C or 5-HT3 subtypes (Hamon, 1994). Although the impact of fish oil-enriched diet on hippocampal [5-HT]ext levels remains elusive, a recent study pointed out that omega-3 PUFAs supplementation in diet increases tissue 5-HT contents in hippocampus and cortex associated to reduced 5-HIAA levels in 3 months-old rats (Vines et al., 2012). The latter findings are relevant in light of our microdialysis data since an accumulation of tissue (i.e., intracellular) 5-HT in fish oil fed animals could reflect lower [5-HT]ext, notably if the release process is dampened (Kodas et al., 2004). It is noteworthy that the putative inhibitory influence of fish oil-enriched diet on [5-HT]ext levels in the hippocampus of BDNF+/- mice may also result from mechanisms involving the tryptophan hydroxylase 2 (TpH2), the rate-limiting enzyme of 5-HT synthesis, and/or the monoamine oxydase (MAO), an enzyme important in the catabolism of 5-HT. However, the observations that omega-3 PUFAs enhance the expression of tryptophan hydroxylase-2 (TPH-2) (McNamara et al., 2009), while attenuating that of MAO-A/B in the brain (Delion et al., 1997; Chalon et al., 1998; Naveen et al., 2013) are not compatible with our neurochemical data.

 

[1] Quesseveur, G., Nguyen, H. T., Gardier, A. M., & Guiard, B. P. (2012). 5-HT2 ligands in the treatment of anxiety and depression. Expert opinion on investigational drugs, 21(11), 1701–1725. https://doi.org/10.1...784.2012.719872

[2] Leem, Y. H., Jang, J. H., Park, J. S., & Kim, H. S. (2019). Exercise exerts an anxiolytic effect against repeated restraint stress through 5-HT2A-mediated suppression of the adenosine A2A receptor in the basolateral amygdala. Psychoneuroendocrinology, 108, 182–189. https://doi.org/10.1...uen.2019.06.005

[3] Lamontagne, S. J., Melendez, S. I., & Olmstead, M. C. (2018). Investigating dopamine and glucocorticoid systems as underlying mechanisms of anhedonia. Psychopharmacology, 235(11), 3103–3113. https://doi.org/10.1...0213-018-5007-4

[4] Ivic, L., Sands, T. T., Fishkin, N., Nakanishi, K., Kriegstein, A. R., & Strømgaard, K. (2003). Terpene trilactones from Ginkgo biloba are antagonists of cortical glycine and GABA(A) receptors. The Journal of biological chemistry, 278(49), 49279–49285. https://doi.org/10.1074/jbc.M304034200

[5] Basselin, M., Chang, L., Seemann, R., Bell, J. M., & Rapoport, S. I. (2005). Chronic lithium administration to rats selectively modifies 5-HT2A/2C receptor-mediated brain signaling via arachidonic acid. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 30(3), 461–472. https://doi.org/10.1038/sj.npp.1300611

[6] Ramasamy, S., Chin, S. P., Sukumaran, S. D., Buckle, M. J., Kiew, L. V., & Chung, L. Y. (2015). In Silico and In Vitro Analysis of Bacoside A Aglycones and Its Derivatives as the Constituents Responsible for the Cognitive Effects of Bacopa monnieri. PloS one, 10(5), e0126565. https://doi.org/10.1...al.pone.0126565







Also tagged with one or more of these keywords: anhedonia, depression, attention, l-dopa, ssre, adaptogen, quetiapine, consummatory anhedonia

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