# Neuropharmacology rants ## [Yet another microdosing study](https://t.me/psy_and_neuro/2967) ([full](https://pmc.ncbi.nlm.nih.gov/articles/PMC9346139/)) I just love’em. So, after **two weeks of 0.5g/day** or a placebo, we’ve got **almost all creativity and attention, word fluency metrics unchanged or worse**: ![STAI State Trait Anxiety Inventory, PSS Perceived Stress Scale, PANAS Positive and Negative Affect Scale, TAS Tellegen Absorption Scale, BIEPS Well-being Scale, MWQ Mind Wandering Questionnaire, FSS Flow State Scale, CPS Creative Personality Scale, TECA Cognitive-Affective Empathy Test, CFS Cognitive Flexibility Scale, RAT Remote Associates Test, AUT Alternative Uses Task, WK Wallach–Kogan Test](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d3c/9346139/89f5b4999385/41398_2022_2039_Fig2_HTML.jpg align="center") Another brick hitting the wall of measly microdosing afficionados 😌 ## [MYT1L + mTOR ⇒ ASD/AD(H)D/etc?](https://www.nature.com/articles/s41380-023-01959-7) ![](https://cdn.hashnode.com/res/hashnode/image/upload/v1730016268382/119c02d9-6110-4bf0-8456-4a55ed73b8d5.png align="center") There’s a rather [old theory](https://www.cuimc.columbia.edu/news/children-autism-have-extra-synapses-brain) (by neuroscientific measures, IMO): *less synaptic pruning → more ‘inefficient’ and synaptic circuits → autism-like phenotypes*. One of the theory facets were that upregulated mTOR led to increased connection formation which, in the absence of enough pruning, led to the aforementioned brain changes. A recent paper had discovered another potential candidate: [MYT1L, myelin transcription factor 1-like gene](https://www.genecards.org/cgi-bin/carddisp.pl?gene=MYT1L), may be responsible for, once again, autism-like phenotypes for essentially the same reason: P.S. There’s even a [separate syndrome](https://rarechromo.org/media/information/Chromosome%20%202/MYT1L%20syndrome%20\(MYT1L%20variants%20and%202p25.3%20deletions\)%20FTNW.pdf) called after the gene! Basically: * MYT1L **helps guide brain cells to the correct parts of the brain**, among other functions, e.g., [controlling neuronal maturation and function + switching non-neuronal genes in neurons](https://www.perplexity.ai/search/what-are-myt1l-functions-in-th-S5uQWllLRYeqt2HodsN0ow) off * Quoting [Perplexity](https://www.perplexity.ai/search/what-are-myt1l-functions-in-th-S5uQWllLRYeqt2HodsN0ow), MYT1L also: * Controls expression of other genes associated with autism and epilepsy, including GABRB2, NR4A2, RELN, and CNR1 * Regulates WNT and NOTCH signaling pathways involved in neurogenesis * Is essential for both excitatory and inhibitory neuron development * Basically, MYT1L is making sure **neurons are efficient, located in the correct places and in correct quantity** * We need two working copies of MYT1L; a change or deletion of one or two leads to an **abundance or deficit of brain cells in different regions** * Basically this **can** **lead to a plethora of conditions,** with the prime ones being ASD and epilepsy-like behaviours ![](https://cdn.hashnode.com/res/hashnode/image/upload/v1730016671152/a4656979-a2d3-45e6-abf6-05965dcc390e.png align="center") *Intense World Theory in its full grace* Together, mTOR and MYT1L seem to contribute to the [Intense World Theory](https://www.perplexity.ai/search/explain-intense-world-theory-i-yYMOfBqUQ0umx34lvF3RYg) a lot: * IWT proposes that ASD (I’d add ADHD, epilepsy at least in part) is characterized by: * Hyper-reactivity and hyper-plasticity in local neural microcircuits * Enhanced perception, attention, memory, and emotional responses * This, in turn, **can be caused by an interplay of dysfunctional mTOR and MYT1L**, among other genes (these conditions are NOT caused by just a couple of genes - recall the [Biopsychosocial model](https://www.physio-pedia.com/Biopsychosocial_Model) and recite it like the Bene Gesserit litany) And the mechanism, again, quoting Perplexity: * MYT1L mutations can affect neuronal development and differentiation * Disrupted neuronal development may lead to altered mTOR signaling * Enhanced mTOR activity creates hyper-connected neural circuits ## [Alt therapies vs. Stimulants for ADHD](https://psychopharmacologyinstitute.com/section/an-overview-of-standard-treatment-vs-cam-for-adhd-2689-5360) ![Manganese in autism spectrum disorder and attention deficit hyperactivity disorder: The state of the art - ScienceDirect](https://ars.els-cdn.com/content/image/1-s2.0-S2666027X24000239-gr1.jpg align="left") Manganese overload/burden is also [presumed to play part](https://www.sciencedirect.com/science/article/pii/S2666027X24000239) in this, despite being crucial for SOD, the antioxidant enzyme. Excessive Mn seems to influence almost everything, mainly neurons, in an extremely negative way… Let’s do it theses-like: * **9.4% of US children** have been diagnosed with ADHD * At least **23% receive no treatment** * Estimated **12-68% of families** (so accurate, much data) try complementary and alternative therapies to treat ADHD symptoms * **~87% of pediatricians** reported they had been asked about CAMs by a patient or parent in the prior three months. However, **<5% reported that they felt knowledgeable** about it * Some parents **prefer CAMs** to medications (they don’t vaccinate, too) * More patients and parents are choosing micronutrient therapy for irritability, emotional regulation, focus and attention * The fun thing is that Methylphenidate seems to, at least, [not influence sleep in a bad way](https://readwise.io/reader/shared/01j49h59gfnfxha2wgt2xrqpyd), likely slightly improving it! ## [Antidepressant discontinuation](https://psychopharmacologyinstitute.com/section/which-antidepressants-have-the-highest-risk-of-discontinuation-symptoms-2830-5756) ![Switching or Augmentation Strategies in MDD - What do we know?](https://psychscenehub.com/wp-content/uploads/2022/07/Cross-Taper-Switch.png align="left") * About 14% experience AD withdrawal symptoms, with 3% experiencing severe ones (tell that to guys and gals @ [SurvivingAntidepressants](https://www.survivingantidepressants.org/) and get instaslamdunked) * 17% of patients had symptoms that were attributable to their own expectations about stopping medications (this was accounted for in #1) * **Half-life** and **potency** are, perhaps, the main predictors of withdrawal severity, with **paroxetine** (extremely potent) and **venlafaxine** (extremely short half-life) taking the crown (tianeptine with a ~2h half-life is laughing nearby, along with clomipramine with its mega-potency) * Usual strategies suggested are: *tapering incl. volumetric dosing*, or *switching* to a longer-acting analog - there’s one king here, **fluoxetine** --- Welcome to **Teleogenic**❣️ Other places I cross-post (not always) to: * [**Hashnode**](https://posts.teleogenic.com) * [**Medium**](https://baldr.medium.com/) * [**Telegram**](https://t.me/ohmyboi) * [**Twitter**](https://twitter.com/ZakharKogan) * [**LinkedIn**](https://www.linkedin.com/in/zakhar-kogan/)