Guanfacine

2022-04-27: Nootropics reference:

Guanfacine #

• Get some dopaminergic studies plz. JC says it lowers mesolimbic DA for instance. How?
• α2A agonist
  • Random reddit guy says it will upregulate NE in the long term. I only assume this is the point behind taking it, or else it’s used with adderall to combat physical sides like increased BP/racing heart.
    • Increased norepinephrine in the frontal lobe. https://old.reddit.com/r/ADHD/comments/ut7mza/an_unofficial_guide_to_intuniv/?context=3 says it’s a pretty non-functional drug for weeks. After a month or 2 it starts effecting executive function in a beneficial way.
      • Sensory-based anxiety will be improved by increased norepinephrine in the Thalamic Reticular Nucleus which allows for better filtering, but NOT by decreased overall arousal for the same reason as above.
      • Might be BS https://old.reddit.com/r/NooTopics/comments/183w00h/understanding_guanfacine_short_term_vs_long_term/katron4/
    • Epitope-tagged receptor knock-in mice reveal that differential desensitization of alpha2-adrenergic responses is because of ligand-selective internalization
      • Guanfacine<Clonidine accelerate desensitization of Ca2+ current.
      • Attenuated by blockade of α2A endocytosis (with concanavalin A).
• Possible 5-HT2B agonist. People say that’s spooky because of valvulopathy but that’s never been recorded according to the Australian Public Assessment Report.
  • Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine2B Receptor Agonists: Implications for Drug Safety AssessmentAn external file that holds a picture, illustration, etc. Object name is sbox.jpg
    • guanfacine was approximately 1000 fold less effective than serotonin at activating 5-HT2B receptors
• Metabolized by CYP3A4 (and CYP3A5)

• Scientific rationale for the use of α2A-adrenoceptor agonists in treating neuroinflammatory cognitive disorders (Arnsten et al. 2023)
  • α2A agonists deactive macrophages; should reduce the release of kynurenine and GCP-II.
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• Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (Arnsten 2007)
  • In classic circuits, such as in the visual cortex PKA (and therefore increased PDE4 activity) enhances plasticity. Well welcome to opposite world.
  • 
    • Notice the omission of RER-mediated signaling in ‘classical’ circuits. Why though?

• Effects of acute and sub-chronic administrations of guanfacine on catecholaminergic transmissions in the orbitofrontal cortex
  • Sub-chronic (7 days iirc) systemic administration:
    • Reduced norephinephrine release in OFC, LC, and thalamic reticulra nucleus.
    • Reduced GABA release in Medial Dorsal Nucleus
    • Enhanced AMPA-induced glutamate, NE, and DA release in OFC.
  • Obviously subchronic is the name of the game, but checking what the acute effects are could be relevant for learning how long benefits take to kick in.
  • **Attenuation of direct noradrenergic LC-OFC transmission at the resting stage and enhancement of direct co-releasing catecholaminergic LC-OFC transmission via GABAergic disinhibition in the intermediate LC-OFC pathway. **
  • Inhibiting HCN (via (guanfacine) inhibiting cAMP or blocking HCN directly) (which colocalizes with α2A) activates limbic-frontal cortex network connectivity, enhancing signal-to-noise ratio and improving focus on a particular stimulus:
    • Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex (Wang, Arnsten et al. 2007)
      • Commentary: Molecules to remember
      • Guanfacine, But Not Clonidine, Improves Planning and Working Memory Performance in Humans
        • The 29 μg/kg dose of guanfacine improved spatial working memory and planning… had no effect on attentional set-shifting.
          • An attentional set is formed when a subject learns that a set of rules can be applied to complex stimuli in order to differentiate relevant from irrelevant cues. Two stages within the AST protocol measure aspects of cognitive flexibility: reversal and the extra-dimensional shift. At the reversal stage, the previously negative stimuli within one dimension (medium in this example) is now positive. At the extra-dimensional shift stage, when the irrelevant dimension (odor in this example, perhaps as opposed to visual) becomes the relevant dimension. R
            • *The neural circuits underlying behavior during the AST are highly conserved across humans, nonhuman primates and rodents..
        • Clonidine is nonselective for α2 Adrenergic Receptor.
      • α2A blockade profoundly impairs spatial Working Memory. R (using yohimbine)
      • Recent studies indicate that elevated cAMP signaling in PFC impairs behavioral measures of WM. In contrast to LTM obviously.
• Chronic Administrations of Guanfacine on Mesocortical Catecholaminergic and Thalamocortical Glutamatergic Transmissions
  • chronic guanfacine administration did not affect intrathalamic GABAergic transmission, but it phasically enhanced thalamocortical glutamatergic transmission
  • Acutely: postsynapic LC→OFC/VTA efferents reduces noradrenergic neurotransmission.
  • Proposed downregulation of α2A in the LC

• Chronic stimulation of alpha-2A-adrenoceptors with guanfacine protects rodent prefrontal cortex dendritic spines and cognition from the effects of chronic stress (Hains, Arnsten et al. 2015)
• Guanfacine as an alpha-2-agonist inducer of growth hormone secretion—a comparison with clonidine
• Role of Alpha2a-Adrenergic Heteroreceptors in Stress-Induced Reinstatement of Cocaine Associated Behaviors: Implications for the Pharmacological Treatment of Stress-Driven Relapse of Drug Use
  • (Along with α2A of course), guanfacine also activates excitatory Gi-coupled heteroreceptors in the bed nucleus of the stria terminalis (BNST). I think α2A-x heteroreceptors, whatever they are
    • Okay so basically α2A can act as a typical autoreceptor, but it can also act as a ‘heteroreceptor’. mGluR3 also doies this.
    • A key brain region in driving stress-induced relapse.

Human Studies #

• Guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder: a placebo-controlled trial
  • Even though the half life is pretty long, it rapidly peaks in plasma—hence XR.
• Guanfacine and clonidine, alpha 2-agonists, improve paired associates learning, but not delayed matching to sample, in humans .1 or 2mg. increased subjective feelings of sedation.
• Effect on Primary Sleep Disorders When Children With ADHD Are Administered Guanfacine Extended Release aged 6-12
  • REM, NREM, and SWS were reduced in proportion to the overall sleep reduction.
• Central effects of guanfacine and clonidine during wakefulness and sleep in healthy subjects #Read
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  • Both drugs (1 or 2mg for guan) reduced systolic blood pressure without significantly altering diastolic blood pressure, pulse rate and objective performance parameters.
  • Guanfacine 1.0 mg did not alter REM sleep and 2.0 mg of guanfacine had less effect than both doses of clonidine in this respect.
  • guanfacine’s action on REM sleep began 5 h after the dose
  • Guanfacine’s peak effects were 4-6 hours after ingestion (observations were limited to 6 hours). 26% suppression.
• [Efficacy of guanfacine extended release assessed during the morning, afternoon, and evening using a modified Conners’ Parent Rating Scale-revised: Short Form.]
  • Response is consistent throughout the day regardless of time of administration.
• Lack of effects of guanfacine on executive and memory functions in healthy male volunteers 1 or 2 mg.
  • This study found no improvement of prefrontal memory or executive functions after guanfacine. Negative effects on blood pressure and poorer effects on digit span backward and slower reaction time indicate a mild sedative effect of guanfacine at these doses, possibly via mechanisms of autoreceptor down-regulation.
• Methylphenidate, Guanfacine, and Combined Treatment Effects on Electroencephalography Correlates of Spatial Working Memory in Attention-Deficit/Hyperactivity Disorder age 7-14.
  • Spatial working memory task, measuing ACC and primary visual cortex.
  • Both monotherapies had limited effects on EEG measures, with guanfacine further showing detrimental effects o performance.
• The Effects of Guanfacine on Working Memory Performance in Patients With Localization-Related Epilepsy and Healthy Controls (2008) #Read
• Effects of the Alpha-2 Adrenoceptor Agonist Guanfacine on Attention and Working Memory in Aged Non-Human Primates
  • Low dose (400μg HED) decreased omission errors by 50.8%.

Dosing #

• Took bitchyblond ~1 month before psychoactive effects were obvious; therapeutic effects like PFC dopamine upregulation are apparently dependent on long-term usage.
• 1mg/mL at 37% ethanol by volume is legit.
• Dryness of the mouth can be a side effect
• Everychem (needs inquiry) $25 for 30mg.
• JC Denton
• TeamLTR $70 for 500mg.
• Something like 1-2mg. Any higher can risk hypotension - that means work up to any high dose slowly, and to quit slowly to avoid rebound hypertension from >4mg..
  • Bitchyblond took 4mg for a while but had ED. Expects 2mg to be good.
  • Bitchy: Over the last 2 years or so, my ability to care that someone was hitting on me had been greatly suppressed somehow, its like I had a cognitive bias towards “I could care less”, feeling removed from any emotional chemistry I might feel. However, drecently I moved my guanfacine dose from 4mg down to 3mg, and finally down to 2mg. Believe it or not, I started looking at my exe’s tik tok account, from 3 years ago. I also went on dating apps seeking emotional connection which has also been repressed recently. Ever since I was a little kid I have had the tendency to romanticize people and fantasize about them in my head, whatever nootropics I have been taking recently got rid of that mostly. Now that my guanfacine dose is lower I have noticed I am starting to have that romantic instinct come back. This type of emotional neediness that holds certain types of human relationships together for long periods of time.

[!Half Life] IR: 10-18 hours; XR: 17 hours

• Prescribed since 1986