How did you settle on HDAC for this? To compare the absolute binding of two different compounds, you would need their computed pKi values and molar masses. Keep in mind different receptor agonists result in different conformational changes and therefore different intracellular cascades, and may not be a fair apples-to-apples comparison. That's true of inhibitors too; reversible tends to be softer and more gradual than irreversible.
Green tea polyphenols are relatively potent HDAC inhibitors iirc. The trouble with natural compounds is they're often relatively non-specific, meaning they are also relatively potent at other sites too. In the case of green tea extract, the undesirable acetylcholine saturation likely (early on) far outweighs any positives you may see from HDAC inhibition. Green tea also influences methylation status, and can make your epigenetic clock appear younger. But I'm leery of the continued alteration of such an important natural system, it's why I go at least 2-3 days a month without my Japanese tea. The taste may only linger on your tongue for several hours, but to adequately purge the body of catechins requires several days.
In terms of the original question, I would suggest magnesium and CBD. YMMV, but I've read into and tried many things from kava to magnolia, and these two stand out not only as the two most effective, but as the two most safe choices as well. Magnesium has hundreds of uses in the body, and the brain cannot relax or properly develop without it. I don't want to be quoted on this, but I think CBD is going to provide an impetus for a wealth of academic research in the coming decades. Everything from the study of the immune system to cortical thinning will be covered. It will inspire many semi-synthetic and synthetic derivatives with higher specificity, but to truly iron out the glitches and follow all the leads to conclusion will take multiple generations of researchers.
We can get into exactly why these two are effective, or what the dominant mechanism is. I think that would be an interesting discussion.
Effects of Elevation of Brain Magnesium on Fear Conditioning, Fear Extinction, and Synaptic Plasticity in the Infralimbic Prefrontal Cortex and Lateral Amygdala
Anxiety disorders, such as phobias and posttraumatic stress disorder, are among the most common mental disorders. Cognitive therapy helps in treating these disorders; however, many cases relapse or resist the therapy, which justifies the search for cognitive enhancers that might augment the efficacy of cognitive therapy. Studies suggest that enhancement of plasticity in certain brain regions such as the prefrontal cortex (PFC) and/or hippocampus might enhance the efficacy of cognitive therapy. We found that elevation of brain magnesium, by a novel magnesium compound [magnesium-l-threonate (MgT)], enhances synaptic plasticity in the hippocampus and learning and memory in rats. Here, we show that MgT treatment enhances retention of the extinction of fear memory, without enhancing, impairing, or erasing the original fear memory. We then explored the molecular basis of the effects of MgT treatment on fear memory and extinction. In intact animals, elevation of brain magnesium increased NMDA receptors (NMDARs) signaling, BDNF expression, density of presynaptic puncta, and synaptic plasticity in the PFC but, interestingly, not in the basolateral amygdala. In vitro, elevation of extracellular magnesium concentration increased synaptic NMDAR current and plasticity in the infralimbic PFC, but not in the lateral amygdala, suggesting a difference in their sensitivity to elevation of brain magnesium. The current study suggests that elevation of brain magnesium might be a novel approach for enhancing synaptic plasticity in a regional-specific manner leading to enhancing the efficacy of extinction without enhancing or impairing fear memory formation.
Cannabidiol Regulation of Learned Fear: Implications for Treating Anxiety-Related Disorders
Anxiety and trauma-related disorders are psychiatric diseases with a lifetime prevalence of up to 25%. Phobias and post-traumatic stress disorder (PTSD) are characterized by abnormal and persistent memories of fear-related contexts and cues. The effects of psychological treatments such as exposure therapy are often only temporary and medications can be ineffective and have adverse side effects. Growing evidence from human and animal studies indicates that cannabidiol, the main non-psychotomimetic phytocannabinoid present in Cannabis sativa, alleviates anxiety in paradigms assessing innate fear. More recently, the effects of cannabidiol on learned fear have been investigated in preclinical studies with translational relevance for phobias and PTSD. Here we review the findings from these studies, with an emphasis on cannabidiol regulation of contextual fear. The evidence indicates that cannabidiol reduces learned fear in different ways: (1) cannabidiol decreases fear expression acutely, (2) cannabidiol disrupts memory reconsolidation, leading to sustained fear attenuation upon memory retrieval, and (3) cannabidiol enhances extinction, the psychological process by which exposure therapy inhibits learned fear. We also present novel data on cannabidiol regulation of learned fear related to explicit cues, which indicates that auditory fear expression is also reduced acutely by cannabidiol. We conclude by outlining future directions for research to elucidate the neural circuit, psychological, cellular, and molecular mechanisms underlying the regulation of fear memory processing by cannabidiol. This line of investigation may lead to the development of cannabidiol as a novel therapeutic approach for treating anxiety and trauma-related disorders such as phobias and PTSD in the future.
