UPDATE: I must state that this theory is highly speculative and the more I’m looking into it, I’m not so sure that dynorphin is implicated or at least it’s hard for me to pin this part down. This article may still explain interactions that lead to dopamine dysregulation and eventually dynorphin upregulation, and perhaps even enhancement. But it’s uncertain if alpha2 receptors could diminish KOR activity. Right now it appears opposite and I’ll update this soon enough.

I’ve recently discovered that there is a connection between adrenergic activity and psychosis. I was exploring and hoping to find solutions for a symptom known as formication. This is a hallucinatory bug crawling sensation. In popular culture we often see cocaine as inducing this symptom, which we call “coke bugs”. Meth users and cocaine addicts are often depicted as picking at their skin due to these hallucinations. While exploring possible mechanisms, it became apparent that the mechanisms involved could apply more broadly to psychosis in general rather than a specifically adrenergic-mediated specific psychosis.

It started with yohimbe bark.

Reports of formication induced by yohimbe bark exist on the internet and it appears to be psychotomimetic. The mechanism of yohimbine (the main active drug in yohimbe bark) is most notably an alpha2 adrenergic receptor antagonist. There are cases of psychosis related to adrenal insufficiency, where a mechanism of low cortisol and subsequent rise in inflammatory cytokines is proposed. The alpha2 adrenoceptor agonist, clonidine, has been shown to reverse hypo-adrenergic psychoses in Korsakoff’s syndrome. Psychotomimetic cannabis appears to attenuate the effects of clonidine, further suggesting a relationship between low alpha2 adrenoceptor function and psychosis. Clonidine has been shown to treat schizophrenia as effectively as neuroleptics. Another study found clonidine, even in low doses, reversed the sensorimotor gating deficits found in schizophrenia.

The mechanism of psychosis from low alpha2 adrenoceptors may be explained by the relationship between adrenergic and dynorphinergic signaling. Yohimbine causes reinstatement of drug seeking by enhancing dynorphin/kappa-opioid receptor (KOR) activity. Another study found that blocking alpha2 adrenoceptors permits the operation of otherwise silent KORs.

I’ve posted before on how dynorphin produces psychotomimetic effects in the article Dynorphin. Check this article out to fully understand this mechanism.

To simplify,

Dynorphin functions by binding as an agonist to kappa opioid receptors and also blocking NMDA receptors. When dynorphin binds to KORs this causes potentiation of D2 receptors. Chronically elevated dopamine levels have been shown to upregulate dynorphin and neutralize learning benefits of dopamine. Dynorphin inhibits dopamine release. Dopamine receptor blockers that prevent dopamine activity from occurring upregulate the receptors. So when dynorphin reduces dopamine activity, this likely upregulates dopamine receptors in response, and once dopamine is releasing again it may upregulate dynorphin levels again, suppressing the hyperactivity of dopamine. This is a feedback loop and provides a mechanism for psychosis. Major theories of psychosis currently involve hyperactivity of D2 receptors and hypoactivity of NMDAr receptors. In one study dynorphin appears to induce formication in 3 of 12 participants. There is also evidence that dynorphin is psychotomimetic. There is a lot more to this, so I highly suggest you read the article Dynorphin.

Moving back to adrenoceptors, the alpha1 and alpha2a adrenoceptors appear to have opposite functions. Alpha1 adrenoceptors seem to shut down function of the prefrontal cortex while alpha2a adrenoceptors protect function. The opposite relationship is true for amygdala function, where alpha1 enhances connectivity and alpha2a reduces connectivity. This is particularly interesting because dynorphin was found to control the gain of amygdala fear processing. Those without KORs expressed an anxiolytic demeanor while KOR agonism appears to inhibit anxiolytic mechanisms. Cannabis as earlier mentioned seems to reduce alpha2 adrenoceptor binding, and anxious reactions to cannabis were linked to dynorphin release. On the other hand, the serotonergic psychedelics appear to attenuate KOR activity. I’ve explained in depth the implications of this, suggesting that this is the mechanism for treating PTSD, depression, fear of death, and possibly enhancing cognition/intelligence in the article Psychedelics and Intelligence.

It seems that serotonin inhibits dynorphin’s ability to function. SERT activation causes hypoactivity of serotonin by uptaking serotonin and dynorphin requires SERT in order to produce aversion learning effects. SERT knockout mice were unable to learn aversions. Chronic administration of SSRIs downregulates SERT, which would potentially reduce depression/stress/psychotic effects of dynorphin by inhibiting it’s ability to utilize SERT. Response to SSRI/SNRI drugs in treatment of depression may depend on alpha2 adrenoceptor expression, strongly suggesting that serotonin modulates dynorphin’s ability to have effects by enhancing alpha2 adrenoceptor activity. Since psychedelics attenuate KOR activity we can narrow down this mechanism to a set of just a few receptors that are agonized by psychedelic drugs and look for receptor heteromers that may mediate this mechanism. Ketanserin, a 5HT2 antagonist, boosts antinociception by enhancing KOR activity. Unfortunately ketanserin directly interacts with alpha2 adrenoceptors so this is likely a bad candidate. Alpha2 adrenoceptor And 5HT2 heteroceptors exist which may hint at a narrower selection of possible mechanisms. Outside of this I have not yet found any specifics on which serotonin receptor is most likely to mediate these anti-KOR mechanisms. Another possibility is that the KOR suppression seen with alpha2 adrenoceptors is mediated by serotonin via these heteroceptors.

I suspect the overlap of serotonergic and adrenergic inhibition of KOR may be mediated by stimulating mu-opioid receptor heteromers. 5HT2a receptors crosstalk with MORs and this seems to mediate painkilling effects in some cases. Another study found that MOR agonists can reverse head-shakes induced by 5HT2a agonists, while this study shows enhanced shakes by MOR agonism, suggesting this relationship may not be so easy to parse. A study on sweetness induced analgesia found positive relationship between both of these receptor’s agonism, both inducing painkilling effects. Alpha2 adrenergic And MOR agonists both share cross-tolerance. Clonidine also exerts analgesic effects.

Many of the functions of MOR are opposite of KOR, for example dopamine release inhibition, dysphoria and aversion by KOR stimulation, while MOR enhances dopamine release, euphoria, and reinforcement. This suggests that 5HT2a may exert its anti-KOR mechanism by enhancing MOR signaling. Increased activity of MOR, 5HT2aR, and alpha2 adrenoceptors may operate by reducing or countering KOR’s mechanisms with opposite mechanisms. MORs have also been found to have functional crosstalk with alpha2 adrenoceptors.

It is likely that psychosis may often be mediated by problems with alpha2 adrenoceptor activity. Alpha2 adrenoceptors are more sensitive to norepinephrine than the alpha1 adrenoceptors, so during extreme stress events it may be that alpha2 adrenoceptors downregulate first, causing an ongoing increased sensitivity to alpha1 effects due to the ratio of alpha1:alpha2 increasing substantially. At this point, dynorphin will no longer be as inhibited by alpha2 adrenoceptor mechanisms. This may explain why trauma or extreme stress is a risk factor for schizophrenia. Alpha2 adrenoceptor agonism reduces plasma norepinephrine, which may help reduce feedback into further downregulation of adrenoceptors and prevent enhanced stress reactivity. The downregulation of alpha2 adrenoceptors would disinhibit norepinephrine, further prompting downregulation due to increased norepinephrine, likely meaning the downregulation is hard to reverse. Activation of alpha2 adrenoceptors would cause downregulation and a lack of their activation due to downregulation would disinhibit norepinephrine and actually lead to more activation. Basically a feedback loop, much like the dynorphin-dopamine problem. Those who live in ongoing insecure environments would likely be most prone to schizophrenia.

Stimulant-induced formication may have the same underlying alpha2 adrenoceptor downregulation as a mechanism. Stimulant drugs increase synaptic norepinephrine by inhibiting reuptake or causing release which eventually downregulates alpha2 adrenoceptors. Prolonged elevated dopamine also upregulates dynorphin as previously mentioned. Stimulants have been shown to reduce serotonin activity over time. This would then allow dynorphin to be unchecked by serotonin and worsen feedback loops between dynorphin and dopamine. With time, psychotic effects will emerge, while the negative symptoms may be partly attenuating by the direct effects of the stimulants, the positive effects will be enhanced. A common manifestation of cocaine-induced psychotic effect is “coke bugs“, in which the user begins to experience formication and possibly delusions of parasite infestation. This provides a potential mechanism for stimulant-psychosis by downregulating anti-dynorphinergic mechanisms causing a disinhibition of psychotomimetic dynorphin activity. And as previously stated, dynorphin caused 25% of participants to experience formication upon dosing.

It’s likely that chronically elevated dopamine upregulates dynorphin by first downregulating D2sh which normally inhibit norepinephrine release via TAAR1 heteromers. After this point, norepinephrine will be disinhibited and alpha2 adrenoceptors would be next to downregulate. Then you’d find both dynorphin-dopamine and adrenoceptor feedback loops in place at this point. Dynorphin sensitizes D2sh which likely mediates dopamine release inhibition and potentially the SERT activating effects that seem to occur with dynorphin/KOR activity.

Treatment of psychosis via clonidine may prove to be a temporary and necessarily chronic solution because of alpha2 adrenoceptor downregulation. While it’s possible that psychedelics may potentially cure psychotic states, it seems to be a substantial risk given the popular culture has deemed psychedelics a risk factor for schizophrenia (despite lack of any evidence at all). And though SSRI drugs may help reduce dynorphin effects via downregulating SERT, SSRIs are not particularly known for their efficacy as antipsychotics. Lastly, we should consider yohimbe bark treatment for psychosis via temporary chronic administration until a tolerance to psychotomimetic effects occurs, then withdrawal treatment, potentially leaving alpha2 adrenoceptors upregulated, diminishing the sensitivity to dynorphin, and potentially breaking the dopamine-dynorphin feedback loops and allowing cognition to return to non-psychotic states long term. Ideally this treatment would produce long-term resilience against psychosis until environmental stressors or traumas cause alpha2 adrenoceptors to downregulate again, for which further treatment with yohimbe may be effective. There is some evidence that yohimbe bark enhances exposure therapy to stressors and working as a treatment for social anxiety according to self-reporting of the patients symptoms.

This model of adrenergic/KOR dysregulation could apply to various mental disorders such as depression, anxiety, PTSD, and schizophrenia. The differences in these conditions may be due to different severities of dysregulation in KOR activity where the most extreme forms would lead to dissociative effects seen with schizophrenia and PTSD. Other differences outside of the core dysregulation presented here may flavor an individual’s reaction to negative events and stressors, for example GABA dominance vs hypoactivity GABA activity may differentiate the response to adrenergic/dynorphin dysregulation. This is only one example of many different sensitivities or hypo-sensitivities that may exist to alter the experience of stress. Alterations in opioid receptors could be another example.

Soon I will test this yohimbine alpha2 adrenoceptor upregulation method on myself and subsequently dose cannabis as a psychotomimetic to see if I have a reduced psychotic-proneness compared to usual. Be sure to check back for updates or contact me if you’d like to see the results.

Here is an interesting ongoing trial on using yohimbe to rapidly reverse depression in a matter of hours by dosing during sleep phases.

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