After a year of consuming cannabis frequently I started to experience an effect known as formication. This is a sensation that insects are crawling on your body and it often leads people to believe they have infestations of parasites. It is usually occurs in those with psychotic disorders or those using dopaminergic drugs such as cocaine and methamphetamine. In my experience, the feeling often coexists with a depressive anhedonic mood. I believe it is possible to explain the mechanism of this phenomenon.
The first episodes of formication left me believing I had bed bugs. It seemed to only occur while I was in bed and seemingly became increasingly pronounced when I held still. After a period of time I began to realize that it occurred after I got under the blanket, specifically as the blanket was depressing onto my skin. This drove the first major epiphany in solving this puzzle: it was actual sensation, misinterpreted. This is distinct from an arbitrary emergence of nonexistent stimuli. Although, both may be possible, even in combination. It seemed that as the blanket depressed on my skin, it moved my body hair, causing an extremely light touch sensation, one that is normally filtered, thus providing an unexpected sensation.
At this point, it was apparent that there was a failure to filter out light skin touch. Most of us usually cannot tickle ourselves since it is filtered out, for example. Those with psychotic disorders somehow can tickle themselves. My running hypothesis for psychotic disorders involves this endogenous hallucinogen known as dynorphin. Dynorphin has produced formication in 25% of participants when injected in heroin addicts. Dopaminergic drugs can upregulate dynorphin through D1-NMDAr complexes. This could explain the ‘coke bugs’ phenomenon that is induced by dopaminergic drugs.
If you haven’t followed the dynorphin posts on this blog, a few key points should be made about dynorphin. It is one of the endogenous opioids. It can block NMDAr like ketamine and PCP. It is the endogenous version of the hallucinogenic drug Salvia Divinorum.
The next piece of the puzzle is TRPV1 and TRPA1.
A receptor known as TRPV1 induces mechanical hypersensitivity and is involved in pain. Mechanical hypersensitivity is described as becoming sensitive to normally innocuous stimuli, such as the inflammation of nerves. TRPV1 is activated by capsaicin (the spicy part of chilis), which has very strangely been shown to produce the rat models of schizophrenia. Capsaicin’s effects involve dynorphin which was found to be linked to its’ antianalgesic effects. Capsaicin is linked to cognitive decline and NMDAr has been implicated in its’ antidepressant effects. All of these results fit the dynorphin model of psychosis.
TRPV1 mediates histamine-induced itch. Another paper mentions that repeated TRPV1 and histamine receptor stimulation leads to sensitization of these receptors, making them more likely to trigger itch sensations. Opioid-induced itch is a common phenomenon and it is mediated by the presence of TRPV1 but is alleviated when TRPV1 is stimulated by capsaicin, but not another TRPV1 agonist known as AITC. Capsaicin might not stimulate the TRPV1 fully, but perhaps only as a selective agonist. This may explain why capsaicin prevents the itch, probably by occupying the receptor but not inducing the effect pathways linked to the itch. On the other hand, AITC may stimulate the pathway and not reduce the itch effect, maybe even inducing it. This is supported by another paper showing that TRPV1 antagonists can reduce the morphine induced-itch. Functional selectivity would also explain why capsaicin induces only sensations of heat but not itch, suggesting separate pathways.
One paper explored the different sensations that arise from TRPV1/TRPA1 modulating substances and noted that ibuprofen, a TRPA1 modulating drug, produced tickling. The pronociceptive effects of dynorphin were found to be mediated by TRPA1, which also induces mechanical hypersensitivity like TRPV1 and suggests that dynorphin may enhance tickling through TRPA1 like ibuprofen.
Dynorphin also induces histamine release. Histamine hyperactivity is induced by psychosis inducing drugs like meth and NMDAr antagonists and is thought to play a role in schizophrenia. Allergy has also been associated to mood disorders and schizophrenia.
Cannabinoids interact with TRPV1, which would explain the effects I experienced. THC also increases TRPA1 activity through an unknown mechanism. There is an interesting paper associating the immune system, endogenous cannabinoids and schizophrenia that may be worth a read. Itch, histamine, and allergy are all related to the immune system. Another paper explores how stress can lead to itch. Stress was linked to dynorphin and the immune system. Stress is also linked to allergies, which may arguably be mediated by dynorphin-induced histamine release.
Self Sensing and Tickle Gate
Repeated use of euphoric drugs like cocaine may stimulate endogenous opioid activity, including dynorphin, which eventually sensitizes the TRPV1 and TRPA1 receptors, leading to enhanced physical sensitivity that picks up subtle tactile sensations. These sensations may be amplified by the sensitized receptors and produce sensations that register as crawling insects. This sensitization may allow one to feel their own body hair which is usually filtered out in most circumstances. The unfamiliarity of these sensations likely won’t be immediately recognized as one’s own body hair because we have had our body hair before the sensations began, yet never experienced these sensations before. This would suggest that the new sensations correlate with new tactile events, not old ones such as body hair. Most people will conclude that the sensations are microscopic tactile events like crawling insects, as opposed to normally filtered signals flooding through. It seems incredibly unlikely for someone to consider the factor of filtered information in their assessment of their formication. Since most will conclude that the sensations are driven by insects, this leads to rationalizations of parasitosis.
The illusory itch of the opioid drugs is likely driven by histamine activity rather than tactile sensations. The experience of the illusory itch seems to differ somewhat from tactile hypersensitivity, feeling more like spontaneous rash or allergic experience. There may be a distinction between hypersensitive exogenously originating stimuli and hypersensitive endogenously originating stimuli (inflammation, rash, etc).
The mechanism that prevents us from tickling ourselves might depend on TRPV1/TRPA1. Perhaps TRPV1/TRPA1 can act as a gate for light tactile sensations and self-touch from body hair, preventing unnecessary constant tactile signals. There may be complex mechanisms underlying self-touch monitoring that leads to a lack of TRPV1/TRPA1 stimulation in most people’s case. In states like psychosis or drug use, the sensitization of TRPV1/TRPA1 may cause these receptors to activate more easily and allow self-tickling to occur. While these receptors are on, they may allow these sensations through and while these receptors are turned off, they may act as a tickle filter, preventing sensations from signaling.
Theanine, an NMDAr partial agonist, seems like it may be a potential treatment for the illusory bug syndrome. Theanine is capable of reducing histamine release from mast cells. Theanine was also found to reduce both the positive and negative symptoms of schizophrenia, including hallucinations, which fits in line with the hypothesis of mechanisms presented in this article. In my own experience, theanine reduced the illusory bug syndrome and with daily theanine use, the syndrome has not yet returned for many months, even during periods of intense stress which usually leads to the onset of the syndrome for me.
It occurred to me that TRPV1 could be involved in hiccups, as both morphine, other opioids, and capsaicin have been known to induce hiccups. Some have hypothesized that opioids induce hiccups in relation to respiratory depression, while capsaicin induces hiccups by irritating the diaphragm. Might it be possible that the mechanism for hiccups in both cases is actually the same? Considering the overlap with TRPV1 effects in both opioids (through histamine) and capsaicin, it may be possible. Histamine was found to be implicated in hiccups. Taken together this information would suggest that TRPV1 may play a role in hiccups.
Special thanks to the two patrons, Abhishaike Mahajan and Charles Wright! Abhi is also the artist who created the cover image for Most Relevant. Please support him on instagram, he is an amazing artist!
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