Next-generation of mushroom-inspired treatments
Future psychedelic derivatives may help to keep in check allergy, headache, and addiction
Histamine sounds like a foe but, in most cases, is a friend. Just like psychedelics may sound dangerously addictive, in fact, are tested to be less addictive than nicotine and alcohol. What do histamine and psychedelic mushrooms have in common? There is an intriguing and promising connection.
Have you heard about antihistamines? Yes, the over-the-counter medications acting on different histamine receptors to combat allergy symptoms or acid reflux. But the importance of histamine modulation goes far beyond annoying seasonal allergies.
The proper level of histamine in the body and brain is essential. Histamine receptors in the nervous system are responsible for behavior, novelty-seeking, arousal, learning memory, and information consolidation. Histamine influences energy metabolism and endocrine control in the body. Histamine receptors act in the brain to regulate waking patterns, attention, motivation, appetite, and many neurophysiological functions. Histamine also acts as an excitatory neurotransmitter responsible for sexual arousal (libido). More histamine may indicate higher libido. Higher than average brain histamine levels seem to be protective against the onset of Parkinson’s disease.
Now, there is scientific evidence natural psychedelic mushroom-derived substance psilocybin is a histamine modulator. That is right; psilocybin is a mild antihistamine.
Psychedelic/psychoactive compounds (used in a medical context) are increasingly recognized to have enormous potential to revolutionize mental healthcare.
But what if there is an even bigger promise — a wider spectrum of disorders to be treated. Are there potential use of this new therapeutic class in dermatology, gastrointestinal disorders, or neurological conditions?
There is an intricate relationship between histamine and brain physiology. Various histamine receptors are expressed in the brain, blood vessels, heart, uterus, and more. Understanding the histaminic system provides some clues on the clinical relevance of histamine metabolism. Broadly neglected in the last 50 years psychedelic/psychoactive compounds are known to act on histamine receptors. That indeed may offer new therapeutic avenues to treat emotional memory disorders. Histamine modulators, including psilocybin, may have clinical efficacy in treating obsessive-compulsive disorders, phobias, generalized anxiety, post-traumatic stress disorder, headaches, and even some allergies.
Defective histamine metabolism may be the root cause of sleep and eating disorders, addictions, and neuroinflammation. Allergic reaction arises when histamine degradation is flawed, whether because of too much histamine or lack of two major metabolizing enzymes. Histamine itch is an activation of H1 receptors, for example. The level of histamine is lower in the brain of people with a genetic vulnerability to alcoholism. Addiction researchers tested common genetic variants of histamine metabolizing enzyme activity in the brain. A widespread genetic variant of HNMT correlates with a two-fold increase in enzyme activity, making some vulnerable to alcohol addiction. For almost a hundred years, the researchers knew of the relation between histamine and headache. Histamine headaches a known phenomenon may be explained by the vasodilation of brain vessels induced by histamine. Broken histamine metabolism (histamine-rich diet, insufficient clearance, genetic errors) causes various disorders of the gastrointestinal system, skin, lungs, cardiovascular system, and brain, depending on the expression of histamine receptors. Rashes, itch, eczema, and even acne, rosacea, psoriasis may all, in fact, be the consequences of histamine processing mistakes.
Psychedelics as a therapy
Psilocybin may soon be legally available for young and old
Histamine's effect on the brain is likely to depend on gender. The brain histamine system, likely due to its sensitivity to sex steroids, plays a role in various gender-specific developmental, reproductive, and behavioral brain functions. That is an important consideration for future clinical trials.
New indications are already in clinical trials
Psilocybin (an active ingredient of certain hallucinogenic mushrooms) competes to bind and block histamine receptors. One of the well-known drugs to block the body’s histamine response in the stomach is cimetidine. Invented in the 70s, 2-Bromo-LSD is a derivative of LSD without psychedelic side effects. Intriguingly synthetic “psychedelic” 2-Bromo-LSD is ten times more potent as a histamine antagonist than cimetidine, the most potent H2-antagonist reported. D-lysergic acid diethylamide is about equipotent to cimetidine. Blockade of H2-receptors explains the behavioral effects of Lysergic acid diethylamide (LSD). Tested in the treatment of cluster headaches, recently, the compound entered clinical development as a second-generation psychedelic in Vancouver, Canada. The plan is to enter early clinical trials to treat major depressive disorder and alcohol dependency by early 2022.
Another exciting compound in development, 3,4-Methylenedioxymethamphetamine (MDMA), also binds to histamine receptors and is tested by several pharmaceutical companies for alcohol use disorder and post-traumatic stress disorder (PTSD). Phase II study is on the way to evaluate MDMA-facilitated cognitive-behavioral couple therapy as a potential treatment for PTSD and relationship distress among couples in which one partner was diagnosed with PTSD.
There is more to understand on how safely and effectively manipulate histamine receptors in the brain. For example, a local blockade of histamine in the amygdala part of the brain reduces fear memory retention. While activation of histamine receptor (HR3) may help eliminating the cause of post-traumatic stress disorder.
The control of histaminergic tone in the brain and body may be an exciting avenue for developing the medical treatment of a variety of treatment-resistant disorders.