Today’s post is about treating a wide range of conditions that share neuroinflammation in common, by targeting the serotonin receptor 5-HT2A.
Severely disabling cluster headaches, that were seen as untreatable, have been resolved by monthly micro dosing with psilocybin.
Psilocybin is a naturally occurring prodrug compound produced by more than 200 species of fungus, including magic mushrooms. Psilocybin is quickly converted by the body into Psilocin.
|
Psilocin Binding Profile |
|||
|
Target |
Affinity |
Species |
|
|
Ki (nM) |
|
||
|
3,801.0 |
Human |
|
|
|
567.4 |
Human |
|
|
|
219.6 |
Human |
|
|
|
36.4 |
Human |
|
|
|
52.2 |
Human |
|
|
|
107.2 |
Human |
|
|
|
4.6 |
Human |
|
|
|
97.3 |
Rat |
|
|
|
> 10,000 |
Human |
|
|
|
83.7 |
Human |
|
|
|
57.0 |
Human |
|
|
|
3.5 |
Human |
|
|
“The neurotransmitter serotonin is
structurally similar to psilocybin.
Psilocybin is rapidly dephosphorylated in the body
to psilocin, which is an agonist for several serotonin
receptors, which are also known as 5-hydroxytryptamine (5-HT) receptors.
Psilocin binds with high affinity to 5-HT2A receptors and low
affinity to 5-HT1 receptors,
including 5-HT1A and 5-HT1D; effects are also mediated
via 5-HT2C receptors.
Various lines of evidence have shown that
interactions with non-5-HT2 receptors also contribute to the
subjective and behavioral effects of the drug. For example, psilocin
indirectly increases the concentration of the neurotransmitter dopamine in
the basal ganglia, and some psychotomimetic symptoms of psilocin are
reduced by haloperidol, a non-selective dopamine receptor antagonist.
Taken together, these suggest that there may be an
indirect dopaminergic contribution to psilocin's psychotomimetic
effects. Psilocybin and psilocin have no affinity for dopamine receptor
D2, unlike another common 5-HT receptor agonist, LSD. Psilocin
antagonizes H1 receptors with moderate affinity, compared to LSD
which has a lower affinity.”
A Canadian company, Pilz Bioscience,
is trialing its version of psilocybin to treat autism.
We already know that micro dosing of Lysergic acid diethylamide (LSD) promotes social behavior
via 5-HT2A/AMPA receptors and
mTOR signaling.
The FDA is
already onside
For those worrying about the law, the
FDA is well aware of the therapeutic potential of low dose psychedelics like Psilocybin, and indeed LSD.
FDA Grants
Psilocybin Second Breakthrough Therapy Designation for Resistant Depression
The US Food and Drug Administration (FDA) has granted the Usona
Institute breakthrough therapy designation for psilocybin for the treatment of
major depressive disorder (MDD).
For really motivated readers, click on
the link below to read the details of Psilocybin
https://www.usonainstitute.org/wp-content/uploads/2020/08/Usona_Psilocybin_IB_V3.0_08.31.2020_cc.pdf
Nova (Pilz Bioscience) Launches Preclinical Autism
Spectrum Disorder Therapeutic Study
A
treatment phase with its proprietary psilocybin compound is scheduled to begin
in February 2021.
PILZ
BIOSCIENCE
INNOVATION IN ASD
Though
ASD symptoms are diverse, underlying causes converge on common biological
mechanisms, priming development of a new approach to diagnostics and treatment.
Scientific studies suggest a strong association between ASD and inflammation,
as well as ASD and microbiota in the gut. Likewise, parallels exist between
social cognition in autism and some of the key behavioral elements already
being treated with psychedelic therapy.
Micro dose LSD
for Autism? via activation of 5-HT2A/AMPA/mTORC1
LSD may offer viable treatment
for certain mental disorders
Researchers from McGill University have discovered, for the first time, one of the possible mechanisms that contributes to the ability of lysergic acid diethylamide (LSD) to increase social interaction. The findings, which could help unlock potential therapeutic applications in treating certain psychiatric diseases, including anxiety and alcohol use disorders, are published in the journal PNAS.
Psychedelic drugs, including LSD, were popular in
the 1970s and have been gaining popularity over the past decade, with reports
of young professionals claiming to regularly take small non-hallucinogenic
micro-doses of LSD to boost their productivity and creativity and to increase
their empathy. The mechanism of action of LSD on the brain, however, has remained
a mystery.
The researchers note
that the main outcome of their study is the ability to describe, at least in
rodents, the underlying mechanism for the behavioural effect that results in
LSD increasing feelings of empathy, including a greater connection to the world
and sense of being part of a large community. "The fact that LSD binds the 5-HT2A receptor
was previously known. The novelty of this research is to have identified that
the prosocial effects of LSD activate the 5-HT2 receptors,
which in-turn activate the excitatory synapses of the AMPA receptor as well as
the protein complex mTORC1, which has been demonstrated to be dysregulated in
diseases with social deficits such as autism spectrum disorder,” as specified by Prof.
Nahum Sonenberg, Professor at the Department of Biochemistry of McGill
University, world renowned expert in the molecular biology of diseases and
co-lead author of the study.
Lysergic
acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory
neurotransmission
Significance
Social behavior (SB) is a
fundamental hallmark of human interaction. Repeated administration of low doses
of the 5-HT2A agonist lysergic acid diethylamide (LSD) in mice
enhances SB by potentiating 5-HT2A and AMPA receptor
neurotransmission in the mPFC via an increasing phosphorylation of the mTORC1,
a protein involved in the modulation of SB. Moreover, the inactivation of mPFC
glutamate neurotransmission impairs SB and nullifies the prosocial effects of
LSD. Finally, LSD requires the integrity of mTORC1 in excitatory glutamatergic,
but not in inhibitory neurons, to produce prosocial effects. This study unveils
a mechanism contributing to the role of 5-HT2A agonism in the
modulation of SB.
Abstract
Clinical studies have reported that the psychedelic lysergic acid
diethylamide (LSD) enhances empathy and social behavior (SB) in humans, but its
mechanism of action remains elusive.
Using a multidisciplinary approach including in vivo electrophysiology,
optogenetics, behavioral paradigms, and molecular biology, the effects of LSD
on SB and glutamatergic neurotransmission in the medial prefrontal cortex
(mPFC) were studied in male mice. Acute LSD (30 μg/kg) injection failed to increase
SB. However, repeated LSD
(30 μg/kg, once a day, for 7 days) administration promotes SB, without
eliciting antidepressant/anxiolytic-like effects. Optogenetic inhibition
of mPFC excitatory neurons dramatically inhibits social interaction and
nullifies the prosocial effect of LSD. LSD potentiates the
α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and 5-HT2A,
but not N-methyl-D-aspartate (NMDA) and 5-HT1A,
synaptic responses in the mPFC and increases the phosphorylation of the
serine-threonine protein kinases Akt and mTOR. In conditional knockout mice
lacking Raptor (one of the structural components of the mTORC1 complex) in
excitatory glutamatergic neurons (Raptorf/f:Camk2alpha-Cre), the prosocial effects of LSD and the
potentiation of 5-HT2A/AMPA synaptic responses were nullified,
demonstrating that LSD requires the integrity of mTORC1 in excitatory neurons
to promote SB. Conversely, in knockout mice lacking Raptor in GABAergic neurons
of the mPFC (Raptorf/f:Gad2-Cre), LSD promotes SB. These results indicate that LSD
selectively enhances SB by potentiating mPFC excitatory transmission through
5-HT2A/AMPA receptors and mTOR signaling. The activation of 5-HT2A/AMPA/mTORC1
in the mPFC by psychedelic drugs should be explored for the treatment of mental
diseases with SB impairments such as autism spectrum disorder and social
anxiety disorder.
D-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis:
Mechanism of Action and Pharmacology
Figure 1. D-Lysergic Acid Diethylamide (LSD) acts at different brain regions with a pleiotropic mechanism of action involving serotonin 5-HT1A, 5-HT2A, 5-HT2C, and dopamine D2 receptors in the Dorsal Raphe (DR); dopamine D2 receptor and Trace Amine Associate (TAAR1) receptors in the Ventral Tegmental area (VTA); and 5-HT2A in the Locus Coerules (LC). These three nuclei project to the prefrontal cortex (PFC), enhancing or inhibiting the release of neurotransmitters and ultimately medicating the psychotic-like effects and cognitive changes. mPFC: medial prefrontal cortex (mPFC); NMDA(NR2B): N-methyl-D-aspartate (NMDA) receptor subunit NR2B.
LSD vs Psilocybin
LSD and psilocybin have effects that overlap, but they are not identical. Both are used by sufferers to treat cluster headaches.
Why does low dose psilocybin provide
long lasting protection from cluster headaches?
These headaches are often thought to be driven by ion channel
dysfunctions (channelopathic). Does psilocybin,
or indeed LSD, directly or indirectly affect ion channels? Nobody knows.
Regular readers will know that certain calcium/sodium channels are implicated in autism, epilepsy and MR/ID. Some of these same ion channels are also associated with headaches. So no surprise that some people with a mutation in one of these genes have additional problems to autism.
Are all types of migraine channelopathies?
Familial hemiplegic migraine (FHM) is characterized by migraine attacks, which is with transient, unilateral motor weakness as its episodic aura. FHM is an autosomal dominant migraine, three encoding protein genes have been identified: CACNA1A encodes α1 subunit of calcium channel Cav2.1, ATP1A2 encodes α2 subunit of Na+/ K+-ATPase pump, and SCN1A encodes α subunit of sodium channel Nav1.1. All these proteins are specially expressed on nervous system, and all the mutations mainly cause brain dysfunction. Series studies on FHM indicated that mutations on Cav2.1 and ATP1A2 increased the concentration of glutamate in synapses and disturbed the excitatory and inhibitory balance, which induced the brain dysfunction. Although the same result has not yet been concluded firmly enough from the functional studies on sodium channels (Nav1.1) owe to the more perplexed expression and structure of Nav1.1 and its encoding gene SCN1A, it firmly concluded that all the mutations of the three genes cause brain dysfunction. All above indicate that FHM is a definitely channelopathy. Are other types of migraine channelopathies?
Conclusion
Tiny doses of psilocybin (magic mushrooms) have been used for years by a small number of people with severe headaches. These headaches are not your typical migraine, they are totally disabling. Note that large doses of Psilocybin frequently cause headaches.
It appears that the same therapy has
an effect on other neurological conditions ranging from depression to autism. Take a look at all the trials to date:
https://clinicaltrials.gov/ct2/results?recrs=&cond=&term=psilocybin&cntry=&state=&city=&dist=
We know from anecdotes that many
Aspies feel better when they activate the serotonin receptor 5-HT2A,
but I suspect that may “overshoot” with dosing. It is a non-hallucinogenic effect that we are
looking for. The dose can be as little as
a micro dose once a month.
Genuinely effective micro dosing is
very attractive, because it is likely to be very safe and indeed very
cheap. Intermittent micro dosing, if
therapeutic, would be even better.
Clearly, a standardized drug like
PLZ-1013 from Pilz Bioscience is what many people will want. It is very encouraging that these researchers
and those at McGill University and the Usona Institute have engaged themselves. But, prepare to wait a decade or two.
It is a pity
we have to wait so long; LSD was first used as an autism therapy before I was
born. LSD was then made a banned substance.
Clearly back in the days that Professor Lovaas was giving LSD to people with
autism at UCLA in the 1960s, he was using the “wrong” dose, but he might have eventually
stumbled upon the micro dose. Here we are
almost 60 years later, still with anecdotes.
Roll on the clinical trial of PLZ-1013.