Science paper Biological studies of clavine alkaloids targeting CNS receptors

Biological studies of clavine alkaloids targeting CNS receptors, Published late 2023
Paper attached

Abstract:

In contrast to well established psychedelics such as lysergic acid diethylamide
(LSD) and psilocybin, ergot alkaloids of the clavine subclass have not been
thoroughly investigated, in spite of their broad occurrence in nature and their
well-established potent physiological effects. This study presents the current
knowledge on the biological properties of clavine alkaloids, draws comparisons
to the pharmacology of ergolines and related psychedelics, and demonstrates
opportunities to develop novel structure–activity relationship (SAR) profiles.
The latter could usher in a new stage of medicinal chemistry studies that enable
an expansion of the currently structurally limited portfolio of psychedelic
therapeutics.

Clavines are psychoactive ergot molecules found in ergot fungi and their plant partners or hosts.

To provide a bit of a visual example of this here is an image from a recent paper on Morning Glory alkaloids:

And some others showing clavine alkaloid content and variation for Ipomoea tricolor and Ipomoea corymbosa.

 

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Images showing Ipomoea alkaloid relations and structures:





And a quote from the paper from the OP of this thread:

With 5-fold reduced activity at 5-HT 2A , the
naturally occurring (+)-lysergol should have reduced psychoactive
effects compared to LSD. Moreover, it displayed a similar profile to
psilocin with about half of psilocin’s activity at 5-HT 2A .

(+)-lysergol is a clavine alkaloid that is likely active and it is found in some interesting active species like Hawaiian Baby Woodrose.

Receptor binding table for lysergic and clavine alkaloids:



Table of Ipomoea alkaloids including HBWR: (Note that several studies of HBWR also show lysergol)




Another table of alkaloids, this one is for two distinct varieties of Hawaiian Baby Woodrose: (The D and HP on the right of the table)





The evidence clearly supports the idea that alkaloid content can vary considerably even in the same species.

One can clearly see that in some forms of Hawaiian Baby Woodrose LAH was found, in others it was not, in some forms Lysergol was detected, in others it was not. This relates to one of the issues with these plants, claims about a single species are problematic as there is considerable variation, even in a single species.

It is worth noting that the evidence suggests that some clavine alkaloids are potent psychoactives and some of them appear to be quite psychedelic.
I consider the clavines to be extremely interesting molecules and propose that their roles are largely overlooked and underestimated in terms of psychedelic experiences facilitated by ergot alkaloid + Ipomoea material like HBWR and I. tricolor seeds.

I have attached a couple of relevant papers as well.

 

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To discuss this material further, I should mention that many of these alkaloids, as shown in the receptor binding data mentioned in this thread, affect numerous receptors in the body and are not particularly selective, though the evidence clearly shows that some of these molecules are selective for certain receptors over others and moreover, that these molecules can be modified functionally to achieve greater selectivity. The initial paper mentions that some of the clavine molecules can be considered psychedelic in action though not necessarily involving the psychedelic imagery of open eye visuals.

It is important to consider safety. The initial paper also mentions that some molecules can be potentially cardiotoxic, that is to say that they can have a detrimental effect upon the heart itself. Vasoconstriction is a notorious effect of ergot alkaloids including some of those found in the Convolvulaceae or Morning Glory Family. Vasoconstriction can have detrimental effects on the body both in a single experience and through repeated exposure. Some of these alkaloids raise blood-pressure considerably for several hours and in people who already have high blood pressure this can create serious health risks. Despite being from morning glories these are still ergot alkaloids and the Periglandula species found associated with morning glories are closely related to ergot fungi and are in the same fungal family called the Clavicipitaceae.

There is some indication that these fungi, which are hosted by plants, were at one time hosted by scale-like insects that fed upon plants and that over time the fungi transitioned from infecting the insects to infecting plants. In terms of effects the properties of the alkaloids as a mix of sedatives, euphoric agents, psychedelics and vasoconstrictive agents, all of these have potential biological applications for controlling the behavior of the animal host of the fungus. The insects that the fungus infected and devoured obtained their nutrition from plants and over time the fungi adapted to live upon the plants themselves. In the case of the morning glory family the fungus eventually came to live as a small fungal colony at the plant meristem, allowing it to colonize the leaf tissue as it forms. This enables the fungus, Periglandula, to colonize the inside of the folded leaves on the adaxial surface which is the side of the leaf that faces the light when it unfolds. The plant itself has now even adapted to feed the fungus through the leaf through secretory trichomes on the leaf where the fungus penetrates slightly into the plant itself. As the plant feeds the fungus it grows and excretes alkaloids into the plant which uses its own transport system to move the alkaloids to the tender new growth of the plants and to the developing fruits and seeds. The fungus also colonizes the floral shoots and even colonizes the meristems of the growing seeds and so is passed down by the mother plant to all of the seeds it makes.

Despite the transition from the insects to the plants the alkaloids of the fungus are still quite closely related to those of their ancestors, who had evolved to grow upon and control the behavior of their hosts. These lysergic and clavine alkaloids have specific and deliberate biological effects upon animal body systems for a reason and not all of them are healthy for the animal. These alkaloids potentially entail greater risk than other naturally occurring and traditionally employed psychedelics like mescaline, psilocin and DMT. This is related directly to the evolutionary history of the fungi that produce them. Though I am sharing the study about the activity of the the clavine alkaloids and their occurrence as well as some of the biology and natural history of the fungi that produce them, I am not suggesting that people experiment with these alkaloids casually. They should be approached with caution as well as the usual respect that any potent mind altering chemical deserves.

 

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Regarding my claim about the leap from animals to plants in regard to the ergot fungi I have attached a paper: Phylogenetic evidence for an animal pathogen origin of ergot and the grass endophytes

 

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Here is a paper about the biology of Periglandula in regards to its location in Ipomoea, to provide further support for my comments about the location and biology of the fungus. It is called: How and Where Periglandula Fungus Interacts with Different Parts of Ipomoea asarifolia

I seek to share accurate information but am not the best when it comes to providing the detailed support for the material I am discussing.
There are many other excellent papers on this particular topic that have been published in the last decade that can be found using search terms like the name of the genus Periglandula.

 

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Diversification of ergot alkaloids and heritable fungal symbionts in morning glories
and
Origins and significance of ergot alkaloid diversity in fungi
and
Derivation of the multiply-branched ergot alkaloid pathway of fungi

I realize that many of these papers could potentially have their own thread and I am hiding the information somewhat in this thread, which despite originating in relation to the paper on Clavine interaction with CNS receptors also addresses what the clavines are, where they occur, how they can vary even in a single species and in terms of their biological and evolutionary roles. I also have provided information about the biology and natural history of Periglandula fungi, still I see this as all relevant information in terms of the subject of the CNS activity of the clavine alkaloids.

Some of these papers have also been shared and discussed here and there at the old forum and so to some people some of this is redundant information but I am doubtful that an overview like that found in this thread exists at the old forum, or anywhere else online for that matter.

Also, to tie into the topic here is another thread and post that relates, in it you can see the actual fungus on a leaf.

 

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A couple more papers on Periglandula, which is the fungus that produces the alkaloids in the psychedelic morning glories.
They are:

Phylogenetic patterns of bioactive secondary metabolites produced by fungal endosymbionts in morning glories (Ipomoeeae, Convolvulaceae)

and

Periglandula, a new fungal genus within the Clavicipitaceae and its association with Convolvulaceae