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Alchemica

Emotional plants, a role for 5-HT1ARs?

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What tools/plants do you find bring you to deeper healing emotional spaces? Always looking for more unscheduled emotional plant spirits and ways of deepening learning in that area. If you've got good suggestions, let me know.

We have some more empathogenic plants like Kanna but I found it eventually didn't sustain Heart-space. Had some Heart-space breakthroughs on Cacao but once again, I'd like to know more legal allies for this.

 

Social and emotional behaviours in the early years were powerful predictors of later life outcomes, making it essential to teach social and emotional skills and behaviours from an early age. So much of our daily life involves interacting with others, it helps to have strong skills and behaviours in social skills and emotional areas. I never got lessons in these areas and was held back by illness from growing in these areas.

Slowly plundering through and exploring with some growth an understanding of the emotional, intellectual, spiritual, interpersonal, social and environmental dimensions of better health and wellness.
 

Whereas before I was a heavily cognitive person, head before heart, these days I cherish the more emotional dimensions. Want to be guided by heart. Spending a long time searching for pro-cognitive things to restore my ailing mind, I've paradoxically found that by developing deeper feeling, cognition has sharpened. Like the heart is sustaining the mind, rather than the mind dwindling on love-impaired soil.
 

The need for love can be compared to the need for water, because both are essential for life. You need to feel positive emotional connection to yourself, and to others,


If this life enhancing bond has not been developed, you will suffer silently, longing for a meaningful relationship, filling the emptiness in often detrimental ways. If love is not flowing you feel like a broken withering limb hanging from a tree cut from the life source.

 

I needed to enhance emotions, break my inner walls down, open to and feel, the spectrum of emotions, broaden-and-build to positive emotions. Actually understand what these emotions were.

 

These days, I like plants that can be applied psychotherapeutically in socio-emotional growth or for amplifying engaged spiritual growth. I don't expect the plant to fix, I see that it works with you, it's an ally.

 

Currently find 5-HT1A receptor mediated processes to be emotionally nice and balancing in that they're pro-emotional, pro-cognitive, sometimes self-transcendent and plain friendly. I observed that with cannabidiol and getting to that with lotus bisbenzylisoquinolines like neferine. Other milder 5-HT1A acting plants include the cacao (through the epicatechin flavonols) etc.

 

5-HT1A receptors have an important role in depression, anxiety and play a pivotal role in emotional impairments. They are implicated in the prosocial effects of empathogens. They definitely change your emotional processing; affective disorders that are characterised by an increased attention to negative stimuli are alleviated, you can ingrain more positive concepts. 5-HT1A receptor activation impairs the fear memory associated with social defeat. The 5-HT1A–NMDAR interaction provides a potential mechanism underlying the role of serotonin in controlling emotional and cognitive processes subserved by PFC. Epigenetic mechanisms that are functionally coupled with 5-HT1A receptors may play a key role in the development of resilience to emotional stress.

 

"The 5-HT1A agonists bind to the cognate receptors at both presynaptic, raphé neuron soma as well as the dendrites of the postsynaptic neurons. 5-HT1AR signaling in the presynaptic neurons causes inhibition of 5-HT firing and reduced availability of 5-HT at the dendritic terminals of the synapses. In the postsynaptic neurons, the elicited 5-HT1AR signaling causes hyperpolarization and inhibition of action potential, but it also results in other signaling effects that could be crucial for the observed effects."

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Thanks to @Siggor for suggesting Salvia species. Some of these have 5-HT1A/DA mediated effects.

  I've also used quite a lot of Salvia sclarea essential oil orally at low doses. I find it nicer than lavender. Lavender has effects in part mediated by 5-HT1ARs, likewise the linalool-type compounds in Clary sage probably do too. Clary oil was found to alleviate stress and have antidepressive effects, effects manifested by activation of dopamine pathways. The anti-stressor effect of clary oil likely involves dopamine D1/D2 and 5-HT1ARs.

"Another piece of research published in the Journal of Medicinal Food found that including clary sage oil in the food of animal subjects lead to a significant reduction in dominant and anxious behavior. "

https://www.medicalnewstoday.com/articles/320423.php

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5HT1A/2A receptor subtypes play an important role in the modulation of socio-cognitive functioning and therefore may be relevant for the treatment of social cognition deficits. They may be important for the normalisation of empathy deficits and increased negative reaction to social exclusion in depressed patients.

 

Recent findings show it is possible to reduce the neural response to negative emotional stimuli and ameliorate social pain in key brain regions responsible for emotion processing and social interactions. There seems to be a strong effect of 5-HT2ARs in mediating things like happiness, trust, closeness to others, enhanced explicit and implicit emotional empathy and impairing the recognition of sad and fearful faces. The neural response to social exclusion in the ACC – a brain region associated with ‘social pain”- was reduced by 5-HT2A/1A agonist administration compared to placebo. Furthermore, emotional empathy was enhanced

 

5-HT2 receptors seem to mediate robustly improved behavioural flexibility, elements of prosociality and emotionality, some aspects of mood improvement and reduction of obsessive compulsive aspects. They also are suggested to cause a shift towards 'active coping' while 5-HT1ARs might mediate 'passive coping'.

 

What happens when you choose or bias a plant medicine's actions towards 5-HT1AR but include other serotonergic elements?

 

What element does 5-HT1A bring to their therapeutic potential? I've been biasing my medicines towards 5-HT1ARs lately and amplifying them in that direction. Utilising a 5-HT1A biased medicine approach seems to personally encourage a more friendly emotional aspect towards self and other IMO. Less fear of ego dissolution etc. The stronger 5-HT1A background seems to promote some prosocial aspects and axiolysis while you're working with a medicine. Brings a stronger empathetic heart dimension.

 

Examples of medicines with strong 5-HT1A mediated effects include stronger heart medicines and things like this include DPT and 5-MeO-DiPT: DPT found quite a bit of use awhile back as a shorter acting option. According to therapists' ratings, there was a significant enhancement in recall of memories and experiences, greater emotional expressiveness, deeper levels of self-exploration, and greater psychodynamic resolution. 5-MeO-DIPT is generally known to generate more empathogenic qualities.

 

To me, 5-HT2A agonism has a key role on emotionality (including empathy), spirituality and boundaries between self and other. It also has a strong beneficial effect on behavioural flexibility at seeming even sub-blatantly psychoactive levels. To me, 5-HT1A receptors are, as literature suggests, involved in mediating the emotional state

 

I consider more selective 5-HT2A agonists can be quite counter-productively mind-trippy, they can induce pure loops of mind crap at times. I've always gravitated to ones with naturally more 5-HT1A affinity as being better medicines.

 

5-HT1A receptor agonism may act to buffer 5-HT2A-mediated effects. 5-HT1ARs are implicated in the prosocial effects of empathogens but that action may be codependent on 5-HT2ARs. 5-HT2A receptors may strongly influence the emotional state, they seem to be 'valves to experiencing self and other' Antagonism of 5-HT2A prevents the prosocial behaviours. 5-HT1A receptors are believed to be crucial in physiological processes linked to emotional balance

 

While it's not always the case that co-agonism of 5-HT1A reduces the intensity of an experience of a classical 5-HT2A (partial) agonist, consider 5-MeO-DMT which is a potent 5-HT1A agonist with lesser 5-HT2A affinity (5-MeO-DMT alters cortical activity via both 5-HT1A and 5-HT2A receptors) - What intrigues me is the therapeutic potential of serotonergics with stronger 5-HT1A effects. Targeting this receptor over a light background of 5-HT2A mediated effect.

 

The action of 5-MeO-DMT is mediated by simultaneous alterations of the activity of sensory and associative (PFC) cortical areas, supporting a role of 5-HT1AR stimulation in sensory and PFC regions, in addition to the well-known action on 5-HT2ARs.

Edited by Alchemica
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The functional selectivity of the Ligands (partial vs. full Agonists, silent vs. active Antagonists, inverse Agonists etc.) seems to play a major role.

There are many transcription factors / downstream effectors of the receptor which could be activated or not by 5-HT1A- Ligands, also there are interactions with 5-HT2A-Agonists like the Tryptamines (partial agonists) and Phenylethylamines (mainly full agonists). These interaction are based on the co-expression of 5-HT1A and 5-HT2A- receptors in mPFC (medial PreFrontal Cortex, self-consciousness, addiction,...) pyramidal neurons.

5-HT2A- receptors excite and

5-HT1A receptors inhibit the activity of pyramidal neurons.

The overall influence of mPFC neurons on serotonergic function is excitatory.

 

As there are many downstream effectors there are also differences between the partial agonists but generally some compounds are considered full agonists (efficacy relative to endogenous agonists like Serotonin).

Full 5-HT1A- agonists are: 8-OH-DPAT, Annonaine, Nornuciferine, Asimilobine and Flibanserine

Partial 5-HT1A- agonists: Vilazodone, Buspirone, Rauwolscine, 5-MeO-DMT, LSD, 10-Shoagol (in dried ginger), 1-Dehydro-6-gingerdione (in ginger), Cannabidiol (CBD, weak agonist), DPT, AMT, Bufotenin, MDMA, Psilocybine, Psilocin and Quetiapin.

Some 5-HT1A agonists can effect the release of adrenaline, dopamine and acetylcholine, the last two meinly in the prefrontal cortex. They are anxiolytic, antidepressant, antiemetic, analgetic, reduce eggression, enhance sociability, reduce impulsiveness and addiction-related craving, extend the REM-dream phase.

A main part of the actions of 5-HT1A- agonists is based on reinforced Oxytocin- and Beta-Endorphine- release and promotion of BDNF- production. However only high dosages of Agonists seem to have relevant effects because the presynaptic autoreceptors lessen the effects. (MDMA acts as Serotonin- and Oxytocin- releaser,  because of its 5-HT1A- action).

As you already mentioned 5-HT1A- Antagonists reinforce hallucinogenic effects of psychedelics and many agonists buffer 5-HT2A- mediated hallucinogenic effects.

DMT and LSD, despite their high potency, are also partial agonists on the 5-HT1A- R., and DMT behaves as full agonist in the adenylate cyclase (a second messenger) assay.

Furthermore these receptors are edited at the level of mRNA to produce spatially restricted isoforms, each with a different activity.

 

Inverse 5-HT1A- Antagonists: Spiperone

Neutral / silent 5-HT1A- Antagonists: WAY 100,635 and UH-301 (both enforce hallucinogenic action of 5-HT2A- partial agonists)

 

I think 5-HT1A agonism plays a role in the lacking of tolerance of DMT and the low side-effect profile of DMT, Psilocin and LSD vs. more risky Bromo-Dragonfly and most Phenylethylamines, but there are also differences in

functional selectivity of 5-HT2A- R. involved (PLC vs. PLA-2 and PLD).

 

Most promising natural 5-HT1A- ligands: Julibroside and Quercitrin in Albizia julibrissin. This plant triggers the LSD- effect as mentioned in the DMT Nexus- forum

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I forgot the very interesting SSRI- interaction with hallucinogens. I know someone who tried mushrooms on SSRI medication and felt nothing.

This phenomenon is poorly explored. There are many reports of people on SSRI- medications who have no effects from LSD, Psilocin and other Tryptamines but yet they had effects from phenylethylamines like Mescaline.

Again Tryptamines could be regarded as partial Agonists with high functional selectivity and Phenethylamines are full agonits.

Under SSRI- medication longer than 3 weeks, the presynaptic 5-HT1A- receptors (reduce Serotonin levels) are back-regulated, for the 5-HT2A- receptors the situation under SSRIs is more complicated. It seems that the population density of them is down-regulated and the downstream effectors are also changed (GIRK- channels), but the receptor-affinity for Serotonin is up-regulated, so they don't have the right constitution for Tryptamines anymore.

Phenylethalamines like Mescaline and DOM bypass this shift in receptor constitution and still hav hallucinogenic action while under SSRI treatment.

I had my own experience where I took the SSRI Citalopram for only 2 days, when LSD was very much potentiated. According to some studies in the first 3 weeks SSRI treatment there is no dysregulation of 5-HT2A- receptors, instead hallucinogens are potentiated.

 

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@ Alchemica: thanks for the like,

I can recommend the studies from R. Carhart-Harris and D. Nichols, they are the newest explanations of the action of Psychedelics on the 5-HT2A and 5-HT1A receptors.

The lectures from R. Carhart-Harris can also be found on youtube.

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Thanks for your awesome contributions @mindperformer Appreciate the directions to look into and the plants you mention

One I'm currently interested in, drying a bit of material can probably spare some for bioassays

 

Galphimia (Galphimia glauca)
Dried herb 0.6–1 g per day standardized to 0.175–0.348 mg of galphimine B
Galphimine B
Clinical trials showing equivalence to synthetic anxiolytics
No adverse reactions found in studies
Generalized anxiety, GAD


While emerging data is encouraging, further placebo-controlled studies are needed.

 

Galphimines have been identified as active compounds in galphimia, with the nor-secotriterpenes galphimine A and galphimine B, being shown to have the strongest anxiolytic activity. Galphimine B has been considered the primary active constituent for galphimia’s anxiolytic and sedative effect, and is the constituent standardized for clinical trials. Galphimine B has been shown to interact with serotonergic transmission in the dorsal hippocampus in rats. This occurs by increasing the frequency of neuronal discharge in CA1 cells, resulting in activation of 5HT(1A) receptors. One study in mice demonstrated that galphimines cross the blood–brain barrier, with galphimine A found to have an effect on the central nervous system.

 

2.5.3 Evidence of Efficacy
2.5.3.1 Preclinical
A number of galphimine constituents, including galphimine B, were evaluated for their anxiolytic effects in mice using the EPM. Mice were intraperitoneally administered 15 mg/kg of a galaphimine derivative 1 hour before testing. An anxiolytic-like effect in the mice was found for both galphimine A and galphimine B, with a significant increase in the time spent in and number of entries into the open arm in the EPM. A second study on mice used a methanolic extract (standardized for galphimine B, 8.3 mg/g) at different doses (125, 250, 500, 1000 and 2000 mg/kg), which were orally administered at three different times (24, 18 and 1 hour before the test). Significant anxiolytic-like effects were found in the light–dark paradigm test and the EPM, but not the forced swimming test.

2.5.3.2 Clinical
Two clinical trials have found galphimia to be an effective anxiolytic. The first was a 4-week, positive-controlled double-blind RCT, with a cohort of 152 patients with a DSM-IV diagnosis of GAD and HAMA scores ≥19 . The two groups received either galphimia aqueous extract (310 mg standardized to 0.348 mg of galphimine B), or the benzodiazepine lorazepam (1 mg). Each treatment was administered in capsule form (identical in appearance) twice daily. Both groups demonstrated a significant reduction in anxiety symptoms. There were no significant side effects reported in the galphimia group, which contrasted with the lorazepam group, in which over 21 % of people reported excessive sedation.


High-quality evidence was found to exist for the use of Galphimia glauca (galphimia) for anxiety disorders [1].

 

"0.175 mg of galphimine-B and administered for 15 weeks to patients with generalized anxiety disorder, showed greater anxiolytic effectiveness than that obtained with lorazepam, with high percentages of therapeutic tolerability and safety." [2, 3]

 

Galphimia glauca has been used for many years in Mexican traditional medicine for treating mental diseases, particularly nervous hyperexcitability disorders. This plant contains galphimines which have been shown to possess the ability of modifying the frequency of discharge of dopaminergic neurons in the ventral tegmental area [4]. Galphimine-B appears to be an allosteric modulator of 5HT1A receptors [5] It was capable of blocking positive and cognitive symptoms associated with psychosis induced by ketamine [6]

 

The plant yields approx. 0.26% galphimines by the looks of it

[1] https://www.ncbi.nlm.nih.gov/pubmed/29575228
[2] https://www.ncbi.nlm.nih.gov/pubmed/22828921
[3] https://www.ncbi.nlm.nih.gov/pubmed/17562493
[4] https://www.ncbi.nlm.nih.gov/pubmed/12567277
[5] https://www.ncbi.nlm.nih.gov/pubmed/21742023
[6] https://www.ncbi.nlm.nih.gov/pubmed/29710504

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11 hours ago, mindperformer said:

Under SSRI- medication longer than 3 weeks, the presynaptic 5-HT1A- receptors (reduce Serotonin levels) are back-regulated, for the 5-HT2A- receptors the situation under SSRIs is more complicated. It seems that the population density of them is down-regulated and the downstream effectors are also changed (GIRK- channels), but the receptor-affinity for Serotonin is up-regulated, so they don't have the right constitution for Tryptamines anymore.

 

 

Sorry to dumb this thread down,  but does this change in 5-HT2A receptors stay around after SSRI medication has ceased? 

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I'm not sure about how long SSRI medications induce changes to 5-HT2ARs particularly with relevance to being 'constitutionally right' for tryptamines, mindperformer is likely more versed, but there are some imaging studies with regard to depression. I'd say a lot of the binding potentials change depending on the course of the illness, too? A remitted depression etc being different. More so, binding pattern for 5-HT1A/2A seems to change in depression and might be long term

...findings should be considered preliminary but suggest that recovered subjects with a history of recurrent major depression have elevated binding potential of cortical 5-HT2A receptors. The correlation of increased 5-HT2A receptor binding potential with increased scores on Dysfunctional Attitudes Scale" [1]

Higher 5-HT1A receptor binding potential has been found in major depressive disorder (MDD) during and between major depressive episodes. [2]

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Because the name of the thread is Emotional plants, there is one plant which fits exactly:

The Telegraph plant (Codariocalyx motorius syn. Desmodium gyrans):

It is ne of the few plants capable of rapid movement of its leaves. The small lateral leaflets , they rotate constantly in a period of 3-5 minutes (visible to the naked eye), dependent on the temperature.

The big leaflets also move but much slower, they have a sleeping position in the night.

It is medium difficult to germinate and a littlebit difficult as young plant but stable and easy to grow when its getting older, most important is high humidity and at least room temperature.

The leaves, sprout and root contain DMT and 5-MeO-DMT.

In the leaves they found the alkaloids:

DMT: 0.0041 %
DMT-N-oxide: 0.0090 %
Bufotenine: 0.0034 %
5-MeO-NMT: 0.0049 %
5-MeO-DMT: 0.0018 %

 

and Flavonoids (major compounds):

Luteolin and its glycoside,

Apigenin-7-O-glucuronide,

Scutellarein-6-O-glucuronide

 

So it is a rather strange coincidence that the only constant moving plant visible to the naked eye is also producing this psychedelics / neurotransmitters.

The Tryptamines may play a role like Serotonin found in plants:

Phytoserotonin also plays a role in the following aspects of plant function:

  • Growth regulation
  • Xylem sap exudation
  • Flowering
  • Ion permeability
  • Plant morphogenesis
  • Regulation of ripening

 

Desmodium gyrans (Telegraphen- Pflanze) 5.JPG

Desmodium gyrans (Telegraphen- Pflanze) 9.JPG

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There were some experiments with this plant reacting to music, it changes its movement dependent on the music played, although it wasn't possible to find a specific pattern, see youtube videos

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@ Alchemica:

I also investigated Galphimia glauca there seem to be many studies, attesting sedative, anxiolytic, anti-allergenic and antidepressant activity. It is distributed in Central America and is also used traditionally.

Galphimin B is sedative and anxiolytic and it is highly possible that it is an Antagonist of the 5-HT1A- receptor.

But: It also acts on 5-HT2A- receptors, highly likely also as Antagonist, whis is also one of the main mechanisms (besides Dopamine- antagonism) of anti-psychotics (neuroleptics), this makes it not so useable for me personally.

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4 hours ago, Xperiment said:

 

Sorry to dumb this thread down,  but does this change in 5-HT2A receptors stay around after SSRI medication has ceased? 

No this long-term- SSRI- change of the 5-HT2A- receptor does not stay / is not permanent.

The neuronal changes (also the reason for the SSRI discontinuation syndrome) after discontinuing SSRIs stay for 1-2 weeks, dependent on the SSRI used because sertraline and fluoxetine (but not paroxetine) have active metabolites with half-lives around 2–3 and 7–15 days respectively.

 

The studies on the level of 5-HT2A- receptor density after 3 weeks SSRI treatment are paradox, some found an decrease and some an decrease, however all in all it is the receptor-binding-affinity specific for serotonin which is upregulated, like the level of Serotonin itself is also upregulated. Additionally some SSRIs like Fluoxetine have 5-HT2A- antagonistic activity.

In the first 0-3 weeks SSRI treatment the situation is completely different, the presynaptic 5-HT1A-autoreceptors downregulate the serotonin- level. This lower serotonin- level means that Serotonin has a lower competitiveness to suppress psychedelic tryptamines from the receptor, so the tryptamines are potentiated in the first 0-3 weeks SSRI treatment.

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It is unknown why (besides the 5-HT1A- downregulation) also the 5-HT2A- downregulation by SSRIs (and antagonism with fluoxetine) plays a role in the antidepressant effect of SSRIs (see also R. Carhart-Harris on this topic).

Because other 5-HT2A- antagonists like atypical antipsychotics augment the therapeutic effects of SSRIs.

Again this could also be explained by the fact that although the level of 5-HT2A- receptor density is downregulated after long-term SSRI treatment (according to most studies), their affinity for Serotonin is upregulated.

An as we all know there are many studies on the permanent antidepressant effect of serotonergic psychedelics which are selective 5-HT2A- Agonists.

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The (functional selective) partial 5-HT2A- agonistic psychedelics are causing the antidepressant activity by enhancing connectiveness in the brain, but decreasing the strong coupling between the DMN (default-mode network) and the MTL (medial temporal lobe), by activating the pyramidal neurons by 5-HT2A- mGlu2- receptor-dimers, by specific activation of it's Phospholipase D- pathway.

All in all in the theory of consciousness (R. Carhart-Harris) the psychedelic state is a state of high entropy ('disorder', see primary consciousness), so more connection possibilities are possible (formlessness).

Versus: Depressive and sedative states, seizure, inflexibility are states of low entropy (high order, petrification).

The sweet spot for 'normal' waking consciousness (constrained, precise, confident cognition, not easily surprised) is between this two extremes but more on the side of low entropy.

See D. Nichols and R. Carhart-Harris.

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I wonder if preference for a low entropy ‘sweet spot’ is a contemporary trend. Maybe society is unbalanced by excessive order, and the psychedelic renaissance is an attempt to reorient ourselves.

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yes, this was also the conclusion of R. Carhart-Harris and for me its also very plausible that a more primary consciousness with high entropy was a psychological atavism, early in the evolution of the human brain.

It may has to do with the neolithic revolution in the levante, especially mesopotamia with its structured system, the first cities, officials and bookkeeping by cuneiform writing,

then also the industrial revolution and so on, so we were forced by the environment to change to a sweet spot with lower entropy.

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