There is a suggestion in some of the literature that some SCs may activate serotonin receptors and inhibit monoamine oxidase.

If the indole moiety in some SC molecules is clinically significant it could induce psilocybin or LSD-like serotonin mediated effects such as visual and mental hallucination, euphoria and excitement, and serotonin syndrome effects such as vomiting, seizure and hyperthermia.

Knowing the precise mechanism that underlies such adverse outcomes could better inform emergency physicians responding to SC poisonings.

See, for example;

" 'Noids in a nutshell: everything you (don't) want to know about synthetic cannabimimetics",

Papanti et al, Advances in Dual Diagnosis 2014

DOI: 10.1108/ADD-02-2014-0006

Duccio will kindly send you the full text if you follow this link;

http://www.researchgate.net/publication/264551702_%27noids%27_in_a_nutshell_everything_you_%28don%27t%29_want_to_know_about_synthetic_cannabimimetics

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Discussion;

>

http://addiction-dirkh.blogspot.com.au/2014/07/avoid-noid-synthetic-cannabinoids-and.html

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Article Noids in a nutshell: Everything you (don’t) want to know abo...

For example, new cannabimimetic indazole derivatives such as AB-PINANCA and AB-FUBINACA contain an indole moiety which means they may act not just at CB1, but also at 5HT2A or other serotonin receptors. There are a number of the latest generation of SC substances which contain an indole moeity.

Synthetic cannabinoid toxicity produces a much higher instance of hallucinations and delusions than phyto-cannabinoid intoxication;

eg see Forrester et al 2012 which showed that a “cannabis-associated psychopathological syndrome" was much more likely with SCs than with plant cannabis, with only 2% occurrence in the "marijuana" users' group versus 11.2% in the SC users’ group having been identified as experiencing hallucinations and delusions.

http://www.ncbi.nlm.nih.gov/pubmed/22859662

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Brakoulias, 2012 showed patients experiencing psychotic episodes related to SC use are also reported to present with higher/more frequent levels of agitation and behavioral dyscontrol in comparison with those psychotic episodes described in cannabis users.

http://anp.sagepub.com/content/46/3/281.extract

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Synthetic cannabinoid toxicity has also been associated with seizures.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726077/

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While these symptoms may indeed be due to a SC exerting strong agonist actions at CB1, an additional serotogenic effect might plausibly account for both increased seizure risk and a higher incidence of psychosis-like symptoms..

Tachycardia is far more common in SC toxicity than in cannabis poisoning; are any readers aware of published research examining catecholamine release following use of SC products, or that examine the ability of these substances or their metabolites to bind to dopamine or (nor)adrenaline receptors?

Are any readers aware of published research demonstrating that any SC substances bind in a clinically significant way to serotonin, dopamine, (nor)adrenaline, glutamate, or any other receptor sites?

The hypothesis seems plausible, however as yet I cannot find any studies that examine whether these substances or their metabolites really do bind to receptors (other than CB receptors) in a way that could produce clinically significant effects. Any links, PDFs, or hints would be greatly appreciated.

Regards,

Paul.

Hello Paul,

Hope this helps you a bit in your question, novel synthethic cannabinoids are made up of many other components, so they lack any CBD activity http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799955/

G'day Ricardo,

I hadn't seen the full text of this article yet, and it is a good review.Thanks for sharing.

It is quite possible that the symptoms provoked by SC toxicity are simply a product of their stronger agonist actions at CB1, combined with (as you point out) the lack of any synthetic equivalent to CBD .However some of the literature suggests that the more florid symptoms may also be due to SC's that contain an indole moiety acting at 5HT2A. 

What I'm trying to ascertain is whether anyone has actually conducted the research to determine if some of the naphtoylindoles or phenylacetylindoles marketed as SC products can act in this way, or whether this suggestion is purely conjecture.  While the hypothesis is plausible and intuitively pleasing, as yet I can't find any hard evidence for any SC acting in a significant fashion at receptors other than CB1. 

I did find the second sentence of the following paragraph interesting;

>

Even though all three references are to subjective. first hand "trip reports" from Erowid, this got me quite excited as these sorts of visual distortions and entopic images are not typical in cannabis intoxication but very common in the hallucinations produced by classical serotogenic hallucinogens such as mescaline, psilocybin, and LSD.

However, when I followed the links to these reports none of them mention hallucinations as a significant feature of the experience.

> and  are mentioned in two of the five reports, but as transient misperceptions only.

All five cases predominately report symptoms that are consistent with "greening out" from eating or smoking far too much plant cannabis. The symptoms described in these trip reports would all be consistent with strong THC-like agonist actions at CB1. 

Here they are;

Dan 2009; http://www.erowid.org/experiences/exp.php?ID=79039

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Skipper 2009; http://www.erowid.org/experiences/exp.php?ID=79428

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Various 2009; http://www.erowid.org/chemicals/spice_product/spice_product_info1.shtml

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Thanks again, and regards,

Paul.

A historical perspective may be helpful here. Cannabinoids were discovered first as materials in the marijuana plant that had certain properties that were later discovered to act through a receptor system. Two primary receptors were found, the CB1 and CB2, but there have been hints at other receptors binding these compounds, a putative CBD receptor for example. Then the endocannabinoid system was discovered, which acts through the CB receptors but also have properties at other receptor systems. More importantly, there is a milieu of endocannaboids, and how they may act together can be important. All along the way scientists have developed specific drugs based on the structure of the phytocannabinoids, and later the endocannabinoids. The first "spice" drugs were based on John Huffman's compounds (JWH compounds). An essential component is that THC is a partial agonist, it can only activate the CB1 receptor so much, but many of these synthetic analogues were full agonists, or started to have activity outside the CB system. This automatically bumps up their toxicity by fully activating the CB1 but also by bringing in other receptor systems. Keep in mind that CB receptors are highly abundant in the brain but also the periphery. Many synthetics have been tested for their binding affinities, in the rodent tetrad test (a basic test of cannabinoid activity) and in operant and self-administration models. However, they are not well tested in humans at all. Nevertheless, there are years of data behind these compounds, much of which is readily available in publications, some of which has probably never been published. Things are getting crazy now though, in that synthetics are coming out that have not seen the light of day before. Who knows what they do? Or even if they qualify as "cannabinoids". These simply can't be lumped under the same heading as "synthetic cannabinoids". 

Hi Caroline,

Thanks for your reply.

You wrote; > and this is well evidenced, (although I should point out that most of the novel cannabinoids currently being marketed are not, strictly speaking, "analogues" of THC. They are substances chemically unrelated to THC but which can bind to CB1 and CB2 receptors).

You also wrote that some SCs  > and this is the bit we don't appear to have any hard evidence for.

I do think it is plausible, given the molecular structure of some of these compounds, (especially the naphtoylindoles or phenylacetylindoles), and given some of the symptom profiles presenting in ED presentations, that some synthetic cannabinoids (or their metabolites) might engage with other receptor systems, especially 5HT2A. 

However as yet I cannot find any published research that conclusively demonstrates significant activity at receptors other than CB1 and CB2. This is quite probably simply because no-one has bothered as yet to carry out such research.

Basically I'm trying to find out if evidence already exists in the published literature, and, if not, to encourage in-vivo, in-vitro, or in-silico research that would establish if some of these compounds or their metabolites can engage serotonin or catecholamine receptors.

Regards,

Paul.

I've just been sent this Annals of Pharmacotherapy article, which mentions the same hypothesis in a footnote;

>

I've attached a PDF of the article (Wells). The footnote referenced another article (El-Subbagh, also attached) that investigated the relevance of an indole moiety in non-SC compounds and concluded it played a major part in bio-activity.

Once again the Wells article is an well-educated guess, but not evidence...

It is an important question but, unfortunatelly, but there is no published data on effects on non-cannabinoid targets. None. Anything that has been mentioned here in the comments is mere speculation. In vitro studies, such as receptor profiling or enyzme screeing, are urgently needed. At a meeting organized by the European drug agency EMCDDA last year I gave a talk on new and some anticipated SCs as well as some similar structures but with different mode of action. Selected slides relevant to this topic can be found in the downloadable pdf file. Note that the list of structurally related substances such as etonitazene or indibuline, is incomplete. Furthermore, it would be interesting to test these latter 'non-cannnabinoid' compounds for CB receptor effect.

Hi Paul,

Although this might be different for other compounds, the following article shows that the typical effects of JWH-073 and JWH-250 (both are indoles) in mice are mediated by the CB1 receptor: http://www.ncbi.nlm.nih.gov/pubmed/26780169. Antagonisation of the effects with the CB1 antagonist AM-251 is of course just an indirect proof - but still convincing in my opinion.

There are lots of compounds around (natural and synthetic) carrying an indole structure without any serotonergic action.

I would suggest indirect mechanisms as the cause for serotonergic action, e.g. http://www.ncbi.nlm.nih.gov/pubmed/23151877 or http://www.ncbi.nlm.nih.gov/pubmed/22386778. Hence, the higher toxicity of synthetic cannabinoids is very likely caused by high potency (dosing problems) and/or full agonism at the CB1 receptor.

Best regards,

Volker

Thanks Volker. I wish I could upvote your response more than once!

Psychostimulant effect of the synthetic cannabinoid JWh-018 and aKB48: Behavioral, neurochemical, and Dopamine Transporter scan imaging studies in Mice.

Ossato et al Frontiers in Psychiatry August 2017

doi: 10.3389/fpsyt.2017.00130

"The present results suggest that SCBs facilitate striatal DA release possibly with different mechanisms than cocaine and amphetamine. Furthermore, they demonstrate, for the first time, that JWH-018 and AKB48 induce a psychostimulant effect in mice possibly by increasing NAc DA release.

These data, according to clinical reports, outline the potential psychostimulant action of SCBs highlighting their possible danger to human health..."