What with the holidays and the decision to move all the articles from Coffeesh0p over here, it’s about time I posted something with a bit more meat. Having said that, this post is also suitable for vegetarians, so read on!

As I mentioned briefly before, I had to give another presentation to my neuropharmacology class in a similar vein to the one on Salvia divinorum I published earlier. In the end, I chose to talk about psychoactive mushrooms, so here’s the slides and a bit of bloggified talking along with each. Before we begin though, I’ll just say this was the worst presentation I’ve ever given – I (probably) had the most severe case of flu ever recorded and only managed to summon the courage to deliver it with Beechams flu plus, aspirin and a cheeky dihydrocodeine. Without these unsung heroes, this talk would not have been possible!

Oh, you can also click on the slides to enlarge them. Without further ado:

I’ll be talking about both the traditional “Magic Mushrooms” and the fly agaric mushroom, which is less well known, but is actually pretty culturally significant. For both of these, I’ll touch on a bit of history and tradition, pharmacology and a few other interesting bits and pieces.
The typical magic mushrooms are actually many species of the Psilocybe genus with each species having its own subtle differences. There are 60 species of Psilocybe mushrooms growing throughout the united states, of which 25 are hallucinogenic. These mushrooms will grow in nearly any kind of habitat, apart from arid deserts, so are found throughout the world. The greatest species diversity falls within the neotropic climate zones, encompassing much of South America.

These mushrooms were traditionally used by the native peoples of middle America for divination & healing purposes as well as religious communion. In fact, these people referred to the mushrooms as “God flesh” in their native language. Traditional use continued until the Spanish invaded, bringing European culture with them in the 14-1500s which pushed mushroom use underground. In 1955, Robert Gordon Wasson was the first westerner to take the mushrooms, and since then, western interest has exploded.

Some of the positive effects brought on by these mushrooms include a euphoric change in mood accompanied by giggling and laughter, as well as an increased flow of ideas and tendency to think “deep”. Objects and lights also appear more interesting and colourful. The neutral effects include a general shift in consciousness, as with most other psychoactive substances, but also an increased emotional sensitivity, pupil dilation & photosensitivity, lethargy and time dilation – the feeling that time is passing faster than it actually is. The negative effects of mushroom use can include intense fear, a headache as the effects begin to wane, gastrointestinal discomfort such as cramps & nausea, anxiety, confusion and fainting. There has been no evidence of organ damage following use.

The pharmacology – The important constituents are two compounds in the tryptamine family, psilocybin and psilocin. Psilocybin is not actually biologically active – rather, it’s a prodrug that gets dephosphorylated by the body to form psilocin, which is psychoactive. I’ve also put a model of 5-HT on there for comparison. Psilocin is an agonist at 5-HT 2A, 2C and 1A receptors, but it’s hallucinatory effects are due to the binding to 5-HT2A receptors in the brain. Psilocin shows no effect on dopaminergic pathways, and only affects noradrenergic pathways in high doses. It is believed to be the degradation of psilocin into some kind of blue pigment responsible for the characteristic blue/black bruising of these mushrooms following handling. The ease at which they bruise is a good indicator of the mushroom’s potency. One species will even turn blue from just blowing on it.

While there are no recognised medical uses of magic mushrooms, they have been used as an experimental treatment for a number of disorders. There’s significant anecdotal evidence to suggest that mushrooms can abort the period where people with cluster headaches are prone to attacks and also prevent relapses. Cluster headaches are quite a serious condition, being described as more painful than childbirth (by women!), so it’s no wonder people are willing to break the law to treat themselves. There are also currently studies under way on the effect of these mushrooms at easing the psychological suffering associated with cancer.

There’s not a lot more to say about these mushrooms, only that making them illegal naturally hampers research into a potentially useful drug.

The Amanita muscaria mushroom is a whole different kettle of fish. Here’s a few pictures so you know what I’m talking about.

Also known as the Fly agaric, this mushroom is the archetypal toadstool of the fairy tales, and is native to many places throughout the northern hemisphere, where it has been used ceremonially and recreationally for thousands of years. The mushroom, when freshly picked, is poisonous, but with careful preparation, the mushroom loses its toxicity. Unlike its psilocybin containing counterpart, this mushroom is completely legal.

Amanita have a long past, appearing in artwork from as long ago as 3500 BC. They also appear in paintings from the renaissance period, becoming more prominent during the Victorian era. This mushroom is associated in particular with fairies, elves and little people in general. They also began appearing on Christmas cards as a symbol of luck, and models of the mushroom were hung on Christmas trees as decorations. This could be due to the natural association between these mushrooms and pine forests.

It’s also been suggested that Santa Clause himself is modelled after the fly agaric mushroom, with his red ‘n’ white suit. Reindeer have also been observed eating this mushrooms in the wild and becoming intoxicated, so could that be behind the stories of flying reindeer? In fact, here’s another article on Amanita muscaria & Christmas – a very interesting read. Alice in Wonderland by Lewis Carol seemed to draw it’s inspiration from Amanita muscaria too.

Here’s a few images of this mushroom appearing in art through time. The top left one is from Disney’s Fantasia from 1940 – another example of just how widespread this mushroom has become within our culture.

Use of these mushrooms has been as widespread as their geographic distribution, but heavy use has been recorded in Siberia in particular. The Siberian shamans use the fly agaric as an alternative method to drumming and chanting to enter a trance state, but in eastern Siberia, the mushrooms were used by everyone both religiously and recreationally.

These mushrooms have a much more of a sedative effect with less hallucinations than the psilocybin containing counterparts. The positive effects include euphoria, analgesia, trance-like states being achieved, synaesthesia, and seeing “little people”. Maybe that one’s not so positive… The neutral effects include sedation, although some people can feel particularly energetic, along with changes in body perception, blurred vision and such. The most common negative effects associated with fly agaric use are nausea & gastrointestinal discomfort, but a powerful dissociation and delirium can occur at higher doses.

The active compounds in Amanita muscaria are Ibotenic acid and it’s derivative, muscimol. Ibotenic acid is a neurotoxin, which has since found a use in research, being a good inducer of brain lesions. This is the compound responsible for the toxic delirium resulting from ingestion of the fresh mushrooms. When dried in a particular manner, the ibotenic acid is decarboxylated into muscimol, making the mushrooms a lot safer to eat.

Muscimol itself is a selective agonist at the GABA-A receptor and a partial agonist at the GABA-C receptor. Muscimol’s effect profile is the sum of its actions at both these receptors, where it binds to the GABA site rather than that of an allosteric modulator, such as benzodiazepines or barbiturates. These GABAergic effects alter neuronal activity in many regions of the brain including the cerebral cortex, the hippocampus and the cerebellum. Muscimol is not metabolised further by the body, but is excreted in large quantities, as we shall see…

Time for some interesting bits and pieces about muscimol. Alcohol withdrawal can lead to hallucinations of little people much like muscimol. Since alcohol also acts on GABAergic pathways, maybe the effects could be related?

Siberian tribes used to drink the urine of their shaman, as it contains a high concentration of muscimol after ceremonial fly agaric use. I can’t think of any reason someone might find this out in the first place though.

And despite the name, Amanita muscaria have negligible muscarinic effects. They do contain muscarine, but in such tiny quantities to not make a difference.

Muscimol has also found use as a pharmacological tool, being a GABA agonist. GABA itself plays an inhibitory role, so GABA agonists applied to the brain will also have an inhibitory role. This is a useful method of simulating axon-sparing brain lesions, making reversible inactivation of brain areas a great way to study brain-behaviour relationships, such as where and when neuronal events for learning and memory take place.

And that’s that!

At this point I handed round a fly agaric cap for extra cool points.

The slides are available as a PDF here: Psychoactive Mushrooms Presentation [1.79 MB]

I’m very excited! We’ve just bought quite a few new things to pad out our Legal Highs and Entheogen categories, which happen to be our favourite. Over the next few weeks, we’ll be trickling new products on here and there, including more kratom, herbal teas and other delicious extracts, as well as popular smoking mixtures in the same league as Spice Diamond. It’s going to take forever to write all the descriptions and produce a nice set of images for each. We’re going to try and put more on there about traditional usage, and maybe some pharmacology too. I just wish I was working on it full time!

Pyramidal neurones in the Cerebral Cortex

As it happens, I’m pretty busy with my second module of the semester: neuropharmacology. In a few weeks, I’ll have to do another presentation in the same vein as my one on salvia. I’m thinking I’ll talk about either kratom, ayahuasca or psychoactive mushrooms. Kratom has some very interesting properties, acting as an opioid, ayahuasca highlights the importance of drug-drug interactions, containing DMT and an MAO inhibitor, while psychoactive mushrooms are just really interesting. The last option also allows me to bring in some whole Amanita muscaria caps (another exciting new product!) in to pass around – everyone would love that, right? As if that wasn’t reason enough, it’s active constituent, muscimol, is also of use pharmacologically. During some preliminary research, I found this great paper on hallucinogens and dissociative agents naturally growing in the United States I thought I’d share with you. Not hard going at all, and totally worth a read.

I’ve also got to pick a 10 week research project to do after Christmas. One of the options, and no doubt the one with the most competition, is on cannabinoids, eating behaviour and GABA signalling. Another one that stands out is the effects of ketamine on the visual cortex. Looks like a busy few weeks ahead.

As I mentioned before, I got to give a 10 minute presentation on Salvia divinorum to my pharmacology class. It went down pretty well, so I thought I’d write it up for you guys! Clicking on any slide will open it full size in a new window/tab.

The first thing you should know about Salvia Divinorum is that it’s a very potent hallucinogen. I mean, realllly potent. It’s name directly translates to “Sage of the Seers” or “Diviner’s Sage”, so already we know it’s gonna be cool. Salvia Divinorum is a member of the mint family, along with other common herbs, such as basil, rosemary and garden sage. In fact, Salvia is the Sage genus, which includes the common sage as well as S. Divinorum. This plant is native to one region only – the Oaxaca ["wahaka"] province of Mexico, where it grows best in a moist, shady environment.

Salvia Divinorum found extensive use among the Mazatec, the indigenous people of this region. Their religion is a blend of traditional superstition and a flavour of Christianity (also superstition!) brought over by the Spanish conquistadors. They make extensive use of the natural psychoactive plants and fungi in their rituals, including Salvia Divinorum, Morning Glory seeds and psilocybin mushrooms. Salvia in particular was used very much as a learning tool to facilitate visions, particularly in the context of healing or divination (hence the name).

Salvia was also a common medicine, prescribed for such ailments as diarrhoea, headaches and rheumatism. It was also the number one cure for a semi-magical disease known as “panzón de borrego“, or swollen belly.It’s no surprise to see a difference in use between the Mazatec and the “west”. The majority of use in the USA, UK and other developed nations is for recreation, while the Mazatec adopt a somewhat more “respectful” approach. Traditionally, salvia leaves were chewed, or an extract was prepared by crushing the leaves and consuming the liquid. There is no indication the plant was ever smoked by these people, which makes sense – the active compound has a very high vaporisation temperature. It is only the western world who smoke high powered extracts though a bong with a turboflame lighter!

The effects are many and varied, depending greatly on the amount consumed. Uncontrollable laughter is perhaps the most obvious effect, but it doesn’t happen to everyone. Other effects include remembering past memories, dissociation of the body and mind, a sensation of a force or pressure pushing or pulling on the body, usually in a particular direction, perceiving membranes or films or multiple small tiles covering surfaces and merging with, or becoming other objects. This is in no way comparable to any of the classic hallucinogens, such as LSD or Mescalin in effect or duration, as the Salvia experience usually lasts 15 to 60 minutes.

The active compound of Salvia Divinorum is Salvinorin-A, a diterpine compound. I know what you’re thinking – “why should I care?” – well, you should! Salvinorin-a is the only known psychoactive diterpene AND the first non-alkaloidal (or non-nitrogenous) hallucinogen to be discovered. It acts as an agonist at the kappa opioid receptor, which is also unusual. The other, classical hallucinogens work at the 5-HT2a receptor, and the other opioid receptor ligands tend to be alkaloids.

Shown here is a receptor selectivity profile, comparing the LSD in red with salvinorin-a in green. As you can see, the salvinorin-a is very selective for the kappa opioid receptor and not a lot else, while LSD shows activity across multiple receptors.

Shown here is the proposed kappa receptor:salvinorin-a binding complex, produced from various mutagenesis studies.An active dose of salvinorin-a can be as low as 200 micrograms, around the same as LSD, making it one of the most potent hallucinogens. But, as I’ve already mentioned, the experience usually lasts under an hour. Salvinorin-A does not remain in the body for long, with a half life of between 20 to 80 minutes in nonhuman primates.

So, an interesting drug, but is it also interesting clinically? Definitely! First off, salvinorin-a has shown promise in analgesia (pain relieving) studies in mice. Salvinorin-a, when injected intraperitoneally, produced an increased tail flick latency in these mice. The tail flick test is designed to measure the pain threshold – the mouses tail is laid out flat on a plate, and at one point along the plate, a beam of light is focused on the plate from underneath, creating a hot spot underneath the end of the mouses tail. As soon as the mouse begins to notice any pain, it flicks its tail to the side, so an increase in this amount of time shows an increased pain threshold. This antinociceptive effect is abolished if the mice are first pre-treated with a kappa antagonist, or are genetically engineered to lack kappa receptors, which proves salvinorin-a acts on these receptors in vivo as well as in vitro, shown by the previous graph. To make sure this effect was consistent and really did show an increased resistance to pain, other assays, such as the hotplate and chemo-nociceptive acetic acid abdominal constriction assays were done and produced results concordant with analgesia.

As I mentioned before, Salvia was administered by the Mazatec for diarrhoea, but it has now been shown to prevent myenteric cholinergic transmission in the small intestines of a guinea pig, effectively stopping muscle contraction.

Salvia may also shed some light on depression. Other kappa selective agonists typically produce depressive like behaviour in animal models, and salvinorin-a seems to produce a similar response. This supports the hypothesis that kappa opioid receptor signalling plays a role in depressive behaviours, but there has been at least one case report where salvia divinorum was used to treat refractory depression – depression that responds to nothing else. Before we can conclude anything from this, further work, including clinical trials must be undertaken. Either way, interesting stuff!

As we’ve seen, salvinorin-a is a bit strange, offering us an exciting new molecule to play around with. Already, chemical tweaking of the molecular structure has given us a selective agonist for the mu receptor and further research might lead to many novel, receptor-specific compounds.

Salvia has also shed some light on kappa receptors and their role in hallucinatory diseases. If the kappa agonist, salvinorin-a is able to produce such intense hallucinations (proving the involvement of kappa receptors in modulating our perception), could a kappa antagonist help reduce hallucinations in diseases with prominent perceptual disturbances, such as Alzheimer’s or Schizophrenia? There are many avenues Salvia Divinorum could lead us down, but if one thing’s for certain, more research is needed!

There are some great papers here, all of which I’d recommend, but if you can’t be bothered, there’s a brilliant TV documentary on there, Sacred Weeds. Definitely worth a watch. Thanks!

The slides are available as a PDF here: Salvia Divinorum Presentation [836kB]