Some science behind the scenes
Mescaline receptor activity
There is scientific proof that mescaline has effects on the dopamine receptors. Scientists who administered some poor little bunnies with 6-OHDA found that when they then gave the bunnies mescaline none of the expected and normal effects of mescaline appeared. [Ref: 6-Hydroxydopamine inhibits some effects of mescaline centrally administered to rabbits.Ferri S, Reina RA, Braga P].
6-OHDA [Oxidopamine] is a very nasty chemical. It is a neurotoxin used by scientists to selectively kill dopaminergic and noradrenergic neurons. 6-OHDA enters the neurons via the dopamine and noradrenaline (aka norepinephrine) reuptake transporters. The scientists gave the bunnies the 6-OHDA, which killed off their dopaminergic neurons, then gave them mescaline and nothing happened.
The same scientists also gave the bunnies, [probably not the same bunnies, because they would have died of unhappiness] Naloxone to see what effects it would have with mescaline. Naloxone is a μ-opioid receptor competitive antagonist, and also has an antagonist action, though with a lower affinity, at κ- and δ-opioid receptors. The mescaline this time worked.
So what we know is that mescaline has an affinity for the dopamine and probably the noradrenaline receptors, and we also know that mescaline does not bind to the opioid receptors. It appears from this that mescaline may be a release agent, a selective reuptake inhibitor of the dopamine receptor or a dopamine receptor agonist.
Now for some more cruelty to animals.
Yet more scientists experimented with cats and mescaline. [Ref Mescaline elicits behavioral effects in cats by an action at both serotonin and dopamine receptors. Trulson ME, Crisp T, Henderson LJ]. They first gave the cats methysergide. Methysergide’s receptor activity is as follows
- 5-HT2C Antagonist;
- 5-HT2B Partial agonist;
- 5-HT1D Antagonist;
- 5-HT2A Antagonist;
- 5-HT1F Antagonist;
- 5-HT7 Antagonist;
- 5-HT1B Antagonist;
- 5-HT5A Antagonist;
- 5-HT1E Antagonist;
- 5-HT6 Antagonist
and they found that “The characteristic behavioral effects of mescaline in cats were nearly completely blocked by pretreatment with low doses of the specific serotonin antagonist (methysergide)”
Given the huge blocking action that methysergide has on the system – it has only minor agonist activity at one of the receptors, all we can conclude from this is that mescaline was unable to get through to one or more of these receptors. This could make it a release agent or a selective agonist at one or more of these serotonin receptors. We can conclude nothing of the agonist activity at 5-HT2B, this may have contributed to the small amount of effect the mescaline did have.
The same scientists then gave said pussy cats haloperidol. Now Haloperidol is itself a fairly complex product. It has the following receptor activity [http://www.iuphar-db.org/DATABASE/LigandDisplayForward?tab=biology&ligandId=86 ]
- D1 Antagonist
- D2 Antagonist
- D3 Antagonist
- D4 Antagonist
- D5 Antagonist
- 5-HT2A Antagonist
- 5-HT1D Antagonist
- 5-HT7 Antagonist
- 5-HT2B Antagonist
- 5-HT1A Antagonist
- H1 Antagonist
And they found that “The characteristic behavioral effects of mescaline in cats were nearly completely blocked by pretreatment with low doses of haloperidol”
Again, all we can conclude from this is that mescaline was unable to get through to one or more of these receptors. Again, however, this could make it a release agent or a selective agonist at the dopamine and serotonin receptors shown. There may also be some histamine effects.
One more additional complexity. Sotalol, beta-Cardone or giving it another alternative name MJ-1999, is an adrenergic beta-antagonist that is used in the treatment of life-threatening arrhythmias. Using this chemical scientists found that the effects of mescaline could be blocked by this drug too [Ref Effect of mescaline on single cortical neurones - Bradshaw CM, Roberts MH, Szabadi E]. “The beta-adrenoceptor blocking agent MJ-1999 … was effective in antagonizing mescaline responses”. There is a link between dopamine and adrenaline, so this might be just a secondary effect, but on the other hand, we can’t rule out a selective action either. So, to put this another way mescaline could be one or more of the following!
Beta adrenoreceptor agonist
There is one thing clear about this, however, and that is that its action is not mediated by any one receptor. The constant emphasis of many drug afficinados upon certain serotonin selectors as being the site of hallucinatory activity simply is not borne out by the results above or other scientific evidence. For example, scientists from Oxford university studied four hallucinogens – LSD, mescaline, 5-MeO-DMT and DOI. [Ref Characterisation of human 5-hydroxytryptamine2A and 5-hydroxytryptamine2C receptors expressed in the human neuroblastoma cell line SH-SY5Y: comparative stimulation by hallucinogenic drugs. - Newton RA, Phipps SL, Flanigan TP, Newberry NR, Carey JE, Kumar C, McDonald B, Chen C, Elliott JM - Oxford University-SmithKline Beecham Centre for Applied Neuropsychobiology, University Department of Clinical Pharmacology, Oxford, England].
And they found that “Comparison of equipotent doses producing 20% of the maximal response induced by 5-HT revealed selective activation of the 5-HT2A receptor by LSD and to a lesser degree by DOI and mescaline; 5-MeO-DMT was relatively nonselective” It is unlikely therefore that hallucinosis is mediated primarily by activity at the 5-HT2C receptor, whereas activity at the 5-HT2A receptor may represent an important but not unique mechanism associated with hallucinogenic drug action”.
How does it work?
So if there is not a ‘magic receptor’ how does mescaline work. This is a hugely complex chemical, let us summarise the main occasionally competing effects from each of these receptors.
Dopamine agonistic action
Agonist action at the Dopamine receptors D1, D2, D3, D4, and D5 achieved through overdose would give us euphoria, orthostatic hypotension leading to hypoxia, incontinence and urinary urgency; befuddlement and possibly insomnia, total relaxation and nausea. It would work on its own.
Adrenoceptor agonist action
It is extremely unclear which beta receptors are affected by mescaline, despite numerous searches in Pubmed I could not find which ones were affected – only that they were affected.
Beta 1 agonists increase the heart rate , but blood flow is diverted from other non-essential organs to skeletal muscle. This may counteract the hypotension caused by the dopamine. At very high levels, however, a real over dose, we may end up lacking oxygen to the brain - hypoxia. Take oxygen from the brain and the reason and memory function are affected.
Beta 2 agonists are bronchodilators. At extreme doses vasodilation occurs and the blood pressure falls – in effect you suffer from hypotension and hypotension can lead to hypoxia. Take oxygen from the brain and the reason and memory function are affected. The mind shuts down the reasoning function and memory as a first line of protection against the system failing.
So in both cases, at overdose levels, the memory and reason are affected.
The histamine H1 agonist action is, I suspect, simply the reaction of the body to it having detected mescaline in the blood stream – it is treating it as a pathogen at the overdose level administered. As a consequence, however, there will be
- Dilation of the post capillary venules - A venule is a small blood vessel.
- Activation of the endothelium - The endothelium is the thin layer of cells that lines the interior surface of blood vessels.
- Increases in blood vessel permeability - Increased vascular permeability causes fluid to escape from capillaries into the tissues.
So mescaline may cause a red face, sweating and heat, possibly a runny nose and watery eyes and possibly some puffiness at the site of entry. There may also be some itching or pain at the site of entry.
We do not know which receptors mediate the action, but there is quite a bit of evidence that mescaline affects the memory.
An example of this research is that of Koupilová M, Herink J Krs O at the Purkynĕ Military Medical Academy, Hradec Králové. [firstname.lastname@example.org]. They studied rats – and although I know rats are not humans - rats are clever little fellow creatures, so can be studied for effects on memory and reasoning power – both of which they possess in abundance.[Ref: Influencing of spatial memory in rats by DSP-4 and mescaline] If you don’t agree with the latter sentence then consider this for a moment. One of the types of test devised was a big pool that the rats and mice had to swim in to find a platform, but the scientists found that “ The earliest and classic measure of learning is latency, which is the time it takes to find the platform [in the pool]. However, rats and mice can cheat. They might develop search techniques that do not rely on spatial information, still getting to the platform relatively quickly”. So reasoning powers going strong here - they may well be more clever than the scientists.
The scientists tried two substances mescaline and DSP-4 - N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine. And they studied “ retention of spatial orientation in the T-maze”. Now T-mazes and other sorts of maze are used in behavioural neuroscience to test for both spatial learning and memory. In effect they tested whether the little fellows could remember where they had been and where to go in a maze. They gave both substances to different rats and watched what happened. Those given mescaline were affected in a major way – “ the lengthening of the latencies in reaching the goal was generally more marked after mescaline in comparison with DSP-4”.
With memory and cognitive functions slightly impaired then the composer can take over. I also think that some of the dopaminergic activity and serotonergic activity also has an effect upon nervous sensations, making us slightly catatonic, releasing us from pain temporarily and thus aiding us into ‘letting go’.