Do Alpha-2 Receptors potentiate psychedelics ?

[Zimurgh]

Hi,

Recently I have been doing a lot of reading about alpha-2 adrenergic receptors and its effects on psychedelic experience.I want to share my thoughts.

Firstly, I had a very strong trip with trichereous cactii when I was on hydergine. Interestingly hydergine is said to possess alpha-2 antagonist activity. Furthermore research revealed that many substances with alpha-2 antagonism said to boost trips.[like pindolol, which in a MAPS research said to boost DMT's effects trifold!] I have come across another reading that says yohimbine (which is an alpha-2 antagonist) is used with ibogaine in Africa to facilitate healing.

But there is a problem when using alpha-2 antagonists with psychedelic amphetamines like MDMA. I have been researching about MDMA toxicity for a while and I think that MDMA is very close to methamphetamine in toxic profile. It has been proven that yohimbine which is a alpha-2 antagonist increases methamphetamine induced toxicity. [shortly don't try yohimbine with MDMA]Therefore I think alpha-2 antagonist boosting is not for methamphetamine derivative psychedelics. Not so suprisingly I have come across another paper that proposes that alpha-2-agonists may decrease MDMA induced neurotoxicity.

My personal opinion is alpha-2 antagonism facilitates catecholaminergic function therefore induces more damage where methamphetamines are present. But when used with pure psychedelics, this gateway may induce anxiety and fear therefore may help to open up issues that has been buried deeply.

Another report on using yohimbine in anxiety therapy and using Ritalin(which in turn increases catecholamines) with LSD to heal frigity may also be relevant.

Sorry for my technical language, this is my first post in Bluelight and hope it may help.

Many Thanks,

 

[Chaos Butterfly]

Shifting to ADD as per user request.

 

[theWorldWithin]

Hmm not certain but I would like to add that in addition to amphetamine based compounds the anesthetic disassociatives are also contraindicted with a2 antagonists. Do not combine yohimbine with ketamine, PCP, tiletamine, etc.

 

[search]

And yet combinations of alpha and beta blockers have been shown to be highly effective in treating MDMA overdose in mice...

 

[fastandbulbous]

But MDMA isn't a psychedelic (5HT2a receptor agonist - at least not so you'd notice). I know ketamine causes sympathetic stimulation, so yeah possibly not good idea.

On it's own, yohimbine can cause horrible anxiety due to it's alpha-2 antagonism (it's a combination of a mushroom like psychedelia and coke like stimulation. Sounds good, but the reality is different)

 

[search]

Oh, MDMA itself has a high affinity for a2 receptors. It has a similar affinity for 5-HT2a receptors, with a demonstrable agonist effect at 5-HT2a;

From: The Pharmacology and Clinical Pharmacology of 3,4-
Methylenedioxymethamphetamine (MDMA, “Ecstasy”)
A. RICHARD GREEN, ANNIS O. MECHAN,1 J. MARTIN ELLIOTT, ESTHER O’SHEA, AND M. ISABEL COLADO, Pharmacol Rev 55:463–508, 2003

Binding affinities for the classical neurotransmitter
receptors can be divided into three groups on the basis of
KDi values: 1 to 10 uM range for 5-HT2, a2-adrenergic,
M1 muscarinic, and histamine H1 receptors; 10 to 100
uM range for M2 muscarinic, a1-adrenergic, b-adrenergic
and 5-HT1 receptors; and above 100 uM for dopamine
D1 and D2, opioid receptors, and benzodiazepine sites
(Battaglia et al., 1988). The affinities of MDA are
broadly comparable (within a factor of 2) to those of
MDMA at these sites. Acute administration of MDMA to
rats at doses of 10 to 20 mg/kg results in brain concentrations
in the micromolar range (Battaglia et al., 1990;
Esteban et al., 2001), so effects at the higher-affinity
group of receptors may be pertinent to the psychotropic
and neurotoxic actions of MDMA.

Affinity of MDMA at 5-HT2 receptors labeled by the
agonist ligand [3H]1-(4-bromo-2,5-dimethoxyphenyl)-2-
aminopropane (DOB) is more than 10 times greater than
that indicated by antagonist radioligands (Lyon et al.,
1987), suggesting an agonist role. This has been confirmed
by the demonstration that MDMA induces phosphatidylinositol
turnover in cells expressing 5-HT2A or
5-HT2C receptors. These responses are highly stereospecific,
the R-(-) isomer exhibiting greater potency and
efficacy at the 5-HT2A receptor than the S-(+) isomer,
which has negligible efficacy, whereas the opposite isomerism
applies at the 5-HT2C receptor (Nash et al., 1994).
Agonism at the 5-HT2A receptor is associated with the
hallucinogenic effects of substituted amphetamines and
ergolines (Egan et al., 1998) and, although efficacy at the
5-HT2A receptor is low (21%), this is also true for LSD
(Newton et al., 1996). However, the affinity of MDMA at
the human 5-HT2A receptor is slightly less than that for
the rat receptor (Sadzot et al., 1989), corresponding with
the low incidence of hallucinations induced by MDMA in
humans.

 

[fastandbulbous]

Acute administration of MDMA to
rats at doses of 10 to 20 mg/kg results in brain concentrations
in the micromolar range

However, the affinity of MDMA at
the human 5-HT2A receptor is slightly less than that for
the rat receptor (Sadzot et al., 1989),

10-20mg/kg in humans equates to a dose of 500-1000mg for a 50kg human or 800-1600mg for an 80kg human (an incredibly large dose). Taken into account along with the second quote means that a standard active dose for humans (1-1.5mg/kg) is going to have very little impact on the 5HT2a receptors, hence my 'not so you'd notice' comment