Drug info - SSRI's, their half-lives, and mesembrine

[Ally420]

(Alpha, I am not to sure what all you wanted me to cover in requesting this thread since you originally asked about a mistake I made concerning the existence of "irreversable SSRI's". That said here is a short discourse on the basics of SSRI's, comparing their half-lives and how mesembrine fits into this picture.)

SSRI, as you probably know, means selective serotonin reuptake inhibitor. I personally find this terminology a bit confusing as it seems to imply that there are multiple varieties of serotonin transporter (SERT) when in reality there is only one type of SERT per individual (1). What makes SSRI’s selective as such is that SERT belongs to the family of monoamine transporters which are all similar and include both DAT and NET. Pure SSRI’s have very little affinity of the latter two transporters (2). The different SSRI’s have varying degrees of selectivity for SERT compared to these others. Alterations in the efficiency of SERT have been associated with alcoholism, PTSD, generalized social anxiety, OCD, hypertension, Alzheimer’s-related aggression, depression and love. Variations in the gene encoding for SERT have also been associated with these major psychological issues as well as schizophrenia (1).

The role of SERT is to remove serotonin from the synaptic cleft after it has been released by the presynaptic neuron. In this fashion SERT also allows for the storage of excess serotonin by a variety of cells including platelets and neurons (1). SSRI’s modulate how effectively SERT performs its job by inhibiting it and thereby increasing the synaptic availability of serotonin. One of the short term effects of taking some SSRI’s appears to be overstimulation of the presynaptic serotonin autoreceptors which in turn stimulates a reduction in serotonin release after activation of the cell. In response the auto receptors are slowly downregulated and in the long run the desired effect of increased availability of synaptic serotonin is achieved (2).

SSRI’s are contraindicated with a variety of drugs. From Wikipedia: Selective serotonin reuptake inhibitor: Contraindications and drug interaction:

“One major contraindication of SSRIs is the concomitant use of MAOIs (monoamine oxidase inhibitors). This is likely to cause severe serotonin syndrome.

People taking SSRIs should also avoid taking pimozide (an antipsychotic diphenylbutylpiperidine derivative). The atypical opioid analgesic tramadol hydrochloride (or Ultram, Ultracet) can, in rare cases, produce seizures when taken in conjunction with an SSRI or tricyclic antidepressant.

Liver impairment is another contraindication for medications of this type.

SSRIs may increase blood levels and risk of toxicities of certain medications:

1. highly protein-bound medications like warfarin (coumadin) and digoxin
2. antiarrhythmic agents like propafenone (Rythmol) or flecainide (Tambocor)
3. beta blockers like metoprolol (Toprol xl) or propranolol (Inderal)
4. tricyclic antidepressants like amitriptyline (Elavil) (may increase risk of serotonin syndrome)
5. benzodiazepines like alprazolam (Xanax) or diazepam (Valium)
6. carbamazepine (Tegretol)
7. cisapride (Propulsid)
8. clozapine (Clozaril)
9. ciclosporin (Neoral)
10. haloperidol (Haldol)
11. phenytoin (Dilantin)
12. pimozide (Orap)
13. theophylline (Theo-dur)

Certain drugs may increase toxicities of SSRIs:

1. alcohol and other CNS depressants
2. diuretics (water pills)
3. MAOIs
4. sympathomimetic drugs like pseudoephedrine (Sudafed)
5. lithium
6. sibutramine (Meridia)
7. MDMA (ecstasy)
8. zolpidem (ambien)[7]
9. Dextromethorphan
10. tramadol (synergistic serotoninergic effect said to increase risk of seizure)”

Although the addictive nature of the SSRI’s is often ignored, minimized, or otherwise dismissed, there is a strong withdrawal syndrome associated with abrupt discontinuation of use. This effect can last for a week or more in many individual depending on SSRI. Often onset of physical signs of withdrawal appear within 24hrs of missing a dose. For a good discourse on how to withdraw from SSRI’s effectively go to http://www.ssri-uksupport.com/files/haltingSSRIs.pdf.

Comparative pharmacokinetic info for the pharmaceutical SSRI’s:

Citalopram:
half-life = 35 hours (3)
90% eliminated: 7.3 days
onset of withdrawal 3-6 days following 50% drop in dose.

Dapoxetine:
half-life = 20 hours (4)

Escitalopram:
half-life = 27–32 hours (5)

Fluoxetube:
half-life = 1-3 days (acute); 4-6 days (chronic); Active metabolite Norfluoxetine 4-16 days (acute and chronic) (6)
90% eliminated: 25 days
onset of withdrawal 2-3 weeks following 50% reduction in dose.

Fluvoxamine:
half-life = 15.6 hours, shortest of any prescription SSRI (7)
Paroxetine:
half-life = highly variable, average: 24 hours (range 3–65 hours) (8)

Sertraline:
half-life = 13–45 hours and, on average, is about 1.5 times longer in women (32 hours) than in men (22 hours), leading to a 1.5-times-higher exposure in women (9).

There is at least one known phytoSSRI, mesembrine, which is found in Sceletium tortuosum (aka kanna) (10, 11). Although half-life if mesembrine does not yet appear to have been determined, axiolytic effects from acute doses appear to last for 5-8 hrs indicating a relatively short half-life (11). It has been suggested that one implication of this short half-life is that because stable SSRI effect is harder to maintain, the adaptive changes in the brain which are associated with chronic use of pharmaceutical SSRIs and which help drive their addiction nature do not readily occur with mesembrine. This claim has not been scientifically tested however. There is a history of mesembrine and kanna being used to intensify the effects of inferior cannabis (aka dagga) suggesting a pharmaceutical synergy between the two substances (12). This is why when mesembrine gets added to the existing formulation of herbal “incense” blends, “Synergy” is added to the name. It is not known whether or not the same contraindications apply to mesembrine as do the other SSRI’s and although such combinations should simply be avoided under most circumstances one should practice extreme care if attempting to go SWIMMING them anyway.

References:
1. http://en.wikipedia.org/wiki/Serotonin_transporter (Accessed 5/26/2009).
2. http://en.wikipedia.org/wiki/SSRI (Accessed 5/26/2009).
3. http://en.wikipedia.org/wiki/Citalopram (Accessed 5/26/2009).
4. http://www.biopsychiatry.com/dapoxetine.htm (Accessed 5/26/2009).
5. http://en.wikipedia.org/wiki/Escitalopram (Accessed 5/26/2009).
6. http://en.wikipedia.org/wiki/Fluoxetine (Accessed 5/26/2009).
7. http://en.wikipedia.org/wiki/Fluvoxamine (Accessed 5/26/2009).
8. http://en.wikipedia.org/wiki/Paroxetine (Accessed 5/26/2009).
9. http://www.ncbi.nlm.nih.gov/pubmed/12452737.
10. http://www.ncbi.nlm.nih.gov/pubmed/18775771.
11. http://patft.uspto.gov/netacgi/nph-P...S=PN/6,288,104 (Accessed 5/26/2009).
12. http://www.erowid.org/plants/kanna/kanna_journal1.shtml.


I hope this is useful. If something more specific is required let me know and I will see what I can do.