Opioids Pharmacology of thebaine? (Opiates not opioids)

[X11400]

What receptors does thebaine bind to?

 

[sekio]

(quoting liberally from this review)

There are very few toxicological data on thebaine. Studies with oral administration are only available for acute toxicity. The robustness of some of the available studies dealing with thebaine's potential hazards is also limited.IHowever, in sum, the findings suggest that the pharmacological effects of theba-ine may differ from those of other opiates, such as morphine. Morever, the effects mediated by thebaine may be based on other modes of action. The available toxicological data suggest that, after acute exposure, thebaine poses a higher toxic potential than morphine or codeine.

n its recent opinion, EFSA stated that the results of animal studies indicate a higher acute toxicity of thebaine compared to morphine (EFSA 2018.). However, it was emphasised that no adequate scientific studies were available to comprehensively assess the sensitive end-points for the toxicity of thebaine after oral intake. Regarding thebaine’s mode of action, EF-SA reported that activation of μ-opioid receptors (ORs) would occur only at very high concentrations, but further noted that to some extent thebaine could be metabolised to other opiates such as morphine or oripavine. In turn. these metabolites can lead to morphine-like effects via the activation of μ-OR (“morphine-like toxicity”). This contribution, however, is considered to be low (EFSA 2018.).

Data from different studies indicate that unlike morphine, thebaine has no or only limited analgesic effect, does not act in a morphine-like manner or even counteracts the effect of morphine, respectively (Gilbert & Martin 1978; UNODC 1980; Kettenes-van den Boschet al. 1981). In contrast to codeine, and morphine in particular, thebaine did not show any activation of μ-OR in the study by Zhang et al.(2012) and exhibited only very low effects on the activation of other ORs. The results of a mouse study performed by Aceto et al.(1999), showing that naturally occurring thebaine exhibits a very low affinity for μ- and δ-OR, substantiated the in vitro findings (Aceto et al. 1999). An earlier receptor binding study from Nikolaev et al. (2007) demonstrated that the affinity of thebaine to μ-OR is about 1000 times lower than that of morphine. A study by Goldinger et al.from 1981 gives an indication of how thebaine might mediate its pharmacological effects (Goldinger et al. 1981). In the described studies on rat nerve or brain tissue, an antagonistic effect of thebaine on glycine or γ-aminobutyric acid (GABA) receptors was identified, which was significantly stronger than that of morphine or codeine. For thebaine, the IC50 (in relation to the effect of strychnine) was 1.0 μM for glycine receptors and 300 μM (in relation to the effect of GABA) for GABA receptors. The levels for morphine were significantly higher (IC50= 40 μM for glycine receptors and 1300 μM for GABA receptors, respectively). The authors concluded from these data that the effect of thebaine in the nervous system could be mediated in particular by the inhibition of glycine receptors and is comparable to the effect of strychnine (Goldinger et al. 1981). In a publication by Sproll et al.(2016) this view is shared and linked to the convulsive effect of thebaine. However, the studies mentioned above are subject to some uncertainties, such as the limited size of the experimental groups, the lack of appropriate controls, or insufficient information on the purity of the substances used. In sum, the available experimental data indicate that thebaine’s mode of action may differ from that of other opiates, such as morphine and codeine. However, more robust studies are needed to allow a conclusive assessment of the mode of action.

Available data indicate that thebaine has a higher acute toxicity than morphine (UNODC 1980; EFSA 2018.). The dose at which 50% of testanimals die within a certain time after a single administration (lethal dose 50%, LD50) was significantly lower for thebaine (oral: LD50 = 54 mg/kg BWT in mice; LD50 = 114 mg/kg body weight (BWT) in rats) than for morphine (oral: LD50 = 524 mg/kg BWT in mice; LD50 = 335 mg/kg BWT in rats) or codeine (oral: LD50 = 250 mg/kg BWT in mice; LD50 = 427 mg/kg BWT in rats) (summarised in (EFSA 2018.). Determi-nation of the LD50 values for other application pathways (s.c. or intraperitoneal (i.p.)) led to comparable results (UNODC 1980; Kettenes-van den Bosch et al. 1981; EFSA 2018.). High acute toxicity was also observed in other studies. In this context, intravenous (i.v.) admin-istration of 2.5 mg/kg BWT thebaine in rabbits led to seizures and rapid death of the animals (Navarro & Elliott 1971; Navarroet al. 1976).

(end quoting)

So, there you go. It's a GABA-A and glycine receptor antagonist. Causes a stimulant effect, and in higher doses, convulsions. Maybe acts as a weak prodrug to other opioids, but not enough to be effective as an analgesic.

Not a fun compound to try.

 

[X11400]

(quoting liberally from this review)

There are very few toxicological data on thebaine. Studies with oral administration are only available for acute toxicity. The robustness of some of the available studies dealing with thebaine's potential hazards is also limited.IHowever, in sum, the findings suggest that the pharmacological effects of theba-ine may differ from those of other opiates, such as morphine. Morever, the effects mediated by thebaine may be based on other modes of action. The available toxicological data suggest that, after acute exposure, thebaine poses a higher toxic potential than morphine or codeine.

n its recent opinion, EFSA stated that the results of animal studies indicate a higher acute toxicity of thebaine compared to morphine (EFSA 2018.). However, it was emphasised that no adequate scientific studies were available to comprehensively assess the sensitive end-points for the toxicity of thebaine after oral intake. Regarding thebaine’s mode of action, EF-SA reported that activation of μ-opioid receptors (ORs) would occur only at very high concentrations, but further noted that to some extent thebaine could be metabolised to other opiates such as morphine or oripavine. In turn. these metabolites can lead to morphine-like effects via the activation of μ-OR (“morphine-like toxicity”). This contribution, however, is considered to be low (EFSA 2018.).

Data from different studies indicate that unlike morphine, thebaine has no or only limited analgesic effect, does not act in a morphine-like manner or even counteracts the effect of morphine, respectively (Gilbert & Martin 1978; UNODC 1980; Kettenes-van den Boschet al. 1981). In contrast to codeine, and morphine in particular, thebaine did not show any activation of μ-OR in the study by Zhang et al.(2012) and exhibited only very low effects on the activation of other ORs. The results of a mouse study performed by Aceto et al.(1999), showing that naturally occurring thebaine exhibits a very low affinity for μ- and δ-OR, substantiated the in vitro findings (Aceto et al. 1999). An earlier receptor binding study from Nikolaev et al. (2007) demonstrated that the affinity of thebaine to μ-OR is about 1000 times lower than that of morphine. A study by Goldinger et al.from 1981 gives an indication of how thebaine might mediate its pharmacological effects (Goldinger et al. 1981). In the described studies on rat nerve or brain tissue, an antagonistic effect of thebaine on glycine or γ-aminobutyric acid (GABA) receptors was identified, which was significantly stronger than that of morphine or codeine. For thebaine, the IC50 (in relation to the effect of strychnine) was 1.0 μM for glycine receptors and 300 μM (in relation to the effect of GABA) for GABA receptors. The levels for morphine were significantly higher (IC50= 40 μM for glycine receptors and 1300 μM for GABA receptors, respectively). The authors concluded from these data that the effect of thebaine in the nervous system could be mediated in particular by the inhibition of glycine receptors and is comparable to the effect of strychnine (Goldinger et al. 1981). In a publication by Sproll et al.(2016) this view is shared and linked to the convulsive effect of thebaine. However, the studies mentioned above are subject to some uncertainties, such as the limited size of the experimental groups, the lack of appropriate controls, or insufficient information on the purity of the substances used. In sum, the available experimental data indicate that thebaine’s mode of action may differ from that of other opiates, such as morphine and codeine. However, more robust studies are needed to allow a conclusive assessment of the mode of action.

Available data indicate that thebaine has a higher acute toxicity than morphine (UNODC 1980; EFSA 2018.). The dose at which 50% of testanimals die within a certain time after a single administration (lethal dose 50%, LD50) was significantly lower for thebaine (oral: LD50 = 54 mg/kg BWT in mice; LD50 = 114 mg/kg body weight (BWT) in rats) than for morphine (oral: LD50 = 524 mg/kg BWT in mice; LD50 = 335 mg/kg BWT in rats) or codeine (oral: LD50 = 250 mg/kg BWT in mice; LD50 = 427 mg/kg BWT in rats) (summarised in (EFSA 2018.). Determi-nation of the LD50 values for other application pathways (s.c. or intraperitoneal (i.p.)) led to comparable results (UNODC 1980; Kettenes-van den Bosch et al. 1981; EFSA 2018.). High acute toxicity was also observed in other studies. In this context, intravenous (i.v.) admin-istration of 2.5 mg/kg BWT thebaine in rabbits led to seizures and rapid death of the animals (Navarro & Elliott 1971; Navarroet al. 1976).

(end quoting)

So, there you go. It's a GABA-A and glycine receptor antagonist. Causes a stimulant effect, and in higher doses, convulsions. Maybe acts as a weak prodrug to other opioids, but not enough to be effective as an analgesic.

Not a fun compound to try.

And the thing about morphine is that it lowers the seizure threshold without GABA through separate means. Thanks for the citations and the comprehensive explanations. I will make sure at a time to read these publications.

 

[sekio]

And the thing about morphine is that it lowers the seizure threshold without GABA through separate means.

Presumably via blocking the glycine receptors.

I think this is also the cause of the convulsant activity seen in codeinone. (Hydrocodone is active, codeine is active, but codeinone is not active as a mu-opioid ligand, IIRC, instead producing seizures)

 

[TheAzo]

(hm, are opiates not also considered opioids? I thought opioid was anything that hit the opioid receptors, while opiate was specifically the naturally occurring ones - though maybe theibane may not be either? Or is it explicitly included as an opiate because of it's structural similarity and prominent role in preparation of the active opiates and semisynthetic opioids?)

 

[negrogesic]

(hm, are opiates not also considered opioids? I thought opioid was anything that hit the opioid receptors, while opiate was specifically the naturally occurring ones - though maybe theibane may not be either? Or is it explicitly included as an opiate because of it's structural similarity and prominent role in preparation of the active opiates and semisynthetic opioids?)

Opioid simply means opium-like. Thebaine (paramorphine) is an opiate in the sense that it an active component of opium, and it does technically possess some narcotic properties.

 

[G_Chem]

Having semi-recently tried a batch of pods which gave me effects which would line up perfectly with what is described.

The anxiety feels as if there is some antagonistic effects around GABA, which then fades into a stimulation which ends around an hour after ingestion. The duration and effects seem to match Thebaines profile perfectly and the pods were cheaper indicating the sellers may have been aware.


My next question is when thebaine is processed similar to morphine via acetylation (think BTH) are the end compounds active? Are we essentially looking at more bioavailable version? I know Thebaol is supposed to be one product but can’t remember the other.

-GC

 

[sekio]

Thebaine lacks a free hydroxyl group and hence cannot form an acetate ester like morphine does. Both the 3 and 6 positions are occuped with a methoxy.

Even if you could produce a prodrug for thebaine, the effects would'nt be expected to be much different. Maybe a faster onset and higher BA, but who wants a more potent convulsant anyway?

 

[X11400]

Opioid simply means opium-like. Thebaine (paramorphine) is an opiate in the sense that it an active component of opium, and it does technically possess some narcotic properties.

Thebaine is considered a morphinian IIRC.

 

[G_Chem]

Thebaine lacks a free hydroxyl group and hence cannot form an acetate ester like morphine does. Both the 3 and 6 positions are occuped with a methoxy.

Even if you could produce a prodrug for thebaine, the effects would'nt be expected to be much different. Maybe a faster onset and higher BA, but who wants a more potent convulsant anyway?

Oh I’m not looking to try any, more curious for those that use BTH, if it would alter the end product much or just be turned into something pharmacologically moot.

I tried researching on the two byproducts formed when thebaine is present during heroin synthesis, and could find only one quick note (from Hodor?) saying they’re probably inactive.

-GC

 

[Akane]

(hm, are opiates not also considered opioids? I thought opioid was anything that hit the opioid receptors, while opiate was specifically the naturally occurring ones - though maybe theibane may not be either? Or is it explicitly included as an opiate because of it's structural similarity and prominent role in preparation of the active opiates and semisynthetic opioids?)

Opiates are only the ones found naturally in poppies, like codeine and morphine.
Opioids include opiates and the ones produced synthetically. So all opiates are also opioids but not all opioids are opiates. Methadone or tramadol aren't opiates. For example.

This is the standard distinction.