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Melatonin enhances rewarding effects and lowers tolerance of Morphine

Valentine4

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Melatonin enhances the rewarding properties of morphine: involvement of the nitric oxidergic pathway
Noushin Yahyavi‐Firouz‐Abadi, Pouya Tahsili‐Fahadan, Mohammad Hossein Ghahremani, Ahmad Reza Dehpour
Journal of pineal research 42 (4), 323-329, 2007

Possible mechanisms of action in melatonin reversal of morphine tolerance and dependence in mice
Vasudeva Raghavendra, Shrinivas K Kulkarni
European journal of pharmacology 409 (3), 279-289, 2000

Reversal of morphine tolerance and dependence by melatonin: possible role of central and peripheral benzodiazepine receptors.
Raghavendra V1,
Kulkarni SK
Author information

Brain Research, 30 Jun 1999, 834(1-2):178-181
DOI: 10.1016/s0006-8993(99)01520-6 PMID: 10407111

The related studies are too numerous to list all. I just wanted to share this, since I am not aware of others trying this (I saw another post where a user was mocked for asking if methadone was a potentiator, but that was all I found)

The melatonin dosage is typically at least 10mg/kg in the studies , so a high melatonin dose to be sure.

Again, there are numerous studies confirming these results. Has anyone tried this?
 

G_Chem

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Funny you post this... I’ve been in pain after surgery and taking benzoylmorphine (which I often take orally and it all metabolizes into morphine) as well as low dose suboxone.

Last night I decided to try 2mg of melatonin to help me sleep which it did, but I was really surprised to find that I needed much less painkillers today than in previous days. I’ve taken less than half what I normally been taking and my pain is much better managed..

Then today I stumble upon this.. Coincidence?

-GC
 

polymath

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Based on a quick Google search it also seems to have some effect against benzodiazepine tolerance, which is not surprising if this has something to do with nitric oxide synthesis.

Just don't use it around the clock, too much melatonin will reduce your sex hormone levels.
 
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Valentine4

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Apparently Melatonin by itself is addictive at very high doses 10mg/kg

That would be 750mg for the average 75kg male! High dose, but melatonin was just as addictive in a place-preference test as 1mg/kg of Amphetamine - i.e. 75mg of amphetamine is just as preference-reinforcing (AKA addictive) as 750mg of melatonin in 75kg animal (this doesnt mean siniliar effects, just that they are just as equally habit forming as each other in lab tests)

That would be 75 10mg melatonin tablets to achieve that dosage.

From the study:

"The increase in the side preference induced by the two most effective doses of melatonin (10 and 50 mg/kg) were comparable to that induced by 1 mg/kg of amphetamine, and was significantly attenuated by the melatonin antagonist, S 22153 (20 mg/kg). In chronic experiment, melatonin (10 mg/kg) caused similar increase of the time spent on conditioned side both in animals administered vehicle for 7 days and in rats receiving 10 mg/kg of melatonin for the same period of time."

More data on melatonin enhancing drugs AND on it being addictive itself at hogh dosages:

Effects of melatonin in a place preference conditioning depend on the time of administration
M Papp, E Litwa, M Łasoń-Tyburkiewicz… - Pharmacological Reports, 2010 - Elsevier
A conditioned place preference paradigm was used to assess potential rewarding properties of melatonin. The conditioning with melatonin was carried out at two periods of the 12-h light/dark cycle: in the morning (08.30–10.00) and in the evening (18.30–20.00). Morning …
Cited by 6 Related articles

Pineal opioid receptors and analgesic action of melatonin. - NCBI - NIH
by M Ebadi · 1998 · Cited by 114 · Related articles
J Pineal Res. 1998 May;24(4):193-200. Pineal opioid receptors and analgesic action of melatonin. Ebadi M(1), Govitrapong P, ...

Melatonin enhances the rewarding properties of morphine: involvement of the nitric oxidergic pathway
N Yahyavi‐Firouz‐Abadi… - Journal of pineal …, 2007 - Wiley Online Library
… and sensory texture cues were used; the inner surface of one compartment was painted in black with a smooth floor; the other was white with a textured floor to create equally preferred compartments … Effects of melatonin on the acquisition of place preference conditioning …
Cited by 12 Related articles
Effect of light/dark cycle alteration on morphine-induced conditioned place preference
P Tahsili-Fahadan, N Yahyavi-Firouz-Abadi… - …, 2005 - journals.lww.com
The influence of acute and chronic light/dark cycle alteration on morphine-induced conditioned place.
Cited by 10 Related articles

Also here is a case were a man was addicted to intravenous Melatonin (despite the pill binders causing infections and other issues). He reports it as euphoric, but I would advise against trying this.

Intravenous melatonin abuse leading to recurrent aortic valve endocarditis: a case report and discussion
MB Warren, J Stabler… - BMC …, 2016 - bmcpsychiatry.biomedcentral.com
Reports of inappropriate medication use are widespread. There is a growing literature detailing abuse of drugs not typically thought to have high abuse liability. Melatonin is considered to be generally safe and is categorized by the Food and Drug Administration as …
Cited by 3 Related articles
 
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polymath

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Look at this:

Abstract
Melatonin, a neuro-hormone released by the pineal gland, has multiple effects in the central nervous system including the regulation of dopamine (DA) levels, but how melatonin accomplishes this task is not clear. Here, we show that melatonin MT1 and MT2 receptors co-immunoprecipitate with the DA transporter (DAT) in mouse striatal synaptosomes. Increased DA re-uptake and decreased amphetamine-induced locomotor activity were observed in the striatum of mice with targeted deletion of MT1 or MT2 receptors. In vitro experiments confirmed the interactions and recapitulated the inhibitory effect of melatonin receptors on DA re-uptake. Melatonin receptors retained DAT in the endoplasmic reticulum in its immature non-glycosylated form. In conclusion, we reveal one of the first molecular complexes between G protein-coupled receptors (MT1 and MT2) and transporters (DAT) in which melatonin receptors regulate the availability of DAT at the plasma membrane, thus limiting the striatal DA re-uptake capacity in mice.
So maybe it could also affect DA reuptake in the reward centers of the brain.

Moreover, the SwissTargetPrediction app gives melatonin some likelihood of binding directly to the dopamine transporter:


The mu opioid receptor wasn't found on the first three pages of possible binding sites, so that's not very likely to be a reason for this.

But the euphoric effect could be of the kind that lasts for, like, 2 minutes and only after injection use.
 
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Valentine4

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Look at this:



So maybe it could also affect DA reuptake in the reward centers of the brain.

Moreover, the SwissTargetPrediction app gives melatonin some likelihood of binding directly to the dopamine transporter:


The mu opioid receptor wasn't found on the first three pages of possible binding sites, so that's not very likely to be a reason for this.

But the euphoric effect could be of the kind that lasts for, like, 2 minutes and only after injection use.
Very interesting, thank for your insight into this. I hadnt considered the dopamine angle.

From what i have read, many theorize melatonin possibly boosts the level of endorphins to induce euphoria. Also it may do this via agonism of Pineal Opiate receptors...or they may play some other role; also its possibly in relation to Melatonins interaction nitric oxide pathways involved in development of drug tolerance.
 

polymath

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There are some contradictory results about the effect of melatonin on dopaminergic neurotransmission, see this:

ABSTRACT

Objective:
Several studies have shown that the time of day regulates the reinforcing effects of cocaine. Additionally, melatonin and its MT1 and MT2 receptors have been found to participate in modulation of the reinforcing effects of such addictive drugs as cocaine. Loss of the diurnal variation in cocaine-induced locomotor sensitization and cocaine-induced place preference has been identified in pinealectomized mice. In addition, several studies in rodents have shown that administration of melatonin decreased the reinforcing effects of cocaine. The objective of this study was to evaluate the effect of melatonin on cocaine-induced locomotor activity in pinealectomized rats at different times of day (zeitgeber time [ZT]4, ZT10, ZT16, and ZT22).

Methods:
Naïve, pinealectomized Wistar rats received cocaine at different times of day. Melatonin was administered 30 min before cocaine; luzindole was administered 15 min prior to melatonin and 45 min before cocaine. After administration of each treatment, locomotor activity for each animal was recorded for a total of 30 min. Pinealectomy was confirmed at the end of the experiment through melatonin quantitation by ELISA.

Results:
Cocaine-induced locomotor activity varied according to the time of day. Continuous lighting and pinealectomy increased cocaine-induced locomotor activity. Melatonin administration decreased cocaine-induced locomotor activity in naïve and pinealectomized rats at different times of day. Luzindole blocked the melatonin-induced reduction in cocaine-induced locomotor activity in pinealectomized rats.

Conclusion:
Given its ability to mitigate various reinforcing effects of cocaine, melatonin could be a useful therapy for cocaine abuse.
 

Valentine4

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I can tell you when 110 to 150 mg of melatonin are taken, you get the opiate itches and sedation... but my methadone hard to notice anything else like euphoria. And its strange but it is definitely stronger at night. Working my way up the dosage using 10mg tablets.
 
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Valentine4

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Again I want to reiterate the dosage required for euphoria, and to potentiate, is exponentially higher than the dose used for treating insomnia:

To replicate the study experiments, a 75KG or 170LB person would have to take 750mg of Melatonin!

... I do want someone to try this though, and despite the intimidating dosage, all studies show that this dosage is perfectly safe for humans to take, as shown in every safety studie conducted on the subject. The normal dose is 1 to 10mg.

Here is what I think is the reason for its euphoria and addictive properties at 1mg/kg and higher doses:

Melatonin exerts its analgesic actions not by binding to opioid receptor subtypes but by increasing the release of β-endorphin an endogenous opioid
S Shavali, B Ho, P Govitrapong, S Sawlom… - Brain research …, 2005 - Elsevier
The occurrence of systematic diurnal variations in pain thresholds has been demonstrated in human. Salivary melatonin levels change following acute pain when other factors that could explain the change have been removed or controlled. Melatonin-induced analgesia is …
 
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checktest

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Some of the older, much older studies on melatonin used really large doses, up to 1000mg and beyond.

This study mentions more dysphoria for some people, but of course there are many others. Elation is briefly mentioned among somnolence and mainly negative ones in 100 mg IV. Higher doses generally were oral.

I dislike melatonin pretty much overall so coming in with a bias. From 300 mcg to 70 mg I never seemed to get a regular beneficial effect and had more interrupted sleep / next day flatness. GI tract slowed.

Mainlining melatonin though, I could see that doing something briefly. Needless to say who knows what receptors could be hit at those doses, serotonergic toxicity.
 
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