Melatonin enhances rewarding effects and lowers tolerance of Morphine

[Valentine4]

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]

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

 

[Valentine4]

Thats quite serendipitous

 

[Painful One]

I am going to try it!

 

[polymath]

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.

 

[Valentine4]

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

 

[polymath]

Look at this:

Melatonin receptors limit dopamine reuptake by regulating dopamine transporter cell-surface exposure - PubMed

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...

www.ncbi.nlm.nih.gov

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:

SwissTargetPrediction

www.swisstargetprediction.ch

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.

 

[Valentine4]

Look at this:

Melatonin receptors limit dopamine reuptake by regulating dopamine transporter cell-surface exposure - PubMed

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...

www.ncbi.nlm.nih.gov

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:

SwissTargetPrediction

www.swisstargetprediction.ch

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]

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

Melatonin decreases cocaine-induced locomotor activity in pinealectomized rats

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]

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.

 

[LucidSDreamr]

i've always like the effects of melatonin even alone, but i love drugs that make me sleepy. even diphennydramine. it feels like a benzo to me, and i love benzos. not as anxiolytic but i can definitley trick myself into thinking I've taken a "better" drug

 

[Valentine4]

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 …

 

[checktest]

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

Negative Effects of Melatonin on Depression - PubMed

In order to test the efficacy of the pineal neurohumor melatonin on depression, the hormone was administered in varying doses to six moderately to severely depressed patients and two patients with Huntington's chorea in double-blind crossover study. Melatonin exacerbated symptoms of dysphoria in...

pubmed.ncbi.nlm.nih.gov

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.

 

[Valentine4]

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

Negative Effects of Melatonin on Depression - PubMed

In order to test the efficacy of the pineal neurohumor melatonin on depression, the hormone was administered in varying doses to six moderately to severely depressed patients and two patients with Huntington's chorea in double-blind crossover study. Melatonin exacerbated symptoms of dysphoria in...

pubmed.ncbi.nlm.nih.gov

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.

Great insights, just wanted to say thank you for the info.

 

[checktest]

6.6 grams of melatonin in some Parkinson's patients. So weird to consider when mcg ranges are used with some effect.

Melatonin and Parkinsonism

To the Editor.— Lerner discovered melatonin (N-Acetyl-5-methoxytryptamine)1 and showed that this pineal hormone can induce sedation in man.2 This agent antagonizes the darkening of the skin and, therefore, perhaps also some other action of melanophore-stimulating hormone (βMSH).3 Since...

jamanetwork.com

 

[polymath]

6.6 grams of melatonin in some Parkinson's patients. So weird to consider when mcg ranges are used with some effect.

Melatonin and Parkinsonism

To the Editor.— Lerner discovered melatonin (N-Acetyl-5-methoxytryptamine)1 and showed that this pineal hormone can induce sedation in man.2 This agent antagonizes the darkening of the skin and, therefore, perhaps also some other action of melanophore-stimulating hormone (βMSH).3 Since...

jamanetwork.com

That abstract seems to say that some of the effects of high-dose melatonin are mediated by the same receptors as those of the hormone beta-MSH... Of the melanocortin receptors affected by beta-MSH, the MC4 seems to have most to do with mood and motivation. In particular, MC4 blockers have an antidepressant effect.

 

[checktest]

I mean it is a really old study but I wonder how that connects.

Local pineal and pituitary gland effects? Is it downstream of melatonin receptor activation?

Long-term expression of metabolism-associated genes in the rat hippocampus following recurrent neonatal seizures and its regulation by melatonin - PubMed

Despite the effective use of antiepileptic drugs (AEDs) for epilepsy, therapeutic failure occurs in 30% of patients. Novel approaches are targeting the inhibition of epileptogenesis. N-acetyl-5-methoxytryptamine (melatonin) is an indoleamine produced mainly by the pineal gland, and has been...

www.ncbi.nlm.nih.gov

DRD2, MC4, k1 opioid receptor down regulation amongst others in seizure mice.

Melatonin receptor activation suppresses adrenocorticotropin production via BMP-4 action by pituitary AtT20 cells

The role of melatonin, a regulator of circadian rhythm, in adrenocorticotropin (ACTH) production by corticotrope cells has not been elucidated. In thi…

www.sciencedirect.com

Here's a random older study with melatonin interfering with morphine analgesia

Attenuation of morphine analgesia by alpha-MSH, MIF-I, melatonin and naloxone in the rat - PubMed

In two experiments the effects of the pituitary peptide alpha-MSH, the hypothalamic tripeptide MIF-I (P-L-G-NH2) and the pineal hormone melatonin were investigated on the attenuation of morphine analgesia measured by a tail flick test. In Experiment 1, alpha-MSH had minimal effect on morphine...

www.ncbi.nlm.nih.gov

Could minor kor affinity /agonism oppose some MOR? Or some dopaminergic modulation.

Don't know much about MT1/MT2 besides some of the newer drugs.

 

[polymath]

Here's a random older study with melatonin interfering with morphine analgesia

Attenuation of morphine analgesia by alpha-MSH, MIF-I, melatonin and naloxone in the rat - PubMed

In two experiments the effects of the pituitary peptide alpha-MSH, the hypothalamic tripeptide MIF-I (P-L-G-NH2) and the pineal hormone melatonin were investigated on the attenuation of morphine analgesia measured by a tail flick test. In Experiment 1, alpha-MSH had minimal effect on morphine...

www.ncbi.nlm.nih.gov

Could minor kor affinity /agonism oppose some MOR? Or some dopaminergic modulation.

So there are contradictory results about its effect on opioid system, too, and not only on dopamine reuptake. It probably doesn't make much sense to obtain gram amounts of melatonin and test these effects, unless it's much cheaper somewhere else than it is where I live.

 

[Valentine4]

From what I have found, a larger amount of the studies, post 2000, seem to study Melatonin's nociceptive effect, and there are manytthat study/discuss an analgesia modulating effect. But there are clearly plenty that also that study its paradoxical hyperalgesic or proalgesic effect. Below are some studies that analyze or test the analgesic/nociceptive/hyperalgesic/proalgesic effects, or make use of its nociceptive effects...see below.

Melatonin in pain modulation: analgesic or proalgesic?
Y Liu, H He, F Huang - 2014 - 41.89.240.73
Melatonin, as an endogenous hormone produced mainly in the pineal gland in a clear circadian fashion, has diverse physiological functions, such as the control of circadian rhythms, sleep regulation, antioxidant, etc. Recently, accumulating researches about …
Cited by 11 Related articles

Melatonin improves tourniquet tolerance and enhances postoperative analgesia in patients receiving intravenous regional anesthesia
HA Mowafi, SA Ismail - Anesthesia & Analgesia, 2008 - journals.lww.com
BACKGROUND: Melatonin has anxiolytic and potential analgesic effects. We assessed the efficacy of me.
Cited by 68 Related articles
[PDF] academia.edu
The clinical impact of preoperative melatonin on postoperative outcomes in patients undergoing abdominal hysterectomy
W Caumo, F Torres, NL Moreira, JAS Auzani… - Anesthesia & …, 2007 - journals.lww.com
BACKGROUND: Melatonin has sedative, analgesic, antiinflammatory, antioxidative, and chronobiotic eff.

Studies on the anti-inflammatory and anti-nociceptive effects of melatonin in the rat
SM El-Shenawy, OME Abdel-Salam, AR Baiuomy… - Pharmacological …, 2002 - Elsevier
The present study aimed to evaluate the anti-inflammatory and anti-nociceptive effects of melatonin in the rat. Acute inflammation was induced by sub-plantar injection of carrageenan (1%) in the rat hind paw. The rats received vehicle or drug 30 min before …
Cited by 165 Related articles
Effects of melatonin, morphine and diazepam on formalin-induced nociception in mice
CS Pang, SF Tsang, JC Yang - Life sciences, 2001 - Elsevier
The possible analgesic effect of melatonin was investigated in young male ICR mice. The formalin test which elicits typically 2 phases of pain response, the acute (first) phase and tonic (second) phase, was used. The test was performed in the late light period when the …
Cited by 87 Related articles
Effect of melatonin on rat spinal cord nociceptive transmission
C Laurido, T Pelissier, R Soto-Moyano, L Valladares… - …, 2002 - journals.lww.com
Melatonin has been shown to exert potent antinociception but the sites and mechanisms of action underlying this effect have not yet been clarified. The effect of melatonin on spinal cord nociceptive transmission was studied in rats by assessing wid-up activity in a C-fiber …
Cited by 53 Related articles
Melatonin: a hormone that modulates pain
M Ambriz-Tututi, HI Rocha-González, SL Cruz… - Life Sciences, 2009 - Elsevier
Aims Melatonin is a hormone synthesized principally in the pineal gland that has been classically associated with endocrine actions. However, several lines of evidence suggest that melatonin plays a role in pain modulation. This paper reviews the available evidence on …
Cited by 187 Related article
[PDF] academia.edu
Melatonin reduces formalin-induced nociception and tactile allodynia in diabetic rats
R Arreola-Espino, H Urquiza-Marín… - European journal of …, 2007 - Elsevier
The purpose of this study was to assess the antinociceptive and antiallodynic effect of melatonin as well as its possible mechanism of action in diabetic rats. Streptozotocin (50 mg/kg) injection caused hyperglycemia within 1 week. Formalin-evoked flinching was …
Cited by 60 Related articles
Evaluation of the anti-inflammatory and anti-nociceptive activities of novel synthesized melatonin analogues
GA Elmegeed, AR Baiuomy… - European journal of …, 2007 - Elsevier
This study aimed at evaluation of the reactivity of melatonin (1) towards various chemical reagents to produce new melatonin analogues containing heterocyclic moieties which would provide basic pharmacological activities. The pyrrolo [1, 2-a] indole derivatives 3, 5 …
Cited by 47 Related articles
Melatonin replacement nullifies the effect of light-induced functional pinealectomy on nociceptive rhythm in the rat
TM John, MC Brown, L Wideman, GM Brown - Physiology & behavior, 1994 - Elsevier
Rats maintained on a 12 h daily photoperiod (12: 12 LD cycle), exhibited a diunal variation in sensitivity to both heat-elicited and pressure-elicited pain, with low sensitivity at 2 h before the end of the scotophase and higher at 4 h after the onset of photophase. Functional …
Cited by 35 Related articles
Pineal opioid receptors and analgesic action of melatonin
M Ebadi, P Govitrapong… - Journal of pineal …, 1998 - Wiley Online Library
… 3). The involvement of multiple receptors and mechanisms in nociception … Analgesic action of melatonin … There are many receptor subtypes that have been implicated in transmission of nociceptive informa- tion in the dorsal horn, which include alpha-2 adrenoceptors, tachykinins …
Cited by 117 Related articles

 

[Valentine4]

I mean it is a really old study but I wonder how that connects.

Local pineal and pituitary gland effects? Is it downstream of melatonin receptor activation?

Long-term expression of metabolism-associated genes in the rat hippocampus following recurrent neonatal seizures and its regulation by melatonin - PubMed

Despite the effective use of antiepileptic drugs (AEDs) for epilepsy, therapeutic failure occurs in 30% of patients. Novel approaches are targeting the inhibition of epileptogenesis. N-acetyl-5-methoxytryptamine (melatonin) is an indoleamine produced mainly by the pineal gland, and has been...

www.ncbi.nlm.nih.gov

DRD2, MC4, k1 opioid receptor down regulation amongst others in seizure mice.

Melatonin receptor activation suppresses adrenocorticotropin production via BMP-4 action by pituitary AtT20 cells

The role of melatonin, a regulator of circadian rhythm, in adrenocorticotropin (ACTH) production by corticotrope cells has not been elucidated. In thi…

www.sciencedirect.com

Here's a random older study with melatonin interfering with morphine analgesia

Attenuation of morphine analgesia by alpha-MSH, MIF-I, melatonin and naloxone in the rat - PubMed

In two experiments the effects of the pituitary peptide alpha-MSH, the hypothalamic tripeptide MIF-I (P-L-G-NH2) and the pineal hormone melatonin were investigated on the attenuation of morphine analgesia measured by a tail flick test. In Experiment 1, alpha-MSH had minimal effect on morphine...

www.ncbi.nlm.nih.gov

Could minor kor affinity /agonism oppose some MOR? Or some dopaminergic modulation.

Don't know much about MT1/MT2 besides some of the newer drugs.

Ironically, here is a study of the same/similar biological mechanisms, but in relation to Melatonin's analgesic effect instead of its proalgesic effect (from the study you cited). This ones far newer, I dont know if that makes it any more accurate though:

Pineal opioid receptors and analgesic action of melatonin
M Ebadi, P Govitrapong… - Journal of pineal …, 1998 - Wiley Online Library
… 3). The involvement of multiple receptors and mechanisms in nociception … Analgesic action of melatonin … There are many receptor subtypes that have been implicated in transmission of nociceptive informa- tion in the dorsal horn, which include alpha-2 adrenoceptors, tachykinins …
Cited by 117 Related articles