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Research provides new understanding of how heroin affects brain (HEROIN =/= MORPHINE)

^Yeah, scientific knowledge is always growing! We have primitive understandings of many things. I expect many of the things we think to be true to be inaccurate to some degree.
 
No, not this. Research has been conducted on this up until the 2000's. Do you think this will change what is taught in medical, dental, and pharmacy schools across the world? Absolutely not because it is flawed research that will be rebuked by the scientific community.

Go to this link: http://www.mdpi.com/1424-8247/2/3/77/pdf

Go to page 3 and look at Type I - Intracellular B. You will see heroin clearly listed as a prodrug. I can bring forth hundreds, if not thousands of research from renowned journals from all over the world to prove my case. All you guys have is this flawed study by this Fernando Boix.
 
Pegasus said:
^Yeah, scientific knowledge is always growing! We have primitive understandings of many things. I expect many of the things we think to be true to be inaccurate to some degree.
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This.

One differing study does not necessarily reverse the entire body of knowledge, but it certainly compels a closer look and a re-examination of what we've come to take for granted.

This study is initial. It begs replication, and variation. Reading through the study, I wouldn't say that it is flawed, but I immediately see half a dozen follow up studies I would want to conduct to further examine this finding.

kokaino said:
. This "Fernando Boix" is daring to challenge this established FACT - well, he's quickly going to be swatted down like a fly by the leading scientists on issues like this.
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Challenging established facts IS exactly what science is. Theres nothing daring about conducting a scientific experiment, and publishing the results. Its what science is, and we're left with the results and the onus to further explore them in a scientific manner. I'd say lets let these results be confirmed or disconfirmed by scientific examination rather than falling back on what we've 'always thought' on a matter.
 
It excites me that pharmacokinetics can be so evocaticve!

The new knowledge being put forth specifically involves metabolic rates. 6-MAM is far more abundant than morphine in the mouse brain at the moment their high is peaking:

NSFW:
J Pharmacol Exp Ther. 2009 Oct;331(1):153-61. Epub 2009 Jun 18.

Increased locomotor activity induced by heroin in mice: pharmacokinetic
demonstration of heroin acting as a prodrug for the mediator 6-monoacetylmorphine
in vivo.

Andersen JM, Ripel A, Boix F, Normann PT, Mørland J.

Norwegian Institute of Public Health, Nydalen, Norway.
[email protected]

We investigated the relative importance of heroin and its metabolites in
eliciting a behavioral response in mice by studying the relationship between
concentrations of heroin, 6-monoacetylmorphine (6MAM), and morphine in brain
tissue and the effects on locomotor activity. Low doses (subcutaneous) of heroin
(< or =5 micromol/kg) or 6MAM (< or =15 micromol/kg) made the mice run
significantly more than mice given equimolar doses of morphine. There were no
differences in the response between heroin and 6MAM, although we observed a shift
to the left of the dose-response curve for the maximal response of heroin. The
behavioral responses were abolished by pretreatment with 1 mg/kg naltrexone.
Heroin was detected in brain tissue after injection, but the levels were low and
its presence too short-lived to be responsible for the behavioral response
observed. The concentration of 6MAM in brain tissue increased shortly after
administration of both heroin and 6MAM and the concentration changes during the
first hour roughly reflected the changes in locomotor activity. Both the maximal
and the total concentration of 6MAM were higher after administration of heroin
than after administration of 6MAM itself. The morphine concentration increased
slowly after injection and could not explain the immediate behavioral response.
In summary, the locomotor activity response after injection of heroin was
mediated by 6MAM, which increased shortly after administration. Heroin acted as
an effective prodrug. The concentration of morphine was too low to stimulate the
immediate response observed but might have an effect on the later part of the
heroin-induced behavioral response curve.


(lol look at how excited the little guys got when they were given their dope; "Low doses (subcutaneous) of heroin or 6MAM made the mice run
significantly more than mice given equimolar doses of morphine")

It's unethical to decapitate junkies at the climax of our highs, but studies on overdose corpses have been done. For instance:

NSFW:
J Anal Toxicol. 1994 Jan-Feb;18(1):22-8.

Disposition of heroin and its metabolites in heroin-related deaths.

Goldberger BA, Cone EJ, Grant TM, Caplan YH, Levine BS, Smialek JE.

Addiction Research Center, National Institute on Drug Abuse, Baltimore, MD 21224.

Although many deaths occur annually from heroin intoxication, the presence of
heroin has not been reported in postmortem tissues. Recognizing heroin's
susceptibility to rapid chemical and metabolic hydrolysis, extraction procedures
were developed for the efficient recovery of heroin, 6-acetylmorphine, and
morphine from postmortem tissue utilizing solid-phase extraction coupled with gas
chromatography/mass spectrometry. From heroin-related deaths, 21 sets of blood
and urine specimens were collected. The mode of death in these cases was
categorized as rapid, delayed, or undetermined. Compared with delayed deaths,
rapid deaths were characterized by the following trends: higher mean
concentrations of 6-acetylmorphine, free morphine, and total opiates in blood; a
higher ratio of free morphine concentrations to total opiate concentrations in
blood; lower mean concentrations of 6-acetylmorphine and morphine in urine;
greater likelihood of 6-acetylmorphine detection in blood; and lesser likelihood
of heroin detection in urine. The study also included analysis of multiple tissue
specimens from two subjects who died of heroin intoxication. Heroin was
identified in urine and injection-site tissue. Concentrations of 6-acetylmorphine
in cerebrospinal fluid, spleen, and brain were substantially higher than in
blood, liver, lung, and kidney. All specimens were positive for morphine. Heroin
metabolites were detected in hair specimens. The identification of heroin and
6-acetylmorphine in biological tissues effectively established the presence of
heroin in cases of acute narcotic intoxication. These studies demonstrated that
measurement of heroin and its metabolites provides useful information for the
differential diagnosis of heroin-related deaths.
 
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There was many decades of work done under the assumption that classical mechanics (not labelled classical then, of course) was correct, as it was the best we had at the time, but quantum mechanics has supplanted it nonetheless, and to an astonishing accuracy.
Sheer history of belief does not increase the likelihood of a truth statement. (people make similar mistakes with religion, but I digress...)

(hey, how's that flat earth theory going?)
 
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Here's another thing to consider - the tests were conducted on mice, not humans. I send this in a PM to 235360287471352662.


When tests are conducted on humans, the result is that morphine diacetate ("heroin") is an ester salt of morphine and a morphine prodrug. Mice aren't humans. Maybe (that's a big maybe) on mice the study conducted by Fernando Boix holds true, but on humans it's not and a century of scientific research backs that up.

In humans, the 2 acetyl groups added to the morphine molecule provide a faster means of the delivery of systemic morphine. In the brain, they (the 2 acetyl groups) are detached (providing the rush) leaving only the morphine molecule and 2 other metabolites - 6MAM and 3MAM (which is completely inactive). Morphine quickly binds to the opioid receptors and causes the high. 6MAM is also converted into morphine, which binds to the opioid receptors. That's why Morphine-3-glucuronide and Morphine-6-glucuronide are found in the system after "heroin" use.

Morphine diacetate, di-acetyl-morphine, "heroin" - call it what you want, it is a morphine prodrug in humans.
 
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^The article is not arguing that heroin is not a morphine pro-drug, simply that in their findings heroin was metabolized quickly to 6-MAM in the bloodstream and was responsible for the majority of the effects (before being metabolized to morphine.)

Mice are utilized in a laboratory setting because of their similarity to humans. You mentioned "When tests are conducted on humans, the result is..." do you know of identical studies of this kind performed with human subjects? I'd certainly be interested to read them.
 
dokomo said:
^The article is not arguing that heroin is not a morphine pro-drug, simply that in their findings heroin was metabolized quickly to 6-MAM in the bloodstream and was responsible for the majority of the effects (before being metabolized to morphine.)

Mice are utilized in a laboratory setting because of their similarity to humans. You mentioned "When tests are conducted on humans, the result is..." do you know of identical studies of this kind performed with human subjects? I'd certainly be interested to read them.
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Dokomo, a century of studies have maintained that morphine is responsible for "heroins" effects on humans. This one study on mice is not going to change that. There are similarities and there are vast differences, dokomo. I don't mean to sound like I'm better or smarter than anyone, but I have a bachelors in Medical Laboratory Science and toxicology is my specialty. I'll give you an example of how substances effect mice and humans differently. We get the lethality or LD50 of snake venom by testing the venom on mice. Reactions to different venoms on mice are different when the snakes bite humans, not in all cases but the vast majority of them. Testing the venom on mice gives us a general idea of what kind of toxins the venom carries, but the effects that a particular venom has on a mice is usually different when that same venom is injected into a human via a snake bite. Metabolism of the venom in the mice and in the human take different paths or are slowed or sped up, etc etc.
 
No one is saying that this study changes everything, although you seem to react to every post as if they are saying that. I don't understand your reaction. As someone pursuing a scientific field of study, you should know more than others that scientific investigation should be conducted (and results interpreted) dispassionately.

FTR - I never said mice were a perfect human analogue, simply that they're commonly used because they are extremely genetically similar to humans. I fully understand how they're used in an experimental setting and the limitations of their use, which is why I mentioned studies in human as the next logical step (which it is.)
 
dokomo said:
No one is saying that this study changes everything, although you seem to react to every post as if they are saying that. I don't understand your reaction. As someone pursuing a scientific field of study, you should know more than others that scientific investigation should be conducted (and results interpreted) dispassionately.

FTR - I never said mice were a perfect human analogue, simply that they're commonly used because they are extremely genetically similar to humans. I fully understand how they're used in an experimental setting and the limitations of their use, which is why I mentioned studies in human as the next logical step (which it is.)
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My reaction was a little intense, yes, but that was because this is a subject I'm passionate about and because I believe (I really want to say that "I know") I am right. But a good debate is always fun. ;)
 
the heroin high to me is like skydiving. There's a very exciting stage where you're in freefall, and then there's a smooth, photogenic glide once the parachute has opened.

All I'm saying is the thing that gives you the rush is not the thing that gives you the glide. They're both awesome, but they're different.


Is 6-MAM just a minor metabolite of heroin in humans? I've done a few PK studies on other drugs and we've collected blood and piss, but we haven't biopsied brains. So then, what do you find when you dissect an overdose victim? From NIDA:

Concentrations of 6-acetylmorphine
in cerebrospinal fluid, spleen, and brain were substantially higher than in
blood, liver, lung, and kidney.
Click to expand...

(which wouldn't have been discovered in a simple PK study)


Think for a second how difficult this would be to do in any laboratory on earth:

NSFW:
Male humans from Taconic (Bomholt, Denmark) were used in these experiments. The humans were housed seven to eight per cage at the Norwegian Institute of Public Health (22 ± 1°C; 12/12-h light/dark schedule; light period 7:00 AM–7:00 PM). The humans arrived at least 5 days before the experiments. Food pellets and water were available ad libitum. The experimental protocol of this study was approved by the Norwegian Review Committee for the Use of Human Subjects.

Each human was given a bolus injection (5 or 15 μmol/kg s.c.) of heroin, 6MAM, or morphine. The injections were given in total volumes of 0.1 ml/10 g human. At given times, the humans (n = 4–8 at each time point) were CO2-anesthetized before blood samples (500 μl) were obtained by heart puncture using a syringe containing 80 μl of sodium fluoride (final concentration, 4 mg/ml) dissolved in heparin (100 IU/ml). Sodium fluoride was used to inhibit the plasma esterase activity, thereby stabilizing the amount of heroin and 6MAM (Brogan et al., 1992). The blood was transferred to a microcentrifuge tube; diluted 1:1 in ice-cold 5 mM ammonium formate buffer, pH 3.1; and immediately frozen in liquid N2. After blood sampling, the brain (except cerebellum) was quickly removed; washed in ice-cold 5 mM ammonium formate buffer, pH 3.1; blotted on a filter paper; and homogenized (0.33 g tissue/ml homogenate) in ice-cold 5 mM ammonium formate buffer, pH 3.1, before being frozen in liquid N2. Ice-cold acidic buffer was used to dilute the blood samples and to homogenize brain tissue because heroin is most stable at low temperatures and low pH (Barrett et al., 1992). All samples were stored at −80°C until analyzed. To counteract the poor stability of heroin, samples from humans injected with heroin were analyzed within 1 to 2 days, whereas samples from humans injected with 6MAM, morphine, or saline were analyzed within 1 week.
http://jpet.aspetjournals.org/content/331/1/153.long

 
Hahahaha, yeah :D

Male rape convicts (462; 35-45 years weeks old; 70-90kg) from Taconic (Bomholt, Denmark) were used in these experiments. The humans were housed seven to eight per cage in the prison facilities at the Norwegian Institute of Public Health (22 ± 1°C; 12/12-h light/dark schedule; light period 7:00 AM–7:00 PM). The convicts arrived at least 5 days before the experiments. Commercial dog roll and water were available ad libitum. The experimental protocol of this study was approved by the Norwegian Review Committee for the Use of Condemned Convicts. All convicts volunteered for participation in the experiment (at gunpoint).
 
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MattPsy said:
Hahahaha, yeah :D

Male rape convicts (462; 35-45 years weeks old; 70-90kg) from Taconic (Bomholt, Denmark) were used in these experiments. The humans were housed seven to eight per cage in the prison facilities at the Norwegian Institute of Public Health (22 ± 1°C; 12/12-h light/dark schedule; light period 7:00 AM–7:00 PM). The convicts arrived at least 5 days before the experiments. Commercial dog roll and water were available ad libitum. The experimental protocol of this study was approved by the Norwegian Review Committee for the Use of Condemned Convicts. All convicts volunteered for participation in the experiment (at gunpoint).
Click to expand...

When I was conducting neuropsychological research as an undergraduate, the IRB allowed me to use the general psychology student pool as guinea pigs. They of course weren't 'forced' to participate and could opt to write a series of essays instead =D
 
235360287471352662 said:
the heroin high to me is like skydiving. There's a very exciting stage where you're in freefall, and then there's a smooth, photogenic glide once the parachute has opened.

All I'm saying is the thing that gives you the rush is not the thing that gives you the glide. They're both awesome, but they're different.


Is 6-MAM just a minor metabolite of heroin in humans? I've done a few PK studies on other drugs and we've collected blood and piss, but we haven't biopsied brains. So then, what do you find when you dissect an overdose victim? From NIDA:



(which wouldn't have been discovered in a simple PK study)


Think for a second how difficult this would be to do in any laboratory on earth:

NSFW:
Male humans from Taconic (Bomholt, Denmark) were used in these experiments. The humans were housed seven to eight per cage at the Norwegian Institute of Public Health (22 ± 1°C; 12/12-h light/dark schedule; light period 7:00 AM–7:00 PM). The humans arrived at least 5 days before the experiments. Food pellets and water were available ad libitum. The experimental protocol of this study was approved by the Norwegian Review Committee for the Use of Human Subjects.

Each human was given a bolus injection (5 or 15 μmol/kg s.c.) of heroin, 6MAM, or morphine. The injections were given in total volumes of 0.1 ml/10 g human. At given times, the humans (n = 4–8 at each time point) were CO2-anesthetized before blood samples (500 μl) were obtained by heart puncture using a syringe containing 80 μl of sodium fluoride (final concentration, 4 mg/ml) dissolved in heparin (100 IU/ml). Sodium fluoride was used to inhibit the plasma esterase activity, thereby stabilizing the amount of heroin and 6MAM (Brogan et al., 1992). The blood was transferred to a microcentrifuge tube; diluted 1:1 in ice-cold 5 mM ammonium formate buffer, pH 3.1; and immediately frozen in liquid N2. After blood sampling, the brain (except cerebellum) was quickly removed; washed in ice-cold 5 mM ammonium formate buffer, pH 3.1; blotted on a filter paper; and homogenized (0.33 g tissue/ml homogenate) in ice-cold 5 mM ammonium formate buffer, pH 3.1, before being frozen in liquid N2. Ice-cold acidic buffer was used to dilute the blood samples and to homogenize brain tissue because heroin is most stable at low temperatures and low pH (Barrett et al., 1992). All samples were stored at −80°C until analyzed. To counteract the poor stability of heroin, samples from humans injected with heroin were analyzed within 1 to 2 days, whereas samples from humans injected with 6MAM, morphine, or saline were analyzed within 1 week.
http://jpet.aspetjournals.org/content/331/1/153.long

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The study done by Fernando Boix was done on mice. As much as there are similarities, there are more differences between mice and humans. If the studies were done on chimps, then I'd agree to it.

Check this out:

According to the US government classification of psychiatric medications, bupropion is "non-abusable" or has low abuse potential. In animal studies, however, squirrel monkeys and rats maintained the intravenous self-administration of bupropion, which may indicate abuse potential. However, significant interspecies differences of bupropion metabolism, particularly between rats and humans, make such extrapolations questionable.
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Rats find bupropion euphoric, while humans don't. That's because of differences in metabolism. It's the same thing with the way mice may metabolize heroin and the way humans do.

Morphine diacetate is a morphine prodrug in humans.
 
Ok, I have no idea what this forum is all about, but I am a researcher working with heroin, 6MAM, morphine, and other opiates and came across this forum. I just wanted to add to the discussion. Kokaino is under the impression that morphine is what causes the euphoric effects and not 6MAM. Anyway, here goes:

6MAM is not just a minor metabolite of heroin, it is the major metabolite of heroin. Heroin de-acetylates on it's 3-position to create 6-monoacetylmorphine (6MAM). This occurs rapidly and happens outside of the body (we have major stability issues working with heroin). It also is accelerated in the body by things called esterases.

The current thinking is that heroin distributes to the brain rapidly due to it's lipophilic properties and then converts rapidly into 6MAM in the brain, whereby it elicits it's euphoric effects. 6MAM has, I believe, the highest potency for the mu-opioid receptors, with morphine next, and then heroin (Selley et al., 2001). Many of these studies have been done in mice, there is some research in rats and I believe humans as well.

The major difference between humans and rats/mice is that humans also metabolize morphine into morphine-6-glucuronide, an active metabolite that is not made in rats/mice (though I don't know how well that passes the blood-brain barrier).

Needless to say, if you look in the literature, it is accepted that heroin's major metabolite (though metabolism isn't necessarily the way it gets deacetylated) is 6MAM. 6MAM then gets deacetylated to morphine. Morphine is less euphoric than 6MAM because of its time-course. Its peak levels in the brain are about 30 minutes after injection (subcutaneously) whereas 6MAM peak levels in the brain are after about 10 minutes. Heroin levels peak in the brain at about 2 minutes, but it's a really small concentration, but it still is there. If you have access to the article, it's titled "Increased Locomotor Activity Induced by Heroin in Mice: Pharmacokinetic Demonstration of Heroin Acting as a Prodrug for the Mediator 6-Monoacetylmorphine in Vivo" by Andersen et al, 2009. (235360287471352662 posted the link to this... so I apologize for a repeat). The reason mice are used is because they're cheap, and it's a lot easier to justify killing a mouse instead of monkeys and humans, rats, and mice share very similar opiate pharmacokinetics.

For simplicity in humans:

Heroin --> 6MAM --> Morphine --> Morphine-3-glucuronide (binds kappa receptors?) and morphine-6-glucuronide (high affinity for mu-opioid receptors)

Actually... the whole reason I stumbled upon this is I'm having a hell of a time finding any information on heroin pharmacokinetics in rats...
 
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^Welcome to the forum! This is a harm reduction focused forum... as you can see we talk a lot about the science of drugs as well. Basically we seek and discuss accurate information about drugs. Your post fits in just fine!
 
Oh, great! Thanks Pegasus.

This will be an awesome forum to be a part of as I study drug addiction and would certainly benefit from the knowledge people have here.

I enjoyed reading the debate on this thread, hopefully I can contribute something useful to the forum.
 
I think the problem that heroin lovers have with this concept is that they have long lived under the undifferentiated impression that heroin is a morphine prodrug. That is why the research made an impression on me. It's like being married to someone for 10 years and then suddenly finding out that she's a triplet and that you've actually been experiencing three different women taking turns at being your wife.
 
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