Health - Treating MDMA users with methylone, bk-MBDB, etc?

[enquirewithin]

This article seems to to state that methylone, bk-MBDB and others may be less neurotoxic than MDMA.

______________________________
NON-NEUROTOXIC RECREATIONAL DRUGS AND A METHOD OF TREATING RECREATIONAL DRUG ABUSE

http://www.wipo.int/pctdb/en/wo.jsp?...5&DISPLAY=DESC

5 Field of the Invention

This invention relates to recreational drugs and in particular to recreational drugs which are non-neurotoxic and/or to methods of treating recreational drug abusers.

I O Background of the Invention

Recreational drugs such as 3,4-methylenedioxy-N-methylamphetamine, commonly known as "MDMA" or "Ecstasy", are widely used around the world. The chemical formulation of MDMA is shown below:

MDMA is known to cause selective serotonergic neurotoxicity in both animal and human recreational users. This neurotoxicity was first reported in the 1980s but its mechanism was not elucidated until the early 1990s. It has now 0 been demonstrated that MDMA neurotoxicity results from the inappropriate reuptake of dopamine into serotonergic neurons followed by MAO-B catalysed oxidation of the dopamine leading to lipid peroxidation and subsequent destruction of cell structures. Neurotoxicity thus requires unnaturally prolonged and excessive release of both serotonin and dopamine at the same time. 5 Additional evidence suggests that the toxic hyperthermia seen in MDMA overdose may be linked to excessive release of noradrenalin.
The multiple effects of MDMA have now been elucidated through research. MDMA has three targets in the brain that are important to its action.

Firstly it binds to the 5HTT serotonin reuptake transporter and causes it to run in reverse, effectively pumping serotonin from the neuron body back out into the synapse. Secondly it binds to the VMAT-2 vesicular monoamine transporter. This stimulates vesicular release of serotonin, dopamine and noradrenalin, in a similar manner to other amphetamines. Thirdly MDMA binds weakly to the 5HT2A receptor which causes the hallucinations of LSD, mescaline etc. MDMA has only mild effects at this target and does not characteristically induce hallucinations.

In order to separate the different effects of MDMA, compounds were developed that would bind selectively to each of the different targets. Animals were then trained to distinguish between the three separate cues, which were labelled "empathogenic", "stimulant" and "hallucinogenic". Compounds selective for the hallucinogen cue (selective 5HT2A agonists) were already known, and include compounds such as LSD, DOM, psilocin and mescaline, with well established activity. Compounds selective for the stimulant cue are non-selective releasers of dopamine, serotonin and noradrenalin (via vesicular release triggered by VMAT-2 binding). These compounds are very dangerous and often induce toxic hyperthermia, convulsions, stroke etc. Some examples of these compounds have made their way onto the illicit market and include drugs such as paramethoxyamphetamine (PMA) and 4-methylthioamphetamine (4MT), both of which have been responsible for multiple deaths in humans.
Compounds were also developed that were selective for the "empathogenic" cue, acting specifically as 5HTT "inverse agonists" to selectively release serotonin with no effect on dopamine or noradrenalin release. These compounds were found to mimic many of the effects of MDMA in animal studies, yet produced no serotonergic neurotoxicity when administered by themselves.

Three compounds that fitted this profile were originally developed. Subsequently several more have been discovered. These compounds are not amphetamines.

The carbon skeleton has been modified in such a way that amphetamines could not be produced from them in any useful quantity. These compounds have all been shown to mimic some MDMA effects yet produce no measurable serotonergic toxicity in animals even following chronic administration of high doses.

As abuse of MDMA is a current problem that is almost certainly causing some degree of brain damage to human users of this known neurotoxin, there have been attempts to develop a non-neurotoxic replacement for MDMA. One such attempt is the benzylpiperazine/trifluoromethylphenylpiperazine products currently available on the market, but while these products simulate MDMA effects in animals, they are not adequate substitutes for human MDMA users. There are also problems associated with the piperazine products (especially when they are combined with alcohol) including abuse potential, unpleasant side effects and isolated incidents of blackouts and convulsions.

Due to the increasing amount of recreational drug users worldwide there is a need to develop less harmful recreational drugs which do not cause neurotoxicity and which would therefore reduce the amount of harm suffered by recreational drug users without necessarily changing their patterns of drug use.

Object of the Invention

It is an object of the invention to provide a recreational drug which is non- neurotoxic and/or a method of treating recreational drug abusers, or at least to provide the public with a useful choice.

Summary of the Invention

In one aspect the invention provides for the use of a non-neurotoxic serotonin releaser in the manufacture of a pharmaceutical formulation for use as a recreational drug.

In another aspect the invention provides for the use of a non-neurotoxic serotonin releaser in the manufacture of a medicament for the treatment of the neurotoxic effects of recreational drug abuse by substituting the medicament for neurotoxic drugs of abuse.

Examples of compounds which are non-neurotoxic serotonin releasers suitable for use in this invention include, but are not limited to: 1-(3,4- methylenedioxyphenyl)-2-(N-methyl) aminopropan-1-one (Methylone), 1-(3,4- methylenedioxyphenyl)-2-(N-methyl) aminobutan-1-one (BK-MBDB), 5,6- methylenedioxy-2-aminoindane (MDAI), 5,6-methylenedioxy-(N-methyl)-2- aminoindane (MDMAI), 5-methyl-6-methoxy-2-aminoindane (MMAI), or a pharmaceutical formulation containing a combination of these compounds.

The chemical structures of these compounds are shown below:

Methylone BK-MBDB

MDAI MDMAI MMAI

In a further aspect the invention provides a pharmaceutical formulation which includes a non-neurotoxic serotonin releaser and at least one excipient. Preferably the excipient is selected from the group comprising DiTab, Povidone, Croscarmellose sodium, Cellulose-Microcrystalline, Magnesium stearate and Silicon dioxide.

Preferably the non-neurotoxic serotonin releaser is present in the amount of 25 to 400 mg per dosage form.

Preferably the non-neurotoxic serotonin releaser is present in the amount of 50 to 200 mg per dosage form.

More preferably the non-neurotoxic serotonin releaser is present in the amount of 100 mg per dosage form.

Preferably the non-neurotoxic serotonin releaser is either 5,6- methylenedioxy-2-aminoindane (MDAI), 5,6-methylenedioxy-(N-methyl)-2- aminoindane (MDMAI) or 5-methyl-6-methoxy-2-aminoindane (MMAI).
Preferably the pharmaceutical formulation further includes a serotonin precursor.
Preferably the serotonin precursor is 5-hydroxytryptophan (5-HTP), or I- tryptophan.

Preferably the pharmaceutical formulation further includes at least one antioxidant.

Preferably the antioxidant or antioxidants are selected from the group comprising Vitamin C, Vitamin E and grape seed extract. Preferably the formulation further includes Vitamin B6, or other vitamins or amino acids.

Preferably the dosage form of the pharmaceutical formulation is as a tablet or capsule for oral use.

Preferably the pharmaceutical formulation includes an injectable formulation, a liquid formulation, a powder formulation, or a formulation for dermal application, for example in a subcutaneous form or in the form of a skin patch.

in another aspect the invention provides for a method of treatment of the neurotoxic effects of recreational drug abuse by substituting a non-neurotoxic serotonin releaser or formulation containing a non-neurotoxic serotonin releaser for neurotoxic drugs of abuse.

Preferably the method of treatment includes the supply of tablets or capsules containing from 25 to 400 mg of a non-neurotoxic serotonin releaser with at least one excipient.

The phrase "neurotoxic drugs of abuse" as referred to herein means drugs of abuse, having known neurotoxicity, which do not typically produce a daily addictive habit, but instead are abused in a cyclic manner characterized by short binges of use, generally in social situations. Relevant examples of such drugs in this instance include, but are not limited to;

3,4-methylenedioxyamphetamine, 3,4-methylenedioxy-
N-methylampetamine, and 3,4-methylenedioxy-N- ethylamphetamine.

The phrase "non-neurotoxic selective serotonin releaser" as referred to herein means compounds which are considered to act primarily by binding to the 5HTT serotonin reuptake transporter and reversing its direction of action, thereby selectively releasing serotonin by retrograde transport. This mechanism is distinct from that of serotonin agonists; selective serotonin reuptake inhibitors;


non-selective monoamine reuptake inhibitors; and compounds which promote the release of monoamines by inducing vesicular trafficking.
Detailed Description Non-neurotoxic serotonin releasers are not amphetamines. They are compounds in which the carbon skeleton has been modified in such a way that amphetamines could not be produced from them in any useful quantity. These compounds have been shown to mimic some MDMA effects yet produce no measurable serotonergic toxicity in animals even following chronic administration in high doses. They act specifically as 5HTT "inverse agonists" to selectively release serotonin with little or no effect on dopamine or noradrenalin release.

The preferred non-neurotoxic serotonin releaser compound for use in this invention is either 5,6-methylenedioxy-2-aminoindane (MDAI), 5,6- methylenedioxy-(N-methyl)-2-aminoindane (MDMAI) or 5-methyl-6-methoxy-2- aminoindane (MMAI), or a combination of these compounds.

More generally this invention may alternatively use other compounds which act as non-neurotoxic selective serotonin releasers, these being 2- aminoindane derivatives having the general structure shown below:

In this more general case, R1 and R2 can be any combination of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, nitrile, or halogen substituents, each containing up to 6 carbon atoms, and R3 can be either hydrogen, methyl, ethyl, propyl or isopropyl.

This also includes cyclic analogues, either substituted with a cyclic moiety at a single site, or linking the R1 and R2 positions.

2-aminoindane derivatives with the structural and pharmacological characteristics outlined above, are selective serotonin releasers with little affinity for the VMAT-2 transporter. As they lack the mechanism by which MDMA neurotoxicity normally takes place, this class of compounds has been shown to be non-neurotoxic. Also, as these compounds do not cause the release of dopamine, they should not have the amphetamine-like abuse potential which is common with the use of MDMA.

Preliminary human trials and toxicity studies have demonstrated that non- neurotoxic selective serotonin releasers are considerably safer than MDMA even in acute overdose. During these trials, the side effects and safety profile of non- neurotoxic selective serotonin releasers were suitably established. The trials showed that non-neurotoxic selective serotonin releasers have subjective effects somewhat similar to MDMA, but with much weaker stimulant and hyperthermia effects, and cause less "come-down" symptoms after use. These results support the hypothesis that non-neurotoxic selective serotonin releasers are selectively releasing serotonin but not dopamine or noradrenalin and so should be considerably safer and less toxic than MDMA. During these trials, no participants experienced adverse incidents requiring medical attention at any time.

Trials demonstrated the efficacy and safety of these compounds for use as recreational drugs that successfully substitute for MDMA in a significant proportion of users. 68.1 % of enrolled participants surveyed significantly reduced their consumption of MDMA during the trial period.

Although the preliminary trials were conducted in order to assess safer alternatives for current recreational drug users, it is considered that such safer alternatives could provide a method of treatment of the neurotoxic effects of recreational drug abuse by substituting a non-neurotoxic serotonin releaser, or a pharmaceutical formulation containing a combination of several non-neurotoxic serotonin releasers, in place of neurotoxic drugs of abuse.
5 For the preliminary trials, 1-(3,4-methylenedioxyphenyl)-2-(N-methyl) aminopropan-1-one (methylone) was used in the manufacture of a formulation for use as a recreational drug as shown in the following example.

Example 1
I O The methylone was formulated into a tablet containing 100mg of racemic methylone hydrochloride, 25mg of 5HTP, 5mg of vitamin B6, vitamin C, vitamin E and grape seed extract. The additional ingredients being antioxidants which were intended to help to reduce any potential for neurotoxicity.

15 In order to limit abuse potential, each trial participant was given access to only 10 doses per month. After the trial, participants were invited to take part in medical and psychological evaluations to ensure that they had not been subjected to additional drug-related harm. Results showed that 68.1 % of participants in the trial had substituted the present formulation for illegal street

20 "Ecstasy" pills, and 90.6% of participants had reduced their use of other drugs, demonstrating that these compounds can be used successfully to substitute for drugs such as MDMA.

The above example formulations are illustrative examples only, and is not 25 intended to in any way limit the scope of the invention. It will be apparent to the skilled reader that various modifications and amendments can be made to the specific formulations and to the method disclosed and still lie within the general concept of the invention. All such modifications and amendments are intended to be included in the scope of the present invention. 30

Reputation Comments on this post:

	good effort thanks for the article.
	interesting find
	Interesting article.
	Great article
	awesome article! very interesting and informative.

[entheogensmurf]

Slowly we work our way to the Brave New World's Soma

Reputation Comments on this post:

Heh heh. Let's hope so.

[tinytom]

thanks for that mate!

it is interesting that these things are being developed, will be good to see how it pans out and if governments embrace it or not.

Reputation Comments on this post:

you really shouldn't advertise giving rep points in your posts

[radiometer]

This study sounds a bit fishy to me, as if it were commissioned by those New Zealand party pills companies or something.


*edit* And looking at the bibliographical info, I was right. STARGATE INTERNATIONAL LIMITED paid for this study. I'd like to see a bit of the data, but none was provided.

[enquirewithin]

Originally Posted by radiometer

This study sounds a bit fishy to me, as if it were commissioned by those New Zealand party pills companies or something.


*edit* And looking at the bibliographical info, I was right. STARGATE INTERNATIONAL LIMITED paid for this study. I'd like to see a bit of the data, but none was provided.

Well spotted. I thought it was a slightly odd study. Curious anyway....


They are real compounds. MDAI =5,6- methylenedioxy-2- aminoindan, for example-- which one report said "was exactly like MDMA" (from another forum).

[FrankenChrist]

MDAI MDMAI MMAI

Woah there... any info on these? Are they even real?

[Paracelsus]

I second radiometer's concerns. There is an obvious conflict of interest, and the 'scientific' information provided should be consumed carefully.

MMAI is 5-methoxy-6-methyl-2-aminoindan, a cousin of 3-methoxy-4-methylamphetamine, both of which are experimental selective serotonin releasers. They are not neurotoxic like MDMA (in rats, anyways).

My opinion: Yes, certain RCs may be safeR alternatives to MDMA. Yes, some people could benefit from substituting these for MDMA. But no, using these RCs as treatment for MDMA 'addiction' is unlikely to happen.
Unlike the physical dependence of, say, opiates, which is treated with certain substitutes (methadone, buprenorphine), MDMA is not physically addicting. MDMA addicts don't need non-neurotoxic alternatives but treatment for their psychological addiction. Giving them said RCs should be a measure of last resort, similar to giving out pharmaceutical heroin to addicts who don't respond to multiple treatment methods.

EDIT: Just noticed that this is a patent. Nevermind. Don't believe them.

Reputation Comments on this post:

thanks for clearing that up

[radiometer]

Perhaps Starboy might spot this thread and give us a bit more detail?

[enquirewithin]

That would be interesting!

[Expat98]

This is also interesting from a legal/policy standpoint (patenting a recreational drug). Look at the patent claims:

Claim 1: The use of a non-neurotoxic serotonin releaser in the manufacture of a pharmaceutical formulation for use as a recreational drug.

Claim 17: A method of treatment of the neurotoxic effects of recreational drug abuse by substituting a non-neurotoxic serotonin releaser for neurotoxic drugs of abuse.

For those not familiar with the patent process, the way it works is that an Examiner will search for prior art that anticipates the patent claims. It will be interesting to follow the prosecution of this application and see what kind of prior art the Examiner finds for these claims.

[medievil]

mdma aint even proven to be neurotoxic...

[KomodoMK]

Nice article, can't believe I didn't come across it before as I was looking for something along these lines. Thanks!

[Montgolfier]

Methylone certainly does feel much less toxic than MDMA with very similar positive effects.

The comedown is also much easier, comparable to a bad alcohol hangover

(so I was told once by a talking sheep)

Would really like to see more study into Methylone as an alternative to MDMA.

[KomodoMK]

Originally Posted by MrCheese

Methylone certainly does feel much less toxic than MDMA with very similar positive effects.

The comedown is also much easier, comparable to a bad alcohol hangover

(so I was told once by a talking sheep)

Would really like to see more study into Methylone as an alternative to MDMA.

The lack or serotonergic effects of MDMA are three fold of that of Methylone, for that reason my little fishy doesn't think it would be of much use. Whilst Methylone is quite good, it doesn't even compare and gets boring first.

Methylone as an alternative for MDMA is the same as Alcohol free beer to replace beer in my fishys opinion.

[nonames]

Would MDAI be considered an analogue of either MDMA or MDA

nonames added 736 Minutes and 40 Seconds later...

According to USA government laws

[dark12]

very cool.
It seems like the dosages of 5HTP are rather low though...