About

Providing straightforward information pertaining to drugs, drug use & drug policy. The Grey Pages promotes drug-related literacy and advocates a system of viable and tolerant drug policies. This is my personal collection of commentaries, essays, tid-bits, and other such writings on everything ranging from drug use, drug policy and drug-myths, to drug-science, addiction, human behavior, and the workings of the human brain. I started this blog with a particular focus on opioids, and over the past year have found my interest gravitate toward the intriguing, ever-changing world of designer intoxicants (i.e. "research chemicals" or "designer drugs").

Saturday, March 29, 2014

Cathinone, Methcathinone, and Substituted Cathinones

General:

potted catha edulis shrub
Cathinone is a naturally occurring monoamine alkaloid with stimulant properties. It occurs naturally in the
shrub Catha Edulis (i.e. "Khat"). Illicit supplies of cathinone may be synthesized clandestinely, or prepared from actual khat. The N-methyl derivative, methcathinone, is much more common than cathinone as an illicit substance.

Cathinone was first isolated from the khat plant in the 1970's. In 1993, the USDOJ placed cathinone, and all cathinone-containing preparations (this would include the khat plant), into schedule 1 of the Controlled Substance Act. 

Methcathinone, also now a controlled substance, is the more potent, more common, N-methyl derivative of cathinone. It was first synthesized in the US in 1928 and patented by pharmaceutical firm Parke Davis in 1957. Methcathinone was used in the Soviet Union in the 1930's and 1940's as a commercial antidepressant. Methcathinone is closely related to methamphetamine and it too is easily prepared clandestinely, via the oxidation of ephedrine or pseudoephedrine, obtained from over-the-counter cold preparations.

In the last decade or so, substituted cathinone derivatives have appeared for sale as intoxicants. These
substances contain the propiophenone skeleton but with various substitutions, and are often not explicitly listed as controlled substances. These substances are usually encountered as nearly pure white or off white powders. Substituted cathinones were usually the main constituents in novelty "bath salts", unlabeled mixtures that gained a great deal of notoriety around 2010-2012, often containing caffeine and other fillers or dilutants. Most substituted cathinones are either stimulants, entactogens, or both.

There are a few substituted cathinones that are used as active pharmaceutical ingredients (API's). This includes diethylpropion, bupropion, and pyrovalerone.

Chemistry:

propiophenone skeleton (ethyl-phenyl-ketone)
Substituted cathinones are molecules which contain the cathinone or methcathinone (propiophenone)
skeleton; inclusive of;

a benzene ring (i.e. phenyl group) linked with a propane chain; the propane chain may, or may not, be extended with anywhere from one to several additional carbons (propane to octane)

an oxygen atom bound to the beta position (carbon 1) of the propane/alkyl chain

a nitrogen atom bound to the alpha (carbon 2) position of the propane chain, this nitrogen being bound with either a lone pair (such as 2 hydrogens, or a hydrogen and a methyl or ethyl group), or incorporated into a cyclic structure (such as a pyrrolidine ring)

....along with various other potential substitutions, added onto carbons 1 through 5 of the benzene ring or attatched to the alpha backbone.

Cathinone is nearly identical in structure to amphetamine; its distinguishing feature being the oxygen atom bound at the beta carbon on the alkyl chain (i.e. beta ketone)... cathinone can also be referred to as beta-keto-amphetamine, or bk-amphetamine. Methcathinone is the N-methyl derivative of cathinone, and also the beta-keto homologue of methamphetamine.

Production:

In 1989 in Ann Arbor Michigan, an intern with Parke Davis obtained samples of methcathinone. Also obtained was the formular for its synthesis. Methcathinone use and its clandestine production would eventually become more commonplace throughout the region and elsewhere. Clandestine production of methcathinone can be acheived with easily sourced materials, and kitchen-style methcathinone labs have in recent years become relatively common. Methcathinone is prepared via the oxidation of ephedrine or pseudoephedrine with various salts; including but not limited to potassium permaganate or sodium hypochlorite. Cathinone itself can be prepared via a similar process, using phenylpropanolamine as a precursor.

Substituted cathinone derivatives can be produced by reacting a suited 2-brominated propiophenone with an amination agent (methylamine, ethylamine, etc), or, in the case of the 2-pyrrolidinyl cathinone derivatives, with pyrrolidine. Most of these unregulated substituted cathinones are produced in China, in clandestine laboratories with professional lab equipment. They are sold in wholesale quantities at relatively cheap prices, and are usually available at retail as nearly pure powders.

Pharmacology:

Cathinone and methcathinone are similar in their action to amphetamine and methamphetamine (they all target NE, 5HT, and DA transporters, enhancing monoaminergic tone), although cathinone and methcathinone have been suggested to show increased dopaminergic activity. It's unknown whether the addition of a beta ketone has a similar SAR-affect on other amphetamine compounds.

Most substituted cathinones acts as stimulants, or as entactogens, or as both; with modes of action and effects resembling amphetamine/methamphetamine (monoamine releasing agents), cocaine (monoamine reuptake inhibitors), or MDMA (serotonin releasing agents).

Effects of Methcathinone:

Methcathinone has a mode of action similar to cathinone, albeit more potent and faster acting.  It has a high affinity for the dopamine and norepinephrine transporters, while its affinity for the serotonin transporter is less than that of methamphetamine. Methcath is a dopamine and norepinephrine reuptake inhibitor (NDRI). Acute methcathinone intoxication is characterized by euphoria (some report more euphoria than methamphetamine and some report less), increased alertness, confusion or mental clouding, and sympathetic arousal; a marked by increase in cardiopulmonary output, mydriasis, sweating, anorexia, increased body temp, and sexual arousal. Mania, and paranoia are also common. The comedown which generally follows periods of heavy use is often said to be less intense than that of methamphetamine. Withdrawal is marked by severe lethargy and depression, sometimes severe.

Cathinones in Today's Drug Scene:

Modifications to the 2-amino-propiophenone skeleton have yielded a range of different compounds, similar in structure and action to methcathinone, methamphetamine, and MDMA; these are known as "synthetic cathinones", substituted cathinones, designer cathinones, or simply cathinones. The slang reference "bath salts" now seems a popular, albeit mindless, term for describing any one of the vast number of cathinone derived compounds; this creates a great deal of confusion.

It was during the early 2000's that designer cathinones started appearing for sale as quasi-legal drugs, starting, namely, with mephedrone, methylone and MDPV. By this time, there had already been established somewhat of a designer drug subculture; consisting of drug chemists, drug users, retailers. Brought together by the internet. The roster of internet-available designer drugs had for the most part been limited to psychedelics, prior to mephedrone. Phenethylamines and tryptamines. Since mephedrone in 2003, demand has grown for entactogenic and stimulant substances; more often than not, cathinones.

At present, new and/or rediscovered cathinones are appearing as others are disappearing, as anti-drug legislation advances. Legislation is becoming more broad, more ambiguous, and more preemptive in the way it is written. States like Nebraska have introduced legislation banning chemicals now not only by structural class, but by biological activity (specifically, binding affinity at a given receptor site). 

Further Reading:

PubMed: Cathinone, a Natural Amphetamine

EMCDDA Publication: Synthetic Cathinones

ACMD: Consideration of the Cathinones

Erowid/Rhodium Archive: Methcathinone Synthesis

Erowid: Methcathinone FAQ

Cayman Chemical: Today's Designer Drugs





Monday, March 17, 2014

Updated List of Federally Scheduled Cathinones/Pyrovalerones

Within the last few weeks, ten more cathinones have been added to Schedule I:

The federal government in late January filed a notice of intent to use its emergency scheduling powers and place ten additional cathinones into schedule I of the Controlled Substances Act for the next two years, in which time they can (and will) make their case for permanent scheduling. As of the end of February, these compounds have virtually vanished, as they are now illegal to possess for any purpose.

Prior to now, as of October 2011, there had been 3 substituted cathinones included in schedule I:

MDPV
Methylone
Mephedrone

Included in the new notice of intent:

3-fluoromethcathinone
4-fluoromethcathinone
4-methylethcathinone
4-methyl-PPP
alpha-PBP
alpha-PVP
Pentedrone
Pentylone
Naphyrone
Butylone

Further Reading:

Federal Register Filing: Notice of Intent

Federal Register Filing: Final Order - March 7th 2014

10 more cathinones are being placed into Schedule I (via Dose Makes Poison)

Substituted Cathinones included in Emergency Ban

Substituted Pyrovalerones included in Emergency Ban






Possible Link Between High-Dose Loperamide and Cardiac Arrhythmias?

A reader suggested a possible link between loperamide and severe heart condition(s). A quick google search led me to this case study. Thank you to whoever brought this to my attention.

Tuesday, January 28, 2014

Rapid Alcohol Consumption and Anterograde Amnesia

Interesting. Binge drinkers who pace themselves are far less likely to experience blackouts. 

Alcohol will impair partially or completely the brain's ability to transfer short term memories created during a drinking episode to long term memory storage centers. Everyone knows this. However, the occurrence of anterograde amnesia (i.e. blackout) has little to do with the amount of alcohol consumed, but is directly related to the amount of time in which a large amount of alcohol is consumed. Studies show test subjects don't experience blackouts when drinking slowly, despite being heavily intoxicated by the end of the experiment.

Wednesday, January 22, 2014

From DoseMakesPoison Blog: 4 Synthetic Cannabinoids Will Be Placed In Schedule I

The Dose Makes The Poison: Notice of Intent - 4 Synthetic Cannabinoids Placed...On January 10, 2014, the Federal government filed its notice of intent to use its emergency scheduling powers to temporarily place four synthetic cannabinoids into Schedule I of the Controlled Substances Act (CSA) for the next two years....

Thanks to dosemakespoison.blogspot.com. All material on this blog is worth further reading.

The Clandestine-PV Legacy Continues

Some new PV-analogues have been surfacing in the US over the last few months. Little is known about their safety or toxicity profile, or about their relation to alpha-PVP in terms of SAR (structure-activity relationship).

There have been some anecdotal reports on their effects, but very few. The one exception being a collection of reports on "PV-8" scattered across various forum/message boards; most of these claim it produces little to no results and is an overall disappointment. PV-8 is the 2-carbon extended homologue of A-PVP.

A 3,4 dimethoxy analogue (i.e. 3,4-dimethoxy-a-PVP) was rumored to have surfaced late last summer, but it seems to only have been talked about briefly. It could legally be considered an analogue of MDPV by federal law and in some cases fall within schedule I. It is very similar to MDPV in its structure differing in only an opening of the dioxole ring structure of the phenyl group. Its hard to say how this chemical would compare to MDPV in other respects, and there are seemingly no first hand accounts on Di-MeO-a-PVP.

It also seems that 4-MeO-a-PVP has more recently surfaced, but as is the case with the 3,4-dimethoxy homologue, there is little to no information available on its toxicological properties, potency, or effects relative to the parent drug.

The ring fluorinated homologue (specifically, 4-fluoro-a-PVP) has appeared and, other than APVP and MDPV, may just be the only chem in the clandestine-PV line with any staying power, with reports suggesting results are similar in nature to MDPV and A-PVP, with some preferring the fluoro. As with 4-fluoroamphetamine, 4-F-PVP seems to be corrosive to tissues, causing discomfort and possible damage with some routes of experimentation.

Though pentedrone has been a known RC for a while, its methylphenyl homologue has been a more recent development in the clandestine RC world. Pentedrone itself still remains common as a designer stimulant, and although it's not a pyrrolidine based cathinone, it shares the pentyl backbone and a similar potency to PV (much stronger than methcathinone and active at less than 10mg). 4-methylpentedrone has been said to produce results close to those of the parent chem, and seems to have generated, for the most part, positive feedback. I currently have no information on its potency off-hand.


Saturday, January 18, 2014

A-F and B-F

A-F




















B-F





















If you don't know the actual names of these compounds then you shouldn't be going anywhere near them.

These compounds should both just be avoided altogether. I can easily see this new trend toward fent analogues ending very badly - either with mislabeled "heroin" products being distributed to unsuspecting buyers (just like 3-methylfentanyl throughout the 80's being sold as "china white" and leading to a rash of overdoses, some fatal), or with another neurotoxic impurity as was seen with MPTP (which caused a permanent state of parkinsonism in a few unlucky consumers). 

Anyone who does run across these compounds should be extremely careful, they should NEVER be used without precision measuring equipment. Both compounds are believed to lie between fentanyl and diamorphine in their potency. Always be aware of your state laws (not to mention federal law) pertaining to both. I will never condone breaking the law.

Wednesday, January 15, 2014

Links of Interest

CDC Issues Release on Desmethylfentanyl (Acetyl-Fentanyl) Related Fatalities - Anyone who runs across this chemical should be extremely careful, in fact it should NEVER be used with out a .01 or .001 scale (a scale with the capacity for ten micrograms or single micrograms). Its potency is believed to lie between between that of fentanyl and diamorphine. Also be aware of your state laws (not to mention federal law) pertaining to A-F.

A Phenomenological Study of Experiences Induced by the Arylcyclohexylamine Derivative MXE - The study suggests it to be more potent in its subjective effects than ketamine. This does not surprise me. Again, tread with caution.

Cheers

Monday, June 24, 2013

PV8

Apparently the structure for "PV-8" is as follows....
Crystalline chunks of a substance said to be the compound in question (this image is not my own. I discovered it on a message board)


Tuesday, June 4, 2013

Obscure Opioids Appearing as RC's

MT-45

Also known as IC-6.

MT-45 is a synthetic opioid analgesic discovered in the 1970's. Its mu agonist properties are evident although it may possess mixed agonist/antagonist properties similar to other compounds in its chemical class. It has a potency of roughly 3/4ths that of morphine. 

MT-45 is a N,N-di-substituted piperazine derivative. It structurally unrelated to most other opioids, with the exception of lefetamine, an atypical opioid with stimulant properties.

Little anecdotal information exists on the subjective effects of MT-45 (not to mention its toxicity profile or excretion patterns), however users have reported morphine-like effects ranging from mild to overbearing which last a few hours. Most users seem to administer MT-45 by the oral route.

AH-7921

Also known by the unofficial name Doxylam.

AH-7921 is a synthetic opioid selective for the morphine (micro, mu) receptor. It has a potency of roughly 3/4ths that of morphine. It is structurally unrelated to most other opioids and has not been used clinically, but has rarely appeared as recreational drug or research chemical.

Most users describe moderate analgesia with little euphoria. AH-7921 can be expected to have effects comparable to pentazocine, butorphanol, and other partial opioid agonists.

Pyrovalerone Derivatives: A Driving Force in the RC Market

Background Info:

In 1967, a series of N-pyrrolidino ketone compounds were patented. The primary compound of this series was 1-(methylphenyl)-2-(pyrrolidinyl)-pentanone, now more popularly known as pyrovalerone. Synonyms for pyrovalerone are Centroton, Thymergix, Valerophenone, O-2371, and of course PV.

The Parent Compound:

Out of all the known/patented pyrovalerone analogues, only the parent compound has been widely studied.
Studies of pyrovalerone form the basis of our understanding of its structural analogues. PV is listed in the US as a Schedule 5 Controlled Substance, and has been used in the clinical setting as an anorectic and wakefulness promoting agent. 

Pyrovalerone (and by extension, its derivatives) is a structural relative of the CNS stimulant cathinone, and can therefore be referred to as a substituted cathinone.

There are 2 key characteristics of pyrovalerones distinguishing them from immediate cathinone derivatives; 1) a tertiary amine rather than a primary or secondary amine, which is incorporated into a heterocyclic five membered, pyrrolidine ring system (4 carbon and 1 nitrogen). And 2) an extended five carbon backbone (affording a pentiophenone structure as opposed to a propiophenone).

In the 1960's Stille and Holliday confirmed stimulant activity of PV in animals. In 1971 it was shown to reduce chronic fatigue in humans. Later it was shown to inhibit NE reuptake and induce NE release in rat heart. A study in the 1990's observed the parallel between its locomotor stimulant activity and its dopamine transporter occupancy in mice. Note; NE = norepinephrine, DA = dopamine.

In 1969, the methylenedioxyphenyl analogue of pyrovalerone, now well known by the abbreviation MDPV, was patented by a pharmaceutical company known by Boehringer Ingelheim. MDPV was never marketed and remained an obscure stimulant until recently appearing as a popular designer drug.

In summary, PV, along with many analogues thereof, are known ligands for the monoamine transporters; with a preference for NET and DAT, and for the most part, negligible interaction with SERT systems. As a general rule, compounds of this class can be presumed to act as powerful CNS and cardiovascular stimulants.

Appearance of Obscure PV Analogues:

MDPV


In the mid-2000's, MDPV (mentioned in section 1 paragraph 5) appeared on the pseudo-legal market as a designer drug, being sold by names such as Cloud 9 and Supercoke. It was also the main constituent in the first generation of novelty "bath salts". Reading news reports from the time of peak popularity for these items, it becomes apparent that the one defining commonality amongst the walking-dead style anti-drug propaganda is the description of a paranoid/agitated state resembling the symptoms of amphetamine-psychosis. It's fair to say that most bath salt users who exhibited these bizarre, stereotypic behaviors were experiencing symptoms of amphetamine psychosis, caused in many cases by the MDPV in the bath salts they were consuming.

MDPV is simply an analogue of PV containing oxygen atoms at carbons 3 and 4 of the benzene ring, bound by a methylene bridge. MDPV, like pyrovalerone, is an NDRI, and in its pure form is a powerful CNS and cardiovascular stimulant. Based on anecdotal reports it is a potent reinforcer, and it also seems to be, relative to other sympathomimetic amines, particularly prone to inducing psychotomimetic symptoms (as is evident by the many stories, albeit dramatized, of bath-salt psychosis).

MDPV is still being synthesized by Chinese labs (China seems to be the main manufacturer and exporter of RC's), but has been rarely encountered in the US since late 2011, when it was classified as a Schedule 1 Controlled Substance, along with a number of other substituted cathinones (namely mephedrone and methylone).

MDPV carried a devoted legion of followers, (specifically heavier stimulant users who prefer the convenience of licit substances), and the 2011 federal ban left a major demand to be filled. Since this time, new PV analogues have appeared periodically, usually touted by the manufacturers as MDPV replacements (although the deepest of MDPV devotees tend to rate each subsequent PV compound as inferior to MDPV).

A-PVP

APVP was mentioned in the 1967 patent for pyrovalerone. It can be described chemically as 1-phenyl-2-
(pyrrolidinyl)-pentanone. Synonyms include O-2387, a-PVP, O-desmethylpyrovalerone, or APVP, or PVP.  No substantial body of research exists on the properties of a-PVP, although its metabolism and excretion patterns in rat urine have been documented. It is presumed to act as a CNS and cardiovascular stimulant.

APVP is simply the O-demethylation product of pyrovalerone. It appeared in the early 2010's and became a popular grey-market product following bans on MDPV. Its effects are reported to be more or less comparable to MDPV. It has seemed to remain the gold standard in terms of MDPV replacements.

Based on reports by users, APVP in its pure form produces powerful CNS/cardiovascular stimulation. Its effects are apparent in doses under 10mg.

A-PVT


A-PVT is an analogue of A-PVP where the benzene ring has been replaced with a thiophene ring. It can be referred to chemically as 1-(thiophenyl)-2-(pyrrolidinyl)-pentanone. Little to no research exists on the properties of A-PVT. 

The exchange of the phenyl ring for a thiophenyl ring in a PV compound was first documented by Lancelot, and was reported to result in compounds of similar potency as both dopamine and norepineprine reuptake inhibitors.

APVT has very recently appeared as an RC. While many US RC merchants have become reluctant to offer APVP (or substituted cathinones in general), APVT has been promoted as a viable alternative. Users have reported mild effects similar to APVP.

MPHP
\
MPHP is a homologue of pyrovalerone, with the only difference being the addition of an extra carbon (or
rather CH3 group) on the alkyl side chain, affording a 6 carbon hexane backbone. It can be referred to chemically as 1-(4-methylphenyl)-2-(pyrrolidinyl)-hexanone.

MPHP has been encountered in recent years as a designer drug, and is speculated to be the chemical dubbed by chinese labs as "PV4", derived from a new naming scheme for pyrovalerone analogues marketed as MDPV replacements. Use of MPHP has been linked with liver and kidney damage.

The general SAR pattern in the pyrovalerone series seems to be 'greater activity with a longer alkyl backbone', with the maximum chain length being seven carbons. The most potent compounds known in this series consist of a five (pentyl) or six (hexyl) carbon backbone.

Side note; MPHP is technically not a true "pyro-valerone", as it contains a lengthened chain, however it should still fall under the category of pyrollinyl ketones.

PV8

There has been a new RC appearing in recent weeks being referred to by manufacturers as "PV8". Manufacturers claim it is the "best MDPV replacement yet". Nothing is known about this compound, and only speculation (although from a semi-reputable source) exists as to what the structure actually is for PV8. The supposed chemical name is 1-phenyl-2-(pyrrolidinyl)-heptanone. If this is indeed the correct chemical then it contains an unusually long alkyl backbone (although still conforms to the rule of 7 carbons or less).

Naphyrone 

Naphyrone is a unique analogue of pyrovalerone. It appeared on the grey market as a replacement for mephedrone, a cathinone derived stimulant and entactogen. It can be referred to chemically as 1-napthylenyl-2-(pyrrolidinyl)-pentanone. Synonyms for naphyrone include O-2482 and napthylpyrovalerone. It was reported to be the ingredient behind a product sold as NRG-1, but later analyses confirmed that only a portion of NRG-1 samples actually contained naphyrone.

Naphyrone differs from pyrovalerone with the fusion of an additional benzene ring to carbons 3 and 4 of pyrovalerone's benzene ring, forming a napthyl feature.

Naphyrone is pharmacologically distinct from other pyrovalerones in that it shows significant affinity to all three monoamine transporters; it acts as a triple reuptake inhibitor, meaning that it inhibits the uptake of norepinephrine, dopamine, and serotonin. This was the only PV compound to show activity in nanomolar (nM) concentrations.

Naphyrone is a schedule 1 controlled substance in the United States.

Further Reading:

EMCDDA Synthetic Cathinones Profile

Pyrovalerone Analogues: A Promising Class of Monoamine Uptake Inhibitors

A Forensic Toxicologist's Review of Pyrovalerone Analogues and a Review of Federal CSA Legislation

DrugsForum - APVP Drug Info Page

Crystal-Chunk APVP

Monday, June 3, 2013

Monoaminergics: Household Names

Common CNS stimulants and their modes of action clarified. I'll probably make additions to this list over time.


NDRI: This is an abbreviation for Norepinephrine and Dopamine Reuptake Inhibitor. NDRI's work by inhibiting the function of the dopamine and norepinephrine transporters, usually causing a subsequent increase in available synaptic dopamine and norepinephrine.

NDRA: This is an abbreviation for Norepinephrine and Dopamine Releasing Agent. NDRA's work by inhibiting the function of the dopamine and norepinephrine transporters while reversing their flow (through a process known as phosphorylation), causing the release of dopamine and norepinephrine into synaptic vescicles.
Dopamine Transporter (Source: Wikipedia)

amphetamine - NDRA, NDRI
methamphetamine - NDRA, NDRI
cathinone - NDRA, NDRI
methcathinone - NDRA, NDRI
napthylaminopropane - Triple-RA/RI, serotonergic agonist/partial agonist
cocaine - SNDRI
methylphenidate - NDRI
APVP - NDRI
Naphyrone - SNDRI
prolintane - NDRI
pipradol - NDRI
bupropion - NDRI
6-APB - Triple-RA/RI, 5HT agonist
5-APB - Triple-RA/RI, 5HT agonist
MDMA - Triple-RA/RI
MDA - Triple-RA/RI, 5HT2A agonist
4-MEC - Triple-RA/RI
4-FA - Triple-RA/RI
2-FMA - NDRA, NDRI