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C A D B _ A _ 13 5062 16/10/05 19:07 (X M L ) Addiction B iology ( Mo n t h 2 0 0 5 ) 0 0 , 1 – 3 SHORT COMMUNICATION Me t h y l o n e a n d m CP P , t w o n e w d r u g s o f a b u s e ? M. G. BOSSONG, J. P. VAN DIJK & R. J. M. NIESINK Drugs Information and Monitoring System (DIMS), Trimbos Institute for Mental Health and Addiction, U trecht, the N etherlands Ab s t r a c t R ecently, tw o new ecstasy- lik e substances, methylone and mC P P , w ere found in street drugs in the N etherlands by the Drugs Information and Monitoring System (DIMS). Methylone (3 ,4 methylenediox ymethcathinone) is the main ingredient of a new liq uid designer drug that ap p eared on the Dutch drug mark et, called ‘ E x p losion’ . mC P P (meta- chlorop henylp ip eraz ine) is a substance often used as a p robe for the serotonin function in p sychiatric research, and has now been found in street drugs, both in tablets and p ow ders. Methylone as w ell as mC P P act on monoaminergic systems, resembling MDMA (3 ,4 - methylenediox ymethamp hetamine), w ith mC P P mainly affecting the serotonin system. The subj ectiv e effects of both new substances ex hibit subtle differences w ith those of MDMA. O nly little is k now n about the harmfulness of both methylone and mC P P . How ev er, because of similarities betw een these substances and MDMA, risk s common to MDMA cannot be ex cluded. In t r o d u c t i o n Ev e r s i n c e e c s t a s y ( X T C , MDMA) w a s c l a s s i fi e d a s a Sc h e d u l e I d r u g , p e o p l e h a v e b e e n t r y i n g t o fi n d n o n s c h e d u le d a lte r n a tiv e s w ith e ffe c ts m a tc h in g th o s e o f e c s ta s y . Ex a m p l e s o f s u c h e c s t a s y - l i k e d e s i g n e r d r u g s a r e 4 - MT A ( W i n s t o c k e t a l ., 2 0 0 2 ) , MBDB ( C a r t e r e t a l ., 2 0 0 0 ) a n d MDEA ( F r e u d e n m a n n & Sp i t z e r , 2 0 0 4 ) . Re c e n t l y , t w o n e w e c s t a s y - l i k e s u b s t a n c e s , m e t h y l o n e a n d m C PP, w e r e d e t e c t e d i n s t r e e t d r u g s i n t h e Ne t h e r l a n d s b y t h e Dr u g s In f o r m a t i o n a n d Mo n i t o r i n g Sy s t e m ( DIMS) . DIMS i s a t o x i c o e p i d e m i o l o g i c m o n i t o r o f i l l e g a l d r u g m a r k e t s . It s m a i n f o c u s e s a r e t o id e n tify th e c o m p o u n d s o f s y n th e tic d r u g s , d e s c r ib e p r e v a l e n c e a n d t r e n d s , a n d i d e n t i f y h e a l t h r i s k s ( Sp r u i t , 2 0 0 1 ) . 3 , 4 - Me t h y l e n e d i o x y m e t h c a t h i n o n e : m e t h y l o n e At t h e e n d o f 2 0 0 4 , a n e w d e s i g n e r d r u g c a l l e d ‘ Ex p l o s i o n ’ a p p e a r e d i n t h e Ne t h e r l a n d s . T h i s n e w d r u g i s s o l d a s a l i q u i d v i a t h e i n t e r n e t a n d i n Du t c h ‘ s m a r t s h o p s ’ , s t o r e s s e l l i n g n o n s c h e d u le d ( h e r b a l) p s y c h o a c tiv e s u b s ta n c e s . T h e p r o d u c t is a d v e r tis e d a s a ‘r o o m o d o r iz e r ’ a n d is s o ld in p la s tic tu b e s c o n t a i n i n g 5 m l o f l i q u i d . T h e t u b e s c o s t b e t w e e n e1 0 a n d e1 5 ( $ 1 3 – $ 2 0 ) a n d d o n o t p r e s e n t a n y in fo r m a tio n a b o u t th e c o m p o s i t i o n o f Ex p l o s i o n ; t h e y c o n t a i n o n l y a l a b e l s a y i n g ‘ Ro o m o d o r i z e r Va n i l l a . Do n o t i n g e s t ’ a n d ‘ Ke e p a w a y f r o m c h i l d r e n . Ne v e r u s e m o r e t h a n o n e b o t t l e ’ . In s p i t e o f t h i s la b e l, u s e r s m e n tio n th a t th e y in g e s t th e liq u id to r e a c h th e in te n d e d p s y c h o a c tiv e e ffe c t.T h e te x t w a s p r o b a b ly p u t o n to t h e l a b e l t o c i r c u m v e n t Du t c h r e g u l a t i o n s f o r i l l i c i t d r u g s a n d p s y c h o a c tiv e s u b s ta n c e s . An a l y s e s o f Ex p l o s i o n h a v e d e m o n stra te d th a t th e m a in in g r e d ie n t o f th e liq u id is th e c o m p o u n d m e th y lo n e ( 3 ,4 - m e t h y l e n e d i o x y m e t h c a t h i n o n e o r 2 - m e t h y l a m i n o - 1 - ( 3 ,4 m e t h y l e n e d i o x y p h e n y l ) p r o p a n - 1 - o n e ) . 3 ,4 - Me t h y l e n e d i o x y m e t h c a t h i n o n e ( MDMC AT o r MDMC ) i s t h e b e n z y l i c k e t o n e a n a l o g u e o f 3 ,4 - m e t h y l e n e d i o x y m e t h a m p h e t a m i n e ( MDMA) : i t c o n t a i n s a n a d d i t i o n a l o x y g e n a t o m a t th e b e n z y l i c p o s i t i o n o f t h e m o l e c u l e ( F i g u r e 1 ) ( C o z z i e t a l ., 1 9 9 9 ) . 3 ,4 - Me t h y l e n e d i o x y m e t h c a t h i n o n e w a s fi r s t s y n t h e s i z e d b y Al e x a n d e r Sh u l g i n . Be c a u s e o f t h e s i m i l a r i t y o f e ffe c ts b e tw e e n m e th a m p h e ta m in e a n d its b e n z y lic k e to n e m e th c a th in o n e , h e e x a m in e d w h e th e r th e r e w a s a c o m p a r a b le c o n n e c tio n b e tw e e n MDMA a n d its b e n z y lic a n a lo g u e . H e c a lle d th e n e w s u b s ta n c e m e th y lo n e ( C o g n i t i v e l i b e r t y .o r g ) . Me t h y l o n e r e s e m b l e s MDMA i n i t s b e h a v i o u r a l p r o fi l e , a s m e t h y l o n e s u b s t i t u t e s f o r MDMA i n r a t s t r a i n e d t o d i s c r i m i n a t e MDMA f r o m s a l i n e . Me t h y l o n e d o e s n o t s u b s t i t u t e f o r a m p h e t a m i n e o r f o r t h e h a l l u c i n o g e n i c DOM i n a n i m a l s t r a i n e d t o d i s c r i m i n a t e b e t w e e n t h e s e d r u g s a n d s a l i n e ( Da l C a s o n e t a l ., 1 9 9 7 ) . F u r t h e r , a l s o i n c o m m o n w i t h MDMA, m e t h y l o n e a c t s o n m o n o a m i n e r g i c s y s t e m s . In v itro, m e t h y l o n e i s t h r e e f o l d l e s s p o t e n t t h a n MDMA a t i n h i b i t i n g p l a t e l e t s e r o t o n i n a c c u m u l a t i o n a n d a s p o t e n t a s MDMA i n i t s C o r r e s p o n d e n c e t o : Ma t t h i j s Bo s s o n g , MSc , T r i m b o s In s t i t u t e f o r Me n t a l H e a l t h a n d Ad d i c t i o n , PO Bo x T h e Ne t h e r l a n d s . T e l : þ3 1 3 0 2 9 7 1 1 0 6 ; F a x : þ3 1 3 0 2 9 7 1 1 1 1 ; E- m a i l : m b o s s o n g @ t r i m b o s .n l ISSN 1 3 5 5 - 6 2 1 5 p r i n t / ISSN 1 3 6 9 - 1 6 0 0 o n l i n e / 0 5 / 0 0 0 0 0 1 – 0 3 ª So c i e t y f o r t h e St u d y o f Ad d i c t i o n t o Al c o h o l a n d Ot h e r Dr u g s DOI: 1 0 .1 0 8 0 / 1 3 5 5 6 2 1 0 5 0 0 3 5 0 7 9 4 7 2 5 , 3 5 0 0 AS U t r e c h t , T a y lo r &F r a n c is 2 M. G . Bossong et al. F igure 1 . Molecular structures of 3,4-methylenedioxymethamfetamine (MDMA) (a) and methylone (b). inhibiting effects on the dopamine and noradrenaline transporters (Cozzi et al., 1999). In spite of these behavioural and pharmacological similarities between methylone and MDMA, the observed subjective effects of both drugs of abuse are not completely identical (Erowid.org). Shulgin wrote about the effects of this drug: ‘methylone has almost the same potency of MDMA, but it does not produce the same effects. It has an almost antidepressant action, pleasant and positive, but not the unique magic of MDMA’ (Cognitiveliberty.org). In the Netherlands, methylone is not yet scheduled as a drug of abuse, but is considered to be a psychoactive medicine. Because methylone is not registered officially, as such, it is forbidden to trade in methylone. The Minister of Health has asked the Coordination point Assessment and Monitoring new drugs group (CAM) to gather information about this substance, resulting possibly in an official risk assessment (van Amsterdam et al., 2004). Until now, no research has been conducted on the toxicity of methylone, so nothing is known about the harmfulness of this new drug. Meta-chlorophenylpiperazine: mCPP In September 2004, another ecstasy-like drug appeared on the Dutch drug market: meta-chlorophenylpiperazine (mCPP). mCPP is a pharmacologically active metabolite of the antidepressant drugs trazodone, nefazodone and etoperidone and of the minor tranquillizer mepiprazole (Rotzinger et al., 1998). Its chemical name is 1-(3-chlorophenyl)piperazine and the chemical formula is C10H13ClN2 (Reynolds, 1996). From September 2004 until April 2005, DIMS registered mCPP 25 times in drugs sold mainly as ecstasy, both in tablets and powders. Two different kinds of tablets containing mCPP were found: a beige-coloured, round-shaped tablet and a white tablet with coloured fl ecks, both types without a logo. The dose of mCPP in the tablets ranged from 2 to 46 mg. In three cases, mCPP was discovered in a powder. Two powders were sold as cocaine and one as speed, containing 7% , 8% and 5% mCPP, respectively, the first-mentioned in combination with 1% cocaine-HCl. In addition to these identifications of mCPP in the Netherlands, mCPP has also been detected in several other European countries. Notifications of the detection of mCPP were received from Sweden, France, Austria and L ithuania, via the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Further, mCPP can be bought on the internet as X4, a tablet containing a combination of four types of piperazines (mCPP, TFMPP, oMPP and pCPP) (Naturensdroger.nu; Modernatur.nu). mCPP is the most extensively used probe of serotonin function in psychiatric research (Kahn & Wetzler, 1991). It has both pre- and postsynaptic effects on the serotonin system. First, mCPP induces a release of serotonin (5-HT) dependent on the serotonin transporter (SERT) (Pettibone & Williams, 1984; Baumann et al., 1993, 2001; Eriksson et al., 1999; Gobbi et al., 2002). Secondly, mCPP possesses agonist properties at some 5-HT receptors (e.g. 5-HT2C) and antagonist properties at others (e.g. 5-HT2B) (Hamik & Peroutka, 1989; Thomas et al., 1996; Gijsman et al., 2004). Concerning these effects on the serotonin system, mCPP is a substance partially comparable with MDMA, as MDMA releases 5-HT via a SERT-mediated process as well (e.g. Rudnick & Wall, 1992; for a review see Cole & Sumnall, 2003). As a consequence, the subjective effects of mCPP and MDMA are also comparable, both positive as well as negative (Tancer & Johanson, 2001, 2003). Examples of mild side effects mentioned after the use of mCPP are anxiety, dizziness and confusion (Gijsman et al., 1998; Tancer & Johanson, 2001, 2003; Feuchtl et al., 2004), whereas migraine and panic attacks are observed frequently as severe negative effects (Gijsman et al., 1998, 2004). Interestingly, MDMA-users (McCann et al., 1999) and cocaine addicts (BuydensBranchey et al., 1997) report a more positive response to mCPP than non-drug using volunteers. An important difference between mCPP and MDMA is the effect on the dopamine system: mCPP only exhibits minimal effects on this system (Baumann et al., 2001; Gobbi et al., 2002). Therefore, mCPP does not display any reinforcing effects (Tancer & Johanson, 2003). Probably, in contrast with MDMA, heart rate, blood pressure and body temperature are only mildly increased following the use of mCPP (Ghaziuddin et al., 2003; Tancer & Johanson, 2003), while both mCPP and MDMA cause a dose-dependent elevation of the hormones ACTH, cortisol and prolactin (Kahn & Wetzler, 1991; Gijsman et al., 1998; Ghaziuddin et al., 2003; Feuchtl et al., 2004). Physiological and subjective effects reach their peak after 1 – 2 hours after oral administration (Tancer & Johanson, 2001, 2003). The effects can last 4 – 8 hours (Gijsman et al., 1998; Tancer & Johanson, 2001, 2003). While MDMA is known to be a neurotoxic compound, mCPP lacks neurotoxic potential (Gobbi et al., 2002). mCPP is able to release 5-HT without causing a long-term depletion of 5-HT (Ulrichsen et al., 1992; Baumann et al., 2001). Possibly, this difference between MDMA and mCPP can be explained by the fact that mCPP releases only the cytoplasmatic 5-HT, while MDMA induces the release of both cytoplasmatic and vesicular 5-HT (Gobbi et al., 2002). The doses of mCPP found in the street drugs analysed by DIMS (2 – 46 mg) are comparable with the doses used in challenge tests of the serotonin system in psychiatry. In these tests, the commonly used oral dose of mCPP ranges from 0.1 to 0.75 mg/kg (7 – 52.5 mg mCPP for a 70-kg person) (Tancer & Johanson, 2001, 2003; Gijsman et al., 2004). However, these are doses of individual tablets. When several tablets are ingested, the clinically used dose can be exceeded. This might result in the serotonin syndrome (Klaassen et al., 1998). Therefore, the use of mCPP in combination with alcohol, ecstasy or antidepressant drugs should be avoided. In contrast with methylone, mCPP is registered officially. Consequently, only licensed traders are allowed to sell this substance. 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