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Addiction Biology (2000) 5, 269 ± 282

INVITED REVIEW

N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB): its properties and possible risks

L. A. G. J. M. VAN AERTS,1 M. MALLARET 2 & H. RIGTER

1Trimbos Institute, Netherlands Institute of Mental Health and Addiction, Utrecht, The Netherlands & 2Centre Hospitalier Universitaire de Grenoble, Laboratoire de Pharmacologie, Grenoble, France.

Abstract MBD B (N -methyl-1 -(1,3-benzodioxol-5-yl)-2-aminobutane) is the a -ethyl homologue of MDMA (3,4-methylenedioxy-N-methylamphetam ine). MBDB is metabolized and excreted similarly to MDMA: presumably, the majority of oral MBDB is excreted in urine unmetabolized. The main metabolic routes in man are thought to be O-dealkylation and subsequent methylation, sulphation and glucuronidation of the newly formed hydroxy groups. The major acute neuropharmacological effects of M BDB in the rat are an increase in release in the brain and an inhibition of serotonin and noradrenaline re-uptake. These effects compare well with those of MDMA, although the latter is more potent. M BDB may also slightly increase release and inhibit dopamine re-uptake, but to a lesser extent than MDMA. This is im portant, as dopamine release has been implicated in the reinforcing qualities of substances such as and . The neuroendocrine effects of MBD B resemble those of MDMA. Both substances increase plasma ACTH, corticosterone, prolactin and renin. The neurophysiological effects of MBD B are characterized by a decrease in electrical activity throughout the brain, most notably in the alpha2 and delta frequency bands. In contrast, increase the activity in the alpha1 band, especially in the corpus striatum. In discrimination tests in the rat, MBD B, like MDMA, can be distinguished clearly from both and hallucinogens. The class of substances to which MBDB belongs may be named entactogens. MBDB dose-dependently increases locomotor activity and decreases explorator y behaviour in the rat and causes distress vocalization and wing extension in the newly hatched chicken. The rewarding properties of MBDB appear to be smaller than those of MDMA, as suggested by a 2.5 times weaker potency in the conditioned place preference test in rats. The main

Correspondence to: Dr L.A.G.J.M. van Aerts, National Institute of Public Health and Environment, Laboratory of Medicines and Medical Devices, PO Box 1, 3720 BA Bilthoven, The Netherlands. Received for publication 12th November 1998. Accepted 16th March 2000. Abbreviations BDB, 1-(1,3-benzodioxol-5-yl)-2-aminobutane; CPP, conditioned place preference; DOB, 2,5-dimethoxy- 4-bromo-amphetamine; DOI, 2,5-dimethoxy-4-iodo-amphetamine; DOM, 2,5-dimethoxy-4-methyl-ampheta- mine; DOPAC, 3,4-dihydroxyphenylacetic acid; EMCDDA, European Monitoring Centre for and Drug Addiction; MBDB, N-methyl-1-(1,3-benzodioxol-5-yl)-2-aminobutane; MDA, 3,4-methylenedioxyamphetamine; MDAI, 5,6-methylenedioxy-2-aminoindan; MDEA, 3,4-methylenedioxy-N-ethylamphetamine; MDMA, 3,4-methylenedioxy-N-methylamphetamine; MMAI, 5-methoxy-6-methyl-2-aminoindan; MMBDB, N,N-dime- thyl-1-(1,3-benzodioxol-5-yl)-2-aminobutane; MTA, 4-methylthioamphetamine. Note: Unless stated otherwise, the weights and concentrations of the substances mentioned in the text are (supposedly) based on the hydrochloride salt form, although this was not always specified in the original papers.

ISSN 1355-6215 print/ISSN 1369-16 00 online/00/030269 -14 € Society for the Study of Addiction to Alcohol and Other Drugs Carfax Publishing, Taylor & Francis Ltd 270 L. A. G. J. M. van Aerts et al. subjective effects of MBDB in man are a pleasant state of introspection, with greatly facilitated interpersonal comm unication and a pronounced sense of empathy and compassion between subjects. In this respect, MBDB again resembles M DMA. However, there are also differences. MBDB has a slower and more gentle onset of action than MDM A, produces less and has less properties. The few toxicological data available suggest that MBDB may cause serotonergic deficits in the brain, although the potency of MBDB to cause this neurotoxic effect is smaller than that of MDMA. Severe acute reactions in man as have been reported for MDMA have not been published for MBDB. The dependence potential of MBDB appears to be small, probably even sm aller than that of MDMA. MBDB has been available at least since 1994 but its position on the synthetic drugs market is marginal. Subjective reports indicate that MBDB is less popular among users than MDMA. The reason may be that M BDB produces less euphoria than M DMA. Another possible explanation is that MBDB largely lacks the stim ulant properties of MDMA. We calculated a margin of safety with a method similar to one used in the risk assessment of pharmaceuticals. The results suggest that MBDB is three times less likely to cause serotonergic brain deficits than MDMA. However, it should be noted that for both substances the margin of safety is less than one, indicating that the risk of neurotoxicity is not negligible. In animals, serotonergic brain deficits after exposure to MDMA have been linked to the degeneration of serotonergic ner ve ter minals.

Introduction d incorporate a mechanism for assessing the risks Much has been done to clarify the mechanism of of these drugs; and the pharmacological actions and toxicity of d comprise a decision-making process through 3,4-methylenedioxy-N-methylamphetamine which these products may be placed under (MDMA, ª ecstasyº ). Even though substantial control in the EU Member States. progress has been made, we still do not know exactly how MDMA works and how risky the use In addition, we present at the end of this paper a of this substance is. Compared with MDMA, method for risk assessment of health risks asso- N-methyl-1-(1,3-benzodioxol-5-yl)-2-aminobu- ciated with the use of MBDB. The purpose of this tane (MBDB) has received little attention from assessment is to illustrate how scientific knowl- the scientific community. Therefore, our under- edge can be used to evaluate the risks of non- standing of the pharmacological and toxicological medically used psychoactive drugs. actions of MBDB is much smaller, and the risks of consuming MBDB are even harder to estimate than for MDMA. In this report, the scientific Chem ical description knowledge on MBDB will be reviewed. The MDMA is short for 3,4-methylenedioxymetham - MBDB data will be compared with those for phetamine it could also be named N -methyl- MDMA, which is similar in structure and action. 1-(1,3-benzodioxol-5-yl)-2-aminopropane. The For a more thorough review of the properties and molecular structure is shown in Fig. 1. The main effects of MDMA, the reader is referred to three precursors for synthesizing of MDMA are piper- recent publications.1 ± 3 onylmethylketone, piperonal, safrole and The data on MBDB reviewed here have been isosafrole. used by the Scientific Committee of the Euro- MBDB is N-methyl-1-(1,3-benzodioxol-5-yl)- pean Monitoring Centre for Drugs and Drug 2-aminobutane (Fig. 1). It is the a -ethyl homo- Addiction (EMCDDA) for the risk assessment on logue of MDMA. The free base is a colourless oil MBDB within the framework of a Joint Action with a melting point of 88ÆC at 0.08 mm Hg. The adopted by the Council of the European Union hydrochloride salt consists of colourless crystals on 16 June 1997.1 4 This Joint Action on New with a melting point of 156ÆC.5 Nuclear magnetic Synthetic Drugs aims to: resonance data were reported by Nichols and co- workers.5 MBDB can be synthesized from d provide for the establishment of an early- 1-(1,3-benzodioxol-5-yl)-2-aminobutane (BDB). warning system to identify new synthetic drugs The extra carbon atom in this precursor com- as they appear on the European market; pared with MDMA precursors prevents MBDB Properties and possible risks of MBDB 271

Table 2. MBDB samples identified by Drug Information and Monitoring System: pharmaceutical forms

Pharmaceutical form Number %

Tablets 169 83 Powders/capsules 32 16 Fluids 3 1 Total 204 100

content of the tablet, but the dynamics of the Figure 1. Structural formulae of MDMA (above) and ecstasy market are such that these markings may MBDB (below). become misleading.1 0 Therefore, MBDB should be considered an integral part of the ecstasy market. from turning up by accident when one attempts to synthesize MDMA or vice versa. BDB is not commercially available. It can be synthesized Route of administration and dosage from piperonal and 1-nitropropane or 1-bromo- As a rule, MDMA is ingested. Accounts of propane. MBDB can be analysed with gas chro- intravenous administration or snorting of this matography/mass spectrometry (GC/MS). With drug are rare. Typical doses taken orally range these methods, MBDB can be distinguished from from 50 to 150 mg. Although many users take congeners such as MDMA, 3,4-methylenedioxy- single doses, multiple dosing is not uncommon. N-ethylamphetamine (MDEA) and 3,4-methyle- Many users concomitantly use other psychoactive nedioxyamphetamine (MDA).6 ± 9 substances, such as tobacco, alcohol, cannabis, amphetamine and LSD. MBDB is also taken orally. Shulgin & Shul- Pharmaceutical form gin11 and Nichols and co-workers5 reported on MDMA is mainly sold as tablets, and occasion- consumption of 150 ± 210 mg, and MBDB con- ally as capsules or powders. Tablets often show taining street samples analysed by Rothe and co- distinctive markings (logos). MDMA is traded workers9 contained, on average, 197 mg. In con- under the name ecstasy (XTC). MBDB is vir- trast, most Member States reported to the tually always sold as ª ecstasyº (Table 1). It has EMCDDA that the mean amount of MBDB the same pharmaceutical appearance as MDMA found in tablets is about 100 mg. (Table 2). The logo may be indicative of the

Pharmacodynamic properties and Table 1. MBDB-containing tablets identified by the Drug preclinical safety data Information and Monitoring System Neuropharmacology The major acute neurochemical effects of MBDB Sold as Number % in the rat are an increase in serotonin release in the brain and an inhibition of serotonin and MBDB 1 < 1 noradrenaline re-uptake. The drug may also XTC 117 69 slightly increase dopamine release and inhibit MDMA 38 22 MDA 1 < 1 dopamine re-uptake. All the evidence reviewed in 2-CB 1 < 1 this paragraph is from studies in the rat. The unknown 11 7 acute effects of MBDB on serotonin in the rat Total 169 100 brain are similar to those of MDMA, the latter being somewhat more potent in most models. Names under which the tablets were sold (1994 ± June MBDB and MDMA were equally potent in 1998 ). releasing serotonin in vitro in slices from the 272 L. A. G. J. M. van Aerts et al. hippocampus in rat brain.1 2 In vivo, MBDB In vitro, neither enantiomer of MBDB inhib- (25 mg/kg) and MDMA (20 mg/kg) compar- ited the re-uptake of dopamine to 50% of the atively reduced the level of serotonin and its controls in striatal synaptosomes when tested up 1 5 metabolite 5-HIAA (5-hydroxyindoleacetic acid) to 5 m M . However, in mixed cortical/hippo- in the frontal cortex 3 hours after an intra- campal/caudate nucleus synapse samples re- peritoneal (i.p.) injection.1 3 A lower dose of uptake of dopamine was inhibited by racemic racemic MBDB given subcutaneously (s.c.) MBDB (IC 50 7.8 m M ), but with far (six times) (5 mg/kg) also decreased the level of serotonin lesser potency than MDMA.1 6 As for serotonin, and 5-HIAA in the frontal cortex, this time the apparent re-uptake inhibition by MBDB measured 40 minutes after injection. S-MDMA could be attributed in part to the release of non- (3 mg/kg, s.c.) had the same effect.1 4 vesicular dopamine.16 Thus, MBDB may increase Inhibition of serotonin re-uptake has been the release and inhibit the re-uptake of dopamine shown in vitro, using nerve cell synapse samples in the brain of the rat, but the potency of MBDB from the hippocampus1 5 or from a mixture of is far less than of MDMA. This is important, as cortex, hippocampus and caudate nucleus tis- dopamine release has been implicated in the sue.1 6 In these experiments, MBDB was about serotonin neurotoxicity of MDMA2,1 9 (see also half as potent in inhibiting serotonin re-uptake Toxicology, below) and in the reinforcing qual- 1 6 (IC5 0 0.8 m M ) as MDMA (IC5 0 0.4 m M ). Ster- ities of substances such as cocaine and ampheta- eoselectivity was found for the re-uptake inhibi- mine12 ,17 (Dependence Potential, below). tion in hippocampal samples, the S-isomer being MBDB affects noradrenaline systems in rat the most active.1 5 The apparent re-uptake inhibi- brain. In vitro, MBDB inhibited re-uptake of tion could be attributed in part to the serotonin noradrenaline in hypothalamic1 5 and mixed cort- releasing effect of MBDB.16 ical/hippocampal/caudate nucleus synapse sam -

In conclusion, MBDB increases the release and ples (IC5 0 1.23 m M ), but less so than MDMA 16 inhibits the re-uptake of serotonin in the brain of (IC5 0 0.41 m M ). Stereoselectivity was found for the rat, albeit with lesser potency than MDMA. the re-uptake inhibition in hippocampal samples, The acute effects of MBDB on brain dopamine the S-isomer being the most active.1 5 In in vivo are weaker than those of MDMA. MDMA, but experiments, both MDMA (20 mg/kg, i.p.) and not MBDB, increased the release of dopamine in MBDB (25 mg/kg, i.p.) did not reduce the tissue superfused rat hippocampal brain slices.12 Also levels of noradrenaline in the cortex 3 hours after unlike MDMA, MBDB failed to raise dopamine injection.1 3 Thus, MBDB inhibits the re-uptake levels in the frontal cortex 3 hours after i.p. of noradrenaline in the brain of the rat, albeit with injection.1 3 A low dose of racemic MBDB (5 mg/ a lesser potency than MDMA. kg, s.c.) was without effect on the dopamine level in the frontal cortex of the rat 40 minutes after injection, in contrast to S-MDMA (3 mg/ Neuroendocrinology kg, s.c.).14 In in vivo microdialysis studies in MBDB profoundly affects the secretion of hor- awake, freely moving rats, a single injection of mones in the rat, the only species studied so far in MBDB (21 mg/kg, i.p.) raised extracellular dopa- this respect. MBDB dose-dependently (5 ± 10 mg/ mine concentrations in the striatum 60 and 90 kg, i.p.) raised the plasma adrenocorticotrophic minutes after injection, but this elevation was hormone (ACTH), corticosterone, prolactin and smaller and of shorter duration than the one seen renin.2 0 These effects could be blocked by the after injection of an equimolar dose of MDMA.1 7 selective serotonin re-uptake inhibitor fluoxetine, Administration of a low dose of MDMA (6.3 mg/ suggesting that MBDB influences the secretion of kg, i.p.) increased extracellular concentrations of these hormones through serotonin by interaction dopamine and its metabolite DOPAC in the with the serotonin re-uptake carrier.2 0 MBDB nucleus accumbens as measured with micro- (5 mg/kg, i.p.), and two other serotonin-releasing dialysis probes, but MBDB (7 mg/kg, i.p.) did agents (MMAI and MTA), also decreased blood not.1 8 The slight increase in dopamine release pressure and heart rate in the rat.20 may be explained by metabolism of MBDB to The neuroendocrine effects of MBDB resem - ± a -ethylepinine (N-methyl-1-(3,4-dihydroxyphe- ble those of MDMA.2 1 24 However, subtle differ- nyl)-2-butanamine), which releases non-vesicular ences between MDMA and MBDB may exist. dopamine.1 6 For example, the MDMA-induced prolactin Properties and possible risks of MBDB 273 secretion was not blocked by fluoxetine.2 3 What unlikely, as MBDB does not strongly influence strikes most, however, are yet again the similar- dopamine release or re-uptake (see Neurophar- ities in action between MDMA and MBDB. Both macology, above). substances increase plasma ACTH, corticoster- one, prolactin and renin in the rat. The effects of MDMA on ACTH, cortisol and prolactin have Behavioural effects in anim als also been demonstrated in man.25 ,26 In rats that When administered subcutaneously, racemic were pretreated with MDMA, an altered MBDB dose-dependently (5 or 10 mg/kg) response of ACTH and prolactin to a fen- increased locomotor activity and decreased fluramine challenge can persist for months.2 7 exploratory behaviour in the rat.14 The effects on Similarly, MDMA users that were MDMA absti- locomotor activity do not simply reflect the nent for at least 3 weeks showed a diminished dopamine- and serotonin-releasing or re-uptake- cortisol and prolactin response to a inhibiting properties of MBDB and other phenyl- challenge when compared with control alkylamines, or their hallucinogenic potential.3 2 groups.2 8,2 9 Recently, MDMA has been found to S-MDMA also changed locomotor activity when affect the release of vasopressin in man.3 0 It is not injected into the nucleus accumbens, suggesting known if these neuroendocrine effects in humans that dopamine or noradrenaline release in the are shared by MBDB. However, since these nucleus accumbens mediates the behavioural effects are mainly serotonin-mediated, it may be effects of this drug. However, racemic MBDB expected that MBDB similarly disrupts the was without effect when injected into this part of human neuroendocrine system. the brain.33 Perhaps MBDB may influence loco-

motion indirectly through 5-HT1 (serotonin) receptors.32 Neurophysiology In another model, newly hatched chickens were Dimpfel and co-workers3 1 studied the neurophy- injected with a drug. Both hallucinogens and siological effects of S-MBDB (1.6 and 2.4 mg/ stimulants such as amphetamine caused the birds kg), S-MDMA (0.4; 0.8; 1.6 and 2.4 mg/kg) and to squeak (distress vocalization) and spread their S-amphetamine (0.2 and 0.4 mg/kg) and the wings. An abnormal body posture suggested that hallucinogens R-DOM (0.1 mg/kg), R-DOB the drug had hallucinogenic properties, while (0.2 mg/kg) and R-DOI (0.1 mg/kg) on brain field amphetamine resulted in loss of the righting potentials in the freely moving rat. Recordings reflex. In this test, MBDB dose-dependently were made in the frontal cortex, hippocampus, caused non-discriminative distress vocalization striatum and reticular formation for 2 hours after and wing extension.34 Only at the highest dose drug administration. In terms of spectral pat- given (24 mg/kg) were abnormal body posture terns, the changes seen after injection of MBDB, and loss of righting reflex seen. Thus, the drug MDMA and amphetamine were similar. The would not appear to be a marked or spectral patterns after injection of the non- stimulant. The N-desmethyl homologue BDB hallucinogens were characterized by a decrease in was more potent than MBDB, whereas the N,N- electrical activity throughout the brain, most dimethylated variant N,N -dimethyl-1-(1,3-ben- notably in the alpha2 and delta frequency bands. zodioxol-5-yl)-2-aminobutane (MMBDB) had One exception was the decrease in theta activity no effect. in the frontal cortex, which was more gradual for Drugs may be consumed because of their MBDB than for amphetamine, whereas MDMA rewarding properties. A method to assess possibly even increased theta activity in the frontal cortex rewarding effects of substances in animals is the for 45 minutes after injection. In contrast, the conditioned place preference (CPP) test. In this hallucinogens increased the activity in the alpha1 paradigm, drugs are tested for their ability to band, especially in the striatum. The authors induce an animal to prefer a site that it disliked related the increase in activity of the alpha1 under control conditions. MBDB was about 2.5 frequency band to the property of hallucinogens times weaker than MDMA in rats in the CPP to activate 5-HT2 A (serotonin) receptors. The test. The effective dose in this respect does not authors suggested that dopaminergic mecha- greatly affect dopamine release.1 7 ,1 8 Therefore, it nisms were responsible for the spectral decreases is far from certain that dopamine release accounts caused by the non-hallucinogens. This proposal is for the weak rewarding effect of MBDB. 274 L. A. G. J. M. van Aerts et al.

Subjective effects in man In the study by Nichols and co-workers5 all In an early study 29 subjects were referred by subjects were familiar with MDMA. They found psychotherapists or friends for a so-called MBDB and MDMA to be generally similar in MDMA session. The drug made the subjects feel effect, with two exceptions. First, the onset of more close and intimate with all those present: action of MBDB was slower and more gentle than they were more communicative, more open to for MDMA; there was little of the anxiety that compliments or criticism and they generally sometimes occurs as soon as MDMA takes effect. appreciated the changes in mood and emotions.35 Secondly, MBDB seemed to produce less eupho- One subject became fearful during the session ria than MDMA. In a double-blind, placebo- and had anxiety attacks a few weeks later, but he controlled cross-over study with four subjects, felt that this was caused by earlier events in his S-MBDB (125 mg, orally) was more active than life, with MDMA releasing tightly controlled the same dose of R-MBDB. MDMA has the same emotions. stereoselectivity of action. These subjects knew The main psychological effects of MDMA in the effects of stimulants such as amphetamine healthy volunteers with no experience with this and , and felt that MBDB was drug were an increase in mood, well-being and different. MBDB usually made them sit or lie emotional sensitivity. There was some anxiety, quietly. but hallucinations and panic reactions were not The picture emerging from users’ comments, noted. Mild depersonalization and derealization gathered by Shulgin & Shulgin,1 1 is in keeping phenomena did occur, together with moderate with the experimental data. The subjective effects thought disorder, first signs of loss of body of 210 mg MBDB, sometimes supplemented with control and alterations in the meaning of per- 50 or 70 mg close to 2 hours after the first dose, cepts. Subjects also displayed changes in the were like those experienced with MDMA. How- sense of space and time, heightened sensory ever, there are minor differences. Notably, people awareness and increased psychomotor drive.3 6 taking MBDB were more relaxed, felt more quiet, Racemic MBDB was tested in 14 subjects, of had lesser drive and less inclination to talk, and both sexes, ranging in age from 35 to 60 years.5 were less stimulated than with MDMA. They also They all had experience with a wide variety of experienced very little visual activity. psychoactive substances. Effective doses of race- In summary, the main subjective effects of mic MBDB were in the range of 150 ± 200 mg. An MBDB are a pleasant state of introspection, with effect was noted in some individuals within 20 greatly facilitated interpersonal communication minutes after administration of the drug. For and a pronounced sense of empathy and compas- most, however, it took 30 ± 45 minutes before a sion between subjects. In this respect, MBDB clear change was observed. In contrast to halluci- resembles MDMA. However, there are also nogens, MBDB’s effect was subtle and gentle in differences. MBDB has a slower and more gentle onset. onset of action than MDMA, produces less The drug produced a pleasant state of intro- euphoria and has less stimulant properties. spection, with greatly facilitated interpersonal communication. Subjects could talk readily about emotionally painful past events if they wished, MBD B is an entactogen without apparent embarrassment or inhibition. In the drug discrimination test, an animal There was a pronounced sense of empathy and (usually a rat) is conditioned to respond, for compassion between subjects. After reaching a instance pressing the left of two levers if given a maximum between the first and second hour after drug, and the right one if given a placebo. Drug- ingestion, MBDB’s action gradually tapered off. appropriate responding occurs either after The effect lasted approximately 5 hours. Subjects administration of the training dose of the original felt able to sleep or drive an automobile and to drug or when a new drug is perceived by the function normally by that time. There were no animal to be similar (substitution).37 In the rat, visual distortions or hallucinations. However, MDMA and MBDB did not substitute for LSD 5 some subjects did report mild nystagmus. There or for S-amphetamine.3 8 Conversely, when was no closed-eye imagery, even in a darkened S-MBDB was used as the training drug, only room. The subjects agreed that MBDB did not partial substitution occurred when the hallucino- resemble a hallucinogen. gens LSD, DOM and , or the stim- Properties and possible risks of MBDB 275 ulants S-amphetamine, S- and and personality changes are not uncommon in cocaine were tested.37 On the other hand, with users of MDMA. They are somewhat impaired in S-MBDB as the training drug, complete substitu- memory tasks2 9,4 4 ± 46 and in impulse control.4 7 tion was seen for racemic, S- and R-MDMA,3 7 Until now, the neurodegenerative effects of and when racemic MDMA was used as the MBDB have only been evaluated in the rat. When training drug complete substitution took place rats were injected with racemic MBDB (25 mg/ with both enantiomers of MBDB.38 Apparently, kg, i.p.) twice a day for 4 consecutive days, tissue MBDB and MDMA are alike in many respects. levels of serotonin and its metabolite 5-HIAA These substances may be representatives of one were reduced in the cortex and the hippocampus and the same class of psychoactive compounds, 2 weeks later. Also, the density of serotonin re- distinct from both hallucinogens and stimu- uptake sites in the cortex was reduced.1 3 lants.5,3 7,3 9 This class may be named ª entacto- Although no further characterization of the neu- gensº , from the Greek roots en for within and gen rotoxic effects of MBDB has been undertaken, for to produce or originate, and the Latin root these findings suggest that MBDB may have tactus for touch. Hence the connotation of this neurotoxic properties similar to those of MDMA. word is that of drugs ª producing a touching There may, however, be a difference in potency. withinº .5,3 9 In contrast to S-MBDB,3 7 racemic Unlike MDMA (20 mg/kg, i.p.), a single dose of MDMA could be substituted for completely by MBDB (21 mg/kg, i.p.) did not reduce tissue S-amphetamine, although at high doses.38 This serotonin and 5-HIAA levels in the striatum in confirms subjective reports that MBDB has less the rat brain 7 days after treatment,1 7 and the stimulant properties than MDMA.5 In other reduction of the serotonin neuronal markers in words, whereas MDMA is an entactogen with the cortex and hippocampus 2 weeks after multi- some stimulant properties, MBDB may be an ple dosing (25 mg/kg, i.p.), twice a day for 4 days) entactogen pur sang. In conclusion, rats can was smaller than after a comparable treatment distinguish both MBDB and MDMA from stim- with MDMA (20 mg/kg).13 Thus, on an equimo- ulants and hallucinogens in drug discrimination lar basis the neurotoxic potential of MBDB is tests. The class of substances to which MBDB smaller than that of MDMA. belongs may be named entactogens. It has been proposed that one step in the neurotoxic mechanisms of MDMA is the ability of the drug to release dopamine.1 9 As mentioned Toxicology above, MBDB is much weaker in releasing MDMA reduces serotonin neuronal markers in dopamine than MDMA. Therefore one may the brains of rodents and non-human primates. argue that MBDB is less neurotoxic because it is These changes may be due to neurodegenerative less potent to release dopamine. However, the processes of terminals of serotonergic neurones in hypothesis that dopamine plays a key role in the dorsal raphe nucleus.1,2 ,19 ,40 Altered ser- MDMA-induced neurotoxicity has been ques- otonin innervation patterns have been found in tioned recently.48 Other factors, such as the the forebrain of monkeys treated with MDMA 7 hyperthermic effect of MDMA, its ability to form years earlier.4 1 When polydrug users who had neurotoxic metabolites and its facilatory effect on taken ecstasy on multiple occasions were sub- the formation of free radicals, leading to oxidative jected to positron emission tomographic imaging, damage, may be more important and do not they showed reduced serotonin re-uptake site necessarily depend on the drug’s ability to release density when compared with a control group dopamine. without any experience with MDMA.4 2 The Combining MBDB with other substances may nature and the scope of any functional con- affect the neurotoxicity of MBDB. Co-admin- sequences of these serotonergic deficits are still istration of the serotonin releasing MDMA unclear. Occasionally, people using this drug analogue 5,6-methylenedioxy-2-aminoindan develop mental disorders such as psychosis, (MDAI) with d-amphetamine reduced serotonin depression and anxiety disorders. It is not known neuronal markers in the rat brain 1 week later, whether these disorders are caused directly by whereas neither of these two substances did so MDMA, the result of pre-existing morbidity when given alone.4 9 Simultaneous intake of aggravated by MDMA, or unrelated to the use of amphetamine and MBDB by recreative drug this drug.43 Recent findings suggest that cognitive users is quite conceivable. Many ecstasy users 276 L. A. G. J. M. van Aerts et al. also use other drugs, including amphetamine. rewarding as cocaine and amphetamine or even Also, tablets purchased as ecstasy may contain MDMA.1 2 ,1 7 Thus, the dependence potential of MBDB as well as amphetamine, although this MBDB is likely to be small, probably even combination is rare according to the Dutch drug smaller than that of MDMA. supply monitor (see ª Pharmaco-epidemiologyº below). Apart from the few data on the neurotoxicity of Pharmacokinetic properties in man MBDB, nothing is known about any other MBDB taken as a single oral dose of 100 mg was toxicity of MBDB. To our knowledge, no further detectable by GC/MS in the urine of a volunteer toxicological investigations with animals have for 36 hours. The urine concentration of MBDB been performed. MDMA may cause severe peaked at 4 hours, and there was a second, adverse reactions, including death.5 0 MDMA- unexplained smaller peak (10% of the first) at 22 induced hyperthermia plays a pivotal role in most hours after ingestion. The N -desmethylated of these reactions. Other serious complications metabolite BDB was also found in the urine for associated with the use of MDMA are arrhythmia the same length of time. The MBDB/BDB ratio and hepatotoxicity.4 0 There are no reports that in urine declined from 69 at 2 hours to 1.3 at 36 any of these adverse effects, or other complica- hours after ingestion.6 A similar excretion pattern tions, also occur when MBDB is used. However, was seen in a volunteer who had taken an oral this drug is not as readily available as MDMA, or dose of 50 mg MDMA. In that case, approx- users may not be aware that the tablets they imately two-thirds of the MDMA was excreted ingested contained MBDB. Fatal arrhythmia unmetabolized.5 2 MBDB concentrations in the after the use of MDMA is thought to result from urine samples from 10 people suspected of petty the stimulant effect of MDMA, leading to hyper- drug offences7 were in the same range as those activity, combined with pre-existing cardiovas- reported by Kintz.6 Kronstrand7 also found BDB cular morbidity.5 1 Since MBDB has hardly any in these urine samples. In all the studies stimulant properties, this drug is unlikely to cited,6,7 ,52 the analysis of the urine samples did precipitate arrhythmia. In summary, the few data not include a hydrolysis step. It is known that available suggest that, like MDMA, MBDB can conjugated metabolites are not detected if a cause serotonergic deficits in the brain, although hydrolysis step is omitted. The predominance of the neurotoxic potency of MBDB is smaller than conjugated O-dealkylated metabolites may there- that of MDMA. Severe acute reactions as have fore have been obscured.5 3 been reported for MDMA have not been The phase I metabolism of methylenediox- documented. yphenylalkylamines, such as MBDB, may consist of two parallel routes. One of these is opening of the methylenedioxy ring leading to Dependence potential O-dealkylation and leaving two hydroxy groups The consumption of some psychoactive sub- attached to the phenyl ring. Subsequent methyla- stances may lead to dependence. Among other tion of one of the hydroxy groups leads to the things, this risk is related to the reinforcing effects formation of a methoxy derivative. The other of the drug. The rewarding potential of MDMA is route involves degradation of the side chain to the believed to result from the release of dopamine in N-dealkyl and, subsequently, deamino-oxo the nucleus accumbens.18 MBDB also releases metabolites.8 The O-dealkylated methoxy metab- dopamine, but only marginally.17 The weak olites are sulphated and/or glucuronidated in potency of MBDB to release dopamine could phase II reactions. The benzoic acid derivative of perhaps explain why this drug largely lacks the MDMA formed by the side-chain degradation reinforcing qualities of such substances as cocaine can be further metabolized to its glycine con- and amphetamine.1 2,1 7 Subjective reports indi- jugate. In contrast, glycine conjugation of the cate that MBDB produces less euphoria than MBDB-derived benzoic acid metabolite has not MDMA.5 ,11 MBDB may not be completely free been reported.8,5 3,5 4 The cytochrome P450 iso- of dependence potential, however. As discussed enzyme CYP2D6 catalyses the first step in the above, MBDB is active in the CPP test in rats, O-dealkylation route.55 The O-dealkylation meta- although much less than MDMA.1 8 Taken bolic route is thought to be predominant in together, these data suggest that MBDB is not as man,52 but because of the known genetic poly- Properties and possible risks of MBDB 277 morphism in Caucasians for CYP2D656 inter- Risk assessment of M BDB as a model for individual differences in metabolism of MBDB in other non -medically used psychoactive humans are likely to exist. substances The purpose of this section is to further the discussion on how risk assessment of non-medi- Pharmaco-epidemiology cally used psychoactive substances can be under- Information from the Member States collected by taken. Such a risk assessment involves many the EMCDDA confirms that MBDB is usually issues. Not only the health risks for the individ- sold as ecstasy. Therefore, MBDB will not turn uals taking a particular drug, but also the impact up in its own right in epidemiological surveys. the use of this drug may have on public health The data we have on the availability of MBDB on and society as a whole need to be evaluated. One the illicit drug market come mainly from other way in which health risks can be assessed will be sources, such as drug seizures and drug supply discussed here and applied to MBDB and monitors. MDMA, for the purpose of illustrating the MBDB was found in hair samples of two of 20 method. regular ecstasy and ª speedº users from the techno-music scene in Germany.9 The period of taking the drug had presumably been brief. In the Using a margin of safety same study, MBDB was only seen in 3 of 127 Risks are taken voluntarily by all of us every day. ecstasy tablets. The average amount of MBDB in A well-known example of ª chemicalº risks is the these tablets was 197 mg. In most Member self-administration of medicines. Toxicological States’ reports to the EMCDDA an average risk assessment of a potential medicine starts with quantity of about 100 mg MBDB per tablets is extrapolation of insights and data from animal mentioned. experiments. The first step is to estimate the levels In Sweden, MBDB was identified in routine of exposure at which specified adverse effects may analysis of a urine sample from a person sus- occur in man. Then the chances that these pected of a petty drug offence. After the first adverse effects take place are weighed against the sample, approximately 4000 samples were neg- therapeutic gain to be expected when using the ative, but than again in a 2-month period nine medicine. This results in a margin of safety. more samples were confirmed positive.7 Data Depending on the size of the therapeutic gain from the Netherlands come from the Drugs expected, the intended availability of the sub- Information and Monitoring (DIMS) project, a stance (e.g. prescription or over-the-counter so-called supply monitor. Drug users voluntarily drugs), the nature and severity of the toxic effects and anonymously hand in a drug sample at one of and other factors, varying levels of the margin of the participating institutions for addiction care. safety may be set as acceptable. The margin of These samples are analysed in a laboratory. One safety is defined as the ratio of the therapeutic week later the person is notified of the contents of dose and the predicted NOAEL in man (as the sample and he is also educated on the possible derived by extrapolation from animal data). No health risks of the drug(s) involved. Also, DIMS Observed Adverse Effect Level, i.e., the highest may issue warning campaigns. Between 1993 and dose of a substance at which no adverse effect was 1998, 10 540 tablets were analysed. In the last 4 found. Ideally, animal and human data should be years, the yearly proportion of ª ecstasyº tablets compared on the basis of systemic exposure, for containing MBDB was never higher than 4%, which pharmacokinetic measures are needed, and mainly around 1% (Table 3). usually the area under the curve (AUC) of a curve MBDB has been available at least since 1994. of the drug concentration in plasma against time, Nevertheless, its position on the synthetic drugs or the maximal concentration reached in plasma market is marginal. From subjective reports it (Cm ax ). If these pharmacokinetic data are want- appears that MBDB is less popular among users ing, allometric scaling may be applied, meaning than MDMA. The reason for this may be that that animals and man are compared using estab- MBDB produces less euphoria than MDMA.5 lished relationships between body weight and Another possible explanation is that MBDB pharmacokinetic parameters. However, this may largely lacks the stimulant properties of not be appropriate when a drug is largely elimi- MDMA. nated by hepatic metabolism. 278 L. A. G. J. M. van Aerts et al. ) l l d s B a l t e

a e f s 2 1 1 4 1 D t l y o o l b B

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e g A B n n i i D M r e + + f 6 o B f t D i a n M c M o M

d e n B n a B i

D e + + n 2 C f B f o 2 i a t M c a m r o f B A n I B E

D + + g C 1 B D u 2 r M M D

y b

d A B e i B f D M i + + t 2 C B D n 2 e M d M i

s t e l b e a n t i

g m B n a i t D + n 1 e i B h a t p M n o m c a - B D B e B n M i D e f + 2 6 6 f o B f

a s t M c n e t n o A B C

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4 5 6 7 8 r 9 9 9 9 9 a e 9 9 9 9 9 Y 1 1 1 1 1 Properties and possible risks of MBDB 279

Such a margin of safety could also be used for the animals had been given a single subcutaneous non-medically used psychoactive drugs. The defi- injection of 10 mg/kg MDMA. A single intra- nition of this margin of safety would be the ratio peritoneal administration of 5 mg/kg MDMA did of a recreational dose and the predicted NOAEL not reduce serotonin and 5-HIAA levels in the rat in man. In analogy to practice in pharmaceutical brain 7 days later, but a 10 mg/kg dose did.6 2 industry, 2 could be set as the margin of safety Intraperitoneal injections of 4 mg/kg once daily below which the health risks are considered to for 4 days did not reduce brain serotonin neu- coincide with the intended effect. A margin of ronal markers in the brain of the Dark Agouti rat safety of 10 or above would be acceptable. For a (a strain of rats that is more sensitive to MDMA- final judgement on the acceptability of margins of induced neurotoxicity than other strains) 7 days safety between 2 and 10, additional factors would later. However, injections twice a day for the need to be weighed, such as the frequency of use same period of time did reduce these markers.6 3 of the substance and the severity of the possible Apparently, administration of 4 ± 10 mg/kg adverse health effects. MDMA causes serotonergic deficits in rat brain As for MBDB, the only NOAEL that can be depending on the experimental conditions. A derived from existing animal data is the one reasonable NOAEL estimate in the rat would be reported by Nash & Nichols1 7 with regard to the 4 ± 5 mg/kg if doses are separated by at least 1 day. lack of a reduction of serotonin neuronal markers This may be too short for man because of a in the rat striatum after a single dose of 21 mg/kg slower elimination half-life of MDMA, and possi- MBDB. Extrapolation of this NOAEL to man, bly slower recovery of neurones in man. using allometric scaling, would yield a predicted Applying allometric scaling factors to these NOAEL of 2.1 mg/kg. Since the recreational dose data gives a predicted NOAEL for MDMA in of MBDB in man is 2.1± 2.9 mg/kg5 ,11 , this would man of 0.34 and 0.4 ± 0.5 mg/kg using single- result in a margin of safety of 0.75 ± 1. This means exposure squirrel monkey and rat data, respec- that if MBDB-induced neurotoxicity occurs in tively. The multiple dosing rhesus monkey data man as it does in rats, recreationally taken doses would yield a predicted NOAEL in man of are likely to adversely affect at least some of the 0.5 mg/kg. However, the corresponding rat data users. suggest that 0.4 mg/kg still could reduce ser- The same method can be applied to MDMA, otonin neuronal markers in man. Thus, 0.4 mg/kg with regard to the same parameter (reduction of would appear to be a reasonable estimate of the brain serotonin neuronal markers). In one study, NOAEL in man for single doses only. As the squirrel monkeys were given 2.5 mg/kg MDMA recreational dose of MDMA is 1± 1.7 mg/kg twice monthly for 4 months by the intragastric (36,64), this results in a margin of safety of route (G. Ricaurte, unpublished observations). 0.24 ± 0.4. This is roughly three times lower than Serotonin or 5-HIAA levels did not change in for MBDB, suggesting that MDMA is more likely eight brain regions. However, a single oral admin- to cause neurotoxicity. istration of 5 mg/kg reduced serotonin in the There are several points cautioning against thalamus and hypothalamus in this primate.57 taking these estimates as absolute figures and, Thus, as far as the reduction of brain serotonin therefore, the calculations presented above neuronal markers is concerned, 2.5 mg/kg is the should be seen as illustrative for the margin of NOAEL in the squirrel monkey. safety method only. First, only one kind of In rhesus monkeys given MDMA orally twice adverse effect (reduction of serotonin neuronal daily for 4 consecutive days, serotonin was markers) was looked at in such a way that a reduced in the hippocampus 1 month later when NOAEL could be derived. To render a risk the dose was 2.5 mg/kg dose, but not at 1.25 mg/ assessment valid, all kinds of toxic effects should kg.58 Thus, for this multiple dosing regimen, be taken into account. In other words, a full 1.25 mg/kg could be taken as the NOAEL in the toxicological investigation should be performed rhesus monkey. in order to identify acceptable safety margins. At In the rat, a single oral administration of 10 mg/ present, toxicological data on MDMA and espe- kg did not affect brain serotonin levels and cially MBDB are so scarce that any risk assess- serotonin re-uptake site densities.5 9 However, ment would be hazardous. Secondly, we extrapo- Schmidt6 0 and Stone and co. workers6 1 found lated average responses in animals to man, reduced brain serotonin in rats 1 or 2 weeks after disregarding intraspecies differences in suscepti- 280 L. A. G. J. M. van Aerts et al. bility for nerve terminal degeneration. Thirdly, 13. Johnson MP, Nichols DE. Neurotoxic effects of the alpha-ethyl homologue of MDMA following sub- the circumstances under which drugs are taken acute administration. Pharm acol Biochem Behav may affect the outcome. 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