Drug Abuse

Summary

Pharmacology and toxicology of PMMA in animals

i. Drug discrimination experiments have demonstrated that PMMA lacks amphetamine-like or hallucinogenic properties. In MDMA-trained rats, PMMA could be substituted for MDMA. In PMMA-trained rats, MDMA could be substituted for PMMA. However, PMMA could not be substituted for amphetamine or the hallucinogen, DOM.

ii. PMMA did not stimulate locomotor activity in rats at dosages of up to 30 mg/kg. However, sympathomimetic stimulation (e.g. salivation, piloerection, lacrimation, convulsions) was observed at doses of 40 and 80 mg/kg of PMMA and these same doses also stimulated locomotor activity in rats.

iii. In vivo chronoamperometry was used to investigate the effects of PMA on dopaminergic and serotonergic neurones. PMA potently inhibited serotonin reuptake but not dopamine reuptake. PMMA was not investigated.

iv. In rats, PMA produced bradycardia and lowered systolic and diastolic BP at 20 °C ambient temperature but these effects did not occur at 30 °C. PMMA was not investigated.

v. Catalepsy was observed in cats and rats after administration of PMMA, suggesting reduced dopaminergic activity in the striatum of these animals.

vi. The neurotoxicity of PMMA, PMA and MDMA was investigated in rats. In all, 80 mg/kg of PMMA or PMA and 20 mg/kg of MDMA were administered each day for four consecutive days. The levels of serotonin were determined in four brain regions one week after the last dose. With the exception of the striatum, the levels of serotonin were significantly lowered. However, the reduction in the hypothalamus did not reach significance when the experiment was repeated. The reduction in serotonin after administration of PMMA is shown in Table 2.

The levels of dopamine were not reduced by PMMA. PMMA and PMA were considerably less neurotoxic than MDMA; 80 mg/kg PMMA or PMA was approximately as toxic as 20 mg/kg MDMA.

vii. The LD50 value of PMMA was 80–100 mg/kg in rats. This value, together with points ii, iii and viii, suggests a narrow margin for non-toxic effects and a high risk of acute toxicity.

viii. Comparison of the limited data that are available suggests that the acute toxicity of PMMA is less than that of PMA.

ix. Pharmacokinetic experiments with five amphetamines revealed a poor penetration of PMA into the brain. The concentration of PMA in rat brain at 3 hours was ~10 % that of MDMA after application of equivalent doses; PMMA was not investigated.
Comparison of the brain concentrations of the amphetamines suggested that PMMA crosses the blood-brain barrier less easily than PMA due to a methylated nitrogen on the side-chain — the concentration of 3,4-methylenedioxyamphetamine was greater than that of 3,4-methylenedioxymethamphetamine, which was greater than that of 3,4 methylenedioxy-N-ethylamine.

x. In vitro experiments demonstrated that PMA is a potent inhibitor of MAO-A. PMA is 20 times more potent than (+)amphetamine; PMMA was not investigated.

xi. PMA, and probably PMMA, are metabolised by cytochrome P450 2D6, which may interfere with the inactivation of certain medicinal drugs, such as fluoxetine.

Human pharmacology and toxicology of PMMA

i. The acute ingestion of PMMA by experienced drug users, as documented on the Internet (n = 5), and in Shulgin’s report (Shulgin and Shulgin, 1991) did not result in consistent psychological effects. A dose of below 90 mg seemed to induce no central effects whereas a 90 mg dose in another subject elicited unusual audiostimulation. A dose of 110 mg in this subject induced stimulation lasting one hour, followed by reduced motivation to talk and to become involved with others, and a slowing of the sensation of time. Shulgin and Shulgin, reported none of the central effects of MDMA after administering 110 mg PMMA. A third subject found 100 mg PMMA to be mildly relaxing and euphoric. A dose of 150 mg caused severe physical ill effects. A single subject ingested 215 mg PMMA and found the experience very similar to taking MDMA. Several of the volunteers reported sedating effects with PMMA.

ii. The acute physical effects were also found to be dose dependent. A dose of up to 50 mg caused a hyperreflexia-like status. Higher doses induced eye muscle disturbances of a nystagmus-like type. Some volunteers reported an increase of pulse rate and all reported muscle stiffness, such as jaw lockdown. Some reported nausea and, after some hours, head and stomach pains.

iii. There are no reports on the metabolism of PMMA. Three volunteers ingested 5 mg of radiolabelled PMA. PMA was 85 to 100 % metabolised within 24 hours. Demethylation of the para-methoxy-group was the main metabolic process followed by side-chain oxidation. An individual with a genetic defect of the P4502D6 cytochrome (its prevalence in Caucasians is ~ 9 %) metabolised PMA much more slowly.

iv. There are no reports of psychological dependence on PMMA.

v. An assessment of the risks associated with acute intoxication with PMMA is not possible due to a lack of data. There is a single report of a fatality in which PMMA, but no PMA, was detected in the blood. Other amphetamines (2 μg/ml MDEA, 0.3 μg/ml MDA) were detected in the blood sample, in addition to 11.51 μg/ml PMMA. The report concluded that the cocktail of several amphetamines caused the death. Extrapolations from animal experiments suggest that 400–500 mg of PMMA is extremely toxic, possibly lethal, in humans. Shulgin and Shulgin, estimated that 150 mg of PMA is toxic.

Structure-activity investigations suggest that PMMA activates serotonergic neurones more selectively than PMA: N-methylation of the side-chain increases affinity to the neuronal serotonin transporter — methamphetamine’s affinity is greater than that of amphetamine. The hyperthermia-rhabdomyolysis syndrome, which is reminiscent of serotonin syndrome in several aspects, with intravasal coagulopathy, hyperkalaemia, arrhythmia, convulsions, culminating in multiorgan failure, is presumably the cause of death following PMMA intoxication.

Conclusions

There is only limited information available about PMMA. More is known about PMA and even more has been published about MDMA. The literature regarding amphetamine, and several of its other derivatives, is extensive. Some of the conclusions in the present report are based on experiments and experiences with compounds structurally related to PMMA; this is indicated in the text.

PMMA is sold on the illicit market as a substitute for ‘ecstasy’. Most tablets also contain PMA. The neuronal actions of PMMA differ from MDMA with respect to dopaminergic neurones and the stronger inhibition of the enzyme MAO-A by PMMA (concluded from the actions of PMA). The dopaminergic neurones are not activated by PMA nor presumably by PMMA. In contrast to these two compounds (which, together with 4-MTA, are exceptions within the amphetamine family), the acute psychostimulant effects of MDMA are mainly caused by the activation of dopaminergic mechanisms. Dopamine is inactivated by both MAO-A, a neuronal enzyme which inactivates 5-HT and noradrenaline, and MAO-B. Based on the strong inhibitory effect demonstrated by PMA on MAO-A, the stimulating effect of a high dose of PMMA (e.g. 215 mg) is probably caused by noradrenaline and not by dopamine.

Experienced users report that the central effects of PMMA are relatively weak compared with MDMA. In some users, a dose of 110 mg PMMA caused euphoric and stimulating effects whereas, in others, no MDMA-like psychological effects were reported. Cardiovascular and muscular effects, however, were present. The reason for the weak psychological effects might be that PMMA penetrates the blood-brain barrier poorly compared with other amphetamines, as demonstrated in animal experiments with PMA.

Thus, the user expects the psychotropic effects of the active substance of the tablet he/she has consumed but is frustrated. The user perceives the cardiovascular and muscular effects, which seem to indicate that the tablet did contain an active compound. Therefore, the user consumes more tablets seeking the familiar psychological effects of ‘ecstasy’. The dose–effect curve with respect to the toxic actions of PMMA and PMA (which is also present in most of these tablets) is much steeper than that of MDMA. Thus, the risk for acute toxic effects is much greater in the case of PMMA/PMA than for MDMA.

The limited data available from animal experiments suggest that PMMA is less toxic than PMA. The reason could be that PMMA penetrates the blood-brain barrier less easily than PMA and that PMMA is possibly more selective for serotonergic neurones than PMA and certainly than MDMA. The neurotoxic risk after repeated intake of PMMA is less than that of MDMA, possibly due to the lack of the involvement of the dopaminergic system: there is some evidence that dopamine is involved in the neurotoxicity of MDMA.

We can only speculate as to why PMMA has been added to PMA tablets in recent years by illicit laboratories. The high risk of acute toxic effects with PMA has been known for 30 years. The chemists may have expected PMMA to cause similar central effects to PMA and ‘ecstasy’, because drug discrimination experiments have demonstrated that PMMA can be substituted for MDMA but not for amphetamine or the hallucinogen, DOM. Animal studies suggest an entactogen-like action for PMMA without the brain stimulating effects of MDMA. This pattern of effects would allow a reduction of the amount of PMA in the tablets. The experiences of human volunteers suggest that very high doses (e.g. 200 mg PMMA) are necessary to elicit MDMA-like effects, possibly due to poor penetration of the blood-brain barrier. However, high doses of PMMA cause very unpleasant physical effects, elicited by the peripheral actions of PMMA.

There is no relevant therapeutic potential for PMMA.

Chemical and pharmaceutical information

Chemical description

PMMA

PMMA was first synthesised in 1938 (Glennon et al., 1988). Its chemical name is 1-(4-methoxyphenyl)-2-methylaminopropane and its chemical formula is C11H17NO. It has a molecular weight of 179 (214.5 as hydrochloride) and a melting point of 177–178 oC. PMMA is also known as paramethoxy-N-methyl-amphetamine; N-methyl-1-4-(methoxyphenyl)-2-aminopropane; 4-methoxy-N-methyl-amphetamine (4-MMA); or 2-methylamino-1-(p-methoxyphenyl)-propane. Shulgin and Shulgin, (1991) described PMMA chemically as MDMA with one oxygen atom removed. Two optical isomers exist, S(+)PMMA and R(-)PMMA (Young et al.,1999) as shown in Figure 3.

Precursor substances required for the synthesis of PMMA are: methylamine, 4-methoxyphenylacetone (4-methoxyphenyl-2-propanone) and cyanoborohydride. Additional substances required are: methanol, dichloromethane, isopropanol, hydrochloric acid, ethyl chloroformiate, triethylamine, carbamate, formamide, lithium aluminium hydride. There is an alternative method of synthesis using PMA.

PMA

PMA’s chemical name is 1-(4-methoxyphenyl)-2-aminopropane. Also known as 4-MA (4-methoxyamphetamine) or paramethoxyamphetamine, its chemical formula is C10H15NO. Its molecular weight is 165 (200.5 as hydrochloride) and it has a melting point of 206–207 oC. The chemical structure of PMA is shown in Figure 4.

Precursor substances used in the synthesis of PMA are: 4-methoxybenzaldehyde, nitroethane, benzene, methanol and cyclohexane. The reaction yields a viscous red oil. Crystallisation yields lemon-yellow crystals. An alternate synthesis utilises 4-methoxybenzaldehyde, nitroethane and N-amylamine. The intermediate product is 1-(4-methoxyphenyl)-2-nitropropene (melting point 45–46 °C). Substances which have only minor toxicological relevance are used to convert this compound into PMA.

The precursors of both PMA and PMMA are widely available commercially.

PMA can also easily be converted into the amphetamine metabolite 4-hydroxyamphetamine (4-HA) with a melting point of 171–172 °C. Two positional analogues of PMA are known: 2-methoxyamphetamine (2-MA) and 3-methoxyamphetamine (3-MA). Their synthesis is straightforward and similar to that of PMA. 3-MA has been explored in man, but no central effects were noted with a 50 mg dose (2 x 25 mg separated by a three-hour time interval). There do not seem to be any reports of human trials of 2-MA (Shulgin and Shulgin, 1991).

Colour reactions are used to indicate amphetamine derivatives in tablets (Table 3). 2–5 mg of the hydrochloride salt of each drug is used. A given set of colour responses to a combination of field test reagents gives an indication of what may be identified by specific analysis.

The fairly simple molecular structure of the amphetamines (see Figure 5) makes their chemical synthesis and purification relatively easy. Immunoassays of urine are generally used as a first presumptive screening test. GC–MS analysis after extraction and acetylation is one of the most popular techniques for confirming positive initial samples. Unambiguous determination of MS data, however, is often a difficult task because of the spectral similarity of many of the amphetamines, their metabolites and their derivatives (Marson et al., 2000).

The ultraviolet, proton magnetic-resonance, and infrared spectra of PMMA, PMA, and related amphetamine derivatives have been published in papers by Bailey and coworkers (1973; 1975), Clark (1984) and Dal Cason (2000 and 2001). Gas–liquid and thin layer chromatographic systems are presented in detail. The collection of spectra comprises structural isomers as well. This is of interest as the compounds with methoxy groups in positions two or three are less active than other configurations.

It may be of note that other simple phenylethylamines have been detected in powder samples and in urine samples. N-methyl-1-phenylethylamine has been found in quantities of several kilograms in illicit laboratories in the USA and in ‘ecstasy’ pills in Germany. Thus, chemists analysing pills from the ‘ecstasy’ scene may find simple phenylethylamines (Marson et al., 2000). 4-methoxyphenyl-2-propanol was identified as a contaminant in some of the tablets seized in the USA (Dal Cason, 2000).

Recently, the presence of other byproducts and impurities from an illicit drug seizure have been described (Coumbaros et al., 1999). Compounds found in PMA preparations in Australia included 4-methoxyphenol, 4-methoxybenzaldehyde, 4-methoxyphenyl-2- propanone, 4-methoxyphenyl-2-propanol, 4-methoxisphenylpropene and, possibly, 4-methyl-5-(4‘methoxyphenyl) pyrimidine. The presence of these compounds suggests that the active drug was prepared from 4-methoxybenzaldehyde via 4-methoxyphenyl- 2-propanone using a Leuckardt reductive amination. It was proposed to apply solidphase microextraction to remove impurities. The possible synthetic routes used by illicit laboratories have been discussed in a recent paper (Kirkbride et al., 2001).

Legitimate uses of the product

It seems that there is no relevant therapeutic use for PMMA.

The N-methyl substituted 2-MA, which is a positional analog of PMMA, is an adrenergic bronchodilator called methoxyphenamine or orthoxine. It has been used in the prevention of acute asthma attacks in doses up to 200 mg (Shulgin and Shulgin, 1991; van der Schoot, et al., 1962). This compound has been controlled in the UK as a prescription medicine. However, it is no longer available as such on the UK market.

PMMA is thought to strongly and specifically inhibit MAO-A, although this has only been demonstrated for PMA (see later section). Therefore, mood disorders could be a medicinal indication for PMMA. However, because of the toxic effects of PMMA described later, and the availability of a medicinal drug which inhibits MAO-A without causing increased extraneuronal levels of serotonin due to exchange diffusion — a combination which induces toxicity — there is no need to use PMMA for medicinal purposes.

The main metabolite of PMA, 4-hydroxyamphetamine, has been employed therapeutically under the brand name ‘Paredrine’ in the USA, as a sympathomimetic in patients with heart block or postural hypotension. Effects of cumulative daily doses of 400 mg have been reported, and acute dosages of 80 mg. No central effects related to alertness or mood have been reported (Alles, 1959). A study in man described the intravenous administration of 2 mg, again without reporting any central effects (Severs et al., 1976).

PMMA is a synthetic precursor of the sympathomimetic agent, pholedrine (‘Veritol’; Cession-Fossion et al., 1966).

Pharmaceutical form

PMMA

PMMA was originally used as a powder (>100 mg). However, the form in which PMMA is commonly encountered now is as tablets. Tablets containing PMA/PMMA have been seized in Denmark, Germany, Spain, Norway, Austria and Sweden.

They are marked with ‘E’, ‘Mitsubishi’ or ‘Jumbo’ logos.

PMA

PMA was originally used as a powder (50–80 mg). Tablets containing PMA only have been seized in Belgium, Germany, France, the Netherlands, Sweden and the UK.

The tablets seized were marked with ‘Superman’, ‘Elephant’, ‘Mitsubishi’, ‘Nike’ or ‘xTc’.

In contrast to MDMA, MDA, or N-ethyl-3,4-methylenedioxamphetamine (MDE), PMA tablets show no colour change using Marquis reagent (Table 3). This means that PMA tablets can be screened for using a Marquis testing kit.

‘DanceSafe’, a US-based non-government organisation that is active in the prevention field of drug abuse, reported that PMA does not have the reputation of being a recreational drug. Unlike ‘ecstasy’, there is no demand for it. It is not being manufactured because people like it: PMA is being manufactured and sold as ‘ecstasy’ because, unlike MDMA, the chemicals needed to make it are easy to obtain and are not strictly controlled by the government.

Route of administration and dosage

The most common route of administration of PMMA or PMA is oral. Inhalation and intravenous injection of PMA were reported in the mid 1970s.

Toxicology and pharmacology in animals

Preclinical safety data

Single dose toxicity

PMMA: It has been demonstrated that, among various environmental factors influencing the toxicity of amphetamine in mice, aggregation (i.e. the presence of other mice) has the greatest single potentiating influence (Chance, 1946, 1947). This is thought to reflect social stress. PMMA did not show any significant difference in acute toxicity in mice under isolated (24 h LD50 = 63 mg/kg) or aggregated (24 h LD50 = 53 mg/kg) conditions, suggesting a lack of amphetamine-like toxicity (Glennon et al., 1988).

Although not fully characterised, the LD50 of PMMA is in the range of 80–100 mg/kg in rats (Table 4). Since this dose is less than twice that required to stimulate locomotor activity (40 and 80 mg/kg), there appears to be a narrow margin between the behaviourally active and the lethal dose of PMMA in rats (Steele et al., 1992).

There are no other published studies of single-dose toxicity.

PMA: 6.2 mg/kg PMA produced abnormal behaviour in two rats (see behavioural studies below). One rat died after one day and a second rat after one week (Smythies et al., 1967).

After producing a rage reaction, PMA was lethal to cats at a dose of 25 mg/kg (Benington et al., 1964; Table 4). The results presented in Table 4 do not allow wellfounded conclusions. Nevertheless, they do suggest a higher acute toxicity of PMA than of PMMA. The reason could be that PMMA penetrates the blood-brain barrier less readily than PMA (see pharmacokinetic section). Provided that hyperthermia is the main cause of acute toxicity, a relatively poor penetration of PMMA into the brain would reduce the risk for the induction of acute toxic actions. Hyperthermia is probably caused by activation of 5-HT2A and 5-HT2C receptors in the brain and spinal cord. However, rhabdomyolysis is probably caused by the direct action of PMA or PMMA on skeletal muscle cells. Destruction of myofibres liberates myoglobin which obstructs renal tubuli. The inhibition of MAO-A causes an increase of noradrenaline, serotonin and possibly dopamine in the peripheral organs. Subsequently, hypertension, hypotension, tachycardia, nausea and diarrhoea may occur.

It is interesting to note that para-methoxy-phenylethylamine (PMPEA), which differs from PMA in that it lacks a 1 methyl group in the side chain, did not produce any effect on behaviour. However, when rats were pre-treated with the MAO inhibitor, iproniazid,  and 6.2 mg/kg PMPEA, their behaviour was completely disrupted and toxic effects rapidly appeared: the rats lay down and died within a few hours (Smythies et al., 1967). This increase in the toxicity of PMPEA following MAO inhibition has also been reported to produce intense rage reactions and hyperthermia in cats (Benington et al., 1964).

Repeated dose toxicity
Steele et al. (1992) found that, in rats, the lethality caused by PMMA and PMA varied between experiments, ranging from 15 to 43 % for the 80 mg/kg dose. The dose was administered by subcutaneous injection twice daily for four days, and further observation was carried out for one week. The neurotoxic potential of PMMA doses higher than 80 mg/kg was not tested because of the high lethality rate.

Comparison of the neurotoxic potential of PMMA, PMA, and MDMA revealed that the 5-HT-depleting effects of 80 mg/kg PMMA were comparable to those of 80 mg/kg PMA, but were generally less than those produced by 20 mg/kg MDMA. The depleting effects were observed in the hippocampus, frontal cortex and hypothalamus of rat brain. In the striatum, the levels of 5-HT were lower than control levels, but these reductions did not attain statistical significance. The reductions of 5-HIAA (the acidic metabolite of 5-HT) in the striatum were significant for PMA (p<0.05) and MDMA (p<0.01) but not for PMMA. In the hypothalamus, all test compounds caused a similar reduction of 50 % in the concentrations of 5-HT and 5-HIAA.

In addition, Steele and co-workers (1992) performed a dose-response experiment with PMMA. After a dose of 80 mg/kg injected twice daily for four days, they found a reduction of 5-HT (p<0.05) in the hippocampus and frontal cortex but not in the striatum and hypothalamus. The animals were killed one week after the last day of treatment. However, it is interesting to note that the depletion of hypothalamic 5-HT produced by 80 mg/kg PMMA did not achieve statistical significance in one of the two experiments conducted in the same study.

The neurotoxic action of PMMA appears to be selective for serotonergic systems since striatal dopamine levels were not reduced on a long-term basis by PMMA. In this regard, PMMA closely resembles MDMA and p-chloroamphetamine (PCA). In terms of potency, however, the neurotoxic activity of PMMA is considerably lower than that of MDMA. Structure-activity relationship analysis of neurotoxic amphetamine derivatives revealed that ring substitution at the para position with halogens (PCA) and methoxy groups (PMA and PMMA) yields potent and selective serotonergic neurotoxins. In contrast, the unsubstituted compounds (+)amphetamine and (+)methamphetamine possess dopaminergic neurotoxic activity. N-monomethylation appears to confer serotonergic neurotoxic activity since methamphetamine, but not amphetamine, persistently alters rat brain serotonergic parameters. Notably, N-monomethylation seems to have little influence on the potency or the spectrum of neurotoxic activity of the para-methoxylated compounds: PMA and PMMA are equipotent, as are MDMA and MDA, and PCA and its N-monomethylated analog (Steele et al., 1992).

The number of 5-HT transporters ([3H]paroxetine binding sites) decreased in rat cortex with 80 mg/kg PMMA, suggesting damage or loss of 5-HT terminals (p<0.05; Steele et al., 1992).

The question arises as to whether these findings about neurotoxicity can be extrapolated from animal experiments to humans. Among the structurally-related amphetamine derivatives of PMMA, the neurotoxicity of MDMA is best documented (Ricaurte et al., 2000). Mouse is the one animal species that is relatively resistant to MDMA-induced 5-HT injury. Compared with rodents, primates are more sensitive to the neurotoxic effects of MDMA. The observation that smaller animal species require higher doses of drug to achieve equivalent effects is predicted by the principle of interspecies scaling. This method utilises known relations between body mass and surface area and accounts for differences in drug clearance. Using this method, it is possible to accurately predict the neurotoxic dose of MDMA in rats (20 mg/kg). Specifically, the equivalent dose in monkeys is found to be 5 mg/kg, a dose that has in fact been shown to be neurotoxic in monkeys. Based on the dosages that are neurotoxic for rats or monkeys, it is possible to predict the dosage of MDMA that would be neurotoxic in humans. Taking the neurotoxic dose of 5 mg/kg in a 1 kg squirrel monkey, the equivalent dose in humans is found to be 1.28 mg/kg; or approximately 96 mg in a 75 kg individual. Please note that this is a model calculation carried out according to Ricaurte and colleagues’ methods and does not necessarily represent the real toxicity.

Extrapolating from the report of Steel et al. (1992) that a dose of 80 mg/kg PMMA causes a reduction of 5-HT in some of the brain regions of rats, the analogue calculation indicates that 384 mg PMMA would be toxic in humans. It should be noted further that the dose of 80 mg/kg is the approximate dose at which 50 % of rats die.

With respect to PMA, Shulgin (1978) speculated that PMA has a therapeutic index of about 2.5 and that as little as 150 mg may prove to be a toxic dose in humans.

Reproductive function

There are no reports about the action of PMMA or PMA on reproductive function, embryo-foetal or perinatal toxicity, nor about their mutagenic and carcinogenic potential.

Pharmacodynamics

In vitro tests

Actions on neurones: There is no information regarding the in vitro activity or metabolism of PMMA. Results on PMA are probably representative for PMMA.

In mouse brain, homogenate with a Ki value of 0.22 μM, PMA is over 20 times as potent as (+)amphetamine (+)amphetamine 6 μM, o-methoxyamphetamine 9 μM, mmethoxyamphetamine 23 μM) as an inhibitor of 5-HT oxidation by MAO. PMA is highly selective towards A-type MAO and possesses only weak activity against B-type enzyme (Green and Hait, 1980). The high inhibitory potency of PMA has been confirmed using crude mitochondrial suspension from rat brain (IC50=0.3 μM). By comparison, the inhibition constants (Ki) of the specific MAO-A inhibitor, clorgyline, is 0.054 μM (competitive initial non-covalent interaction) and of moclobemide is 200 μM (Cesura and Pletscher, 1992). Others reported a Ki-value of 0.0063 μM for clorgyline using crude mitochondrial fraction from rat brain as the source of MAO-A (May et al., 1991).

The high inhibitory potency of PMA is an important observation with respect to the toxic actions of PMA and probably of PMMA. As mentioned before, phenylpropylamines such as PMA and PMMA are much more toxic than phenylethylamines. This is explained by the fact that the former compounds are poor substrates for MAO.

Therefore, the inactivation of phenylpropylamines by oxidative transamination of the side chain is much slower than that of the phenylethylamines. Studies with positional analogues demonstrate that the inhibitory potency is highest in para-substituted amphetamines such as PMMA and PMA, and that the difference in potency is more than 40-fold compared with the ortho- and meta-substituted compounds.

Another series of experiments should be mentioned which might contribute to the understanding of the in vivo actions of PMMA. These are related to the effects of PMMA on dopaminergic and serotonergic neurones. While there are no relevant studies for PMMA or PMA, there are findings with MDMA, which is structurally similar to PMMA. MDMA has a strong binding affinity for the 5-HT (serotonin) transporter (SERT), and inhibits 5-HT reuptake into hippocampal synaptosomes (EC50)=0.35±0.03 μM) more potently than dopamine uptake into striatal synaptosomes (EC50=1.14±0.03 μM; Crespi et al., 1997). On the other hand, amphetamine binds with a high affinity to the dopamine transporter (DAT) and inhibits dopamine reuptake into striatal synaptosomes (EC50=0.13±0.04 μM) more potently than 5-HT reuptake into hippocampal synaptosomes (EC50=4.51±0.64 μM). Lastly, fenfluramine binds with a high affinity to SERT and is a much more potent inhibitor of 5-HT reuptake (EC50=0.90±0.40 μM) than of dopamine reuptake (EC50=11.2±0.13). Fenfluramine is mentioned because it is a model substance for the activation of serotonergic neurones with numerous reports on the in vivo effects. It is important to note, however, that although MDMA has a higher affinity for SERT, there is a greater total efflux of extracellular dopamine over that seen for 5-HT at behaviourally active doses (White et al., 1996).

Metabolism: Phenylisopropylamines interact with CYP 2D6 as substrates and/or as inhibitors. The apparent Ki values of PMA (24 μM), (+)methamphetamine (25 μM) and (+)amphetamine (26.5 μM) were similar (Wu et al., 1997). PMMA was not investigated. From findings with amphetamine and methamphetamine, it can be concluded that N-methylation does not affect the affinity of phenylisopropylamines to the cytochrome isoenzyme. Therefore, PMMA probably has the same affinity to CYP 2D6 as PMA (~24 μM).

The use of PMMA may cause metabolic interactions with other drugs that are CYP 2D6 substrates and the potential for polymorphic oxidation via CYP 2D6 may be a source of interindividual variation in its toxicity. Interacting medical drugs would be fluoxetine, tricyclic antidepressants, ß-adrenoceptor blockers, and methoxymorphinans.

Deficiency in the 4-hydroxylation of amphetamine and the O-demethylation of PMA (and probably PMMA) were two early observations that led to the discovery of the CYP 2D6 polymorphism (Kitchen et al., 1979).

In vivo tests

Effects on central nervous system: Rats given the highest doses of PMMA (40 and 80 mg/kg) exhibited clear signs of sympathomimetic stimulation; including salivation, piloerection, lacrimation, and sometimes convulsions (Steele et al., 1992). It is not clear whether the neuronal basis of this is sympathomimetic activation as assumed by the authors. Most of the symptoms can be induced by serotonergic stimulation as well. However, the inhibition of MAO-A produces an increase of noradrenaline in the brain (Hegadoren et al., 1995). Thus, both types of neurones presumably contribute to the in vivo effects of PMMA.

PMMA produced an unusual cataleptic effect in cats and rats when administered by the intracisternal or intraventricular route. This effect, though less marked, was also observed in mice given PMMA (Michaux, 1967; Michaux et al., 1965).

PMMA did not produce significant locomotor stimulation at doses up to 30 mg/kg in mice. At doses greater than its LD50 dose, PMMA produced behavioural effects such as hyperactivity and vocalisation, which were similar to those observed with amphetamine. In this respect, PMMA was weaker than PMA which, in turn, was weaker than racemic amphetamine and racemic methamphetamine (Glennon et al., 1988). It can be concluded from both reports that PMMA is a very weak central stimulant and less active than PMA. Amphetamine is at least six times more potent a central stimulant
than PMMA.

The neuronal basis for the hyperactivity and sympathomimetic stimulation is not clear. The inhibition of MAO-A could contribute to the central and peripheral effects observed in animals and in some, but not all, human volunteers after the intake of PMMA. High doses of serotonergic compounds, such as fenfluramine, induce a socalled ‘serotonin syndrome’ with hyperactivity, hyper-reactivity, hind limb abduction, lateral head weaving, reciprocal forepaw treading, rigidity, Straub tail, tremor and piloerection in animals. Even higher doses cause convulsions, coma and death. It is important to note that many of these effects were observed only when rodents had been pre-treated with MAO inhibitor (e.g. iproniazid).

It is important to note that the carrier-mediated release of 5-HT is calcium and actionpotential independent (Figure 6). The effect is greatly increased by the concomitant application of transmitter precursors (e.g. 5-hydroxytryophan) or inhibitors of metabolising enzymes (e.g. MAO inhibitors). The extent to which both mechanisms contribute to the behavioural effects of PMMA is not clear. 4-MTA, which has similar effects and is presumably equipotent for the inhibition of MAO-A, induced a maximal increase of 5-HT in the dorsal hippocampus of rats of about 2000 % compared with baseline 40 minutes after a 5 mg/kg injection. The levels declined slowly thereafter, which was thought to be due to the MAO-A inhibitory properties of 4-MTA (Scorza et al., 1999). From studies with MDMA, it is known that low doses (3 mg/kg of the more potent, positive, MDMA enantiomer) elicit hypermotility in rodents by activating 5-HT1B/1Creceptors. This effect is inhibited by specific receptor blockers and is not seen in 5-HT1B knock-out mice. Higher doses induce hypermotility involving the 5-HT2A and
dopamine receptors (Bankson and Cunningham, 2001).

The actions of PMMA and PMA observed in animals and humans strongly suggest a dominant role for 5-HT neurones. This notion is supported by behavioural experiments delineating the effects of specific 5-HT receptor agonists and antagonists, and the effects of PMMA and PMA in knock-out mouse models. The activation of 5-HT1B receptors, which probably mediate the actions of low doses of PMMA, causes hypophagia, hypothermia, penile erection, increased release of corticosterone and prolactin. 5-HT1B receptor agonists have an anti-aggressive action and induce myoclonic jerks. The activation of 5-HT2A receptors, which probably mediate the action of medium and high doses of PMMA, causes motor activity, hyperthermia, head twitches (in mice), wet dog shakes (in rats), discriminate DOM (a hallucinogen, from 5-TH1-R agonists) hallucinations, and elevation of cortisol, ACTH, renin, and prolactin. The activation of 5-HT2C receptors, which probably also mediate the actions of medium and high doses of PMMA, causes hypolocomotion, hypophagia, anxiety, hyperthermia, penile erection, tonic inhibition of dopaminergic mesolimbic/mesocortical neurones, inhibition of noradrenaline release, and hallucinations.

When evaluating the in vitro and in vivo actions of PMMA, pharmacokinetic aspects should always be considered (see section below). PMA is a weak central stimulant (ED50=9.5 μmol/kg) compared with amphetamine (ED50=1.8 μmol/kg) and methamphetamine (ED50=1.5 μmol/kg) (Young and Glennon, 1986).

In comparative studies, 5.28 mg/kg PMA caused no change in striatal levels of dopamine whereas metabolites were lowered, suggesting inhibition of MAO (Hegadoren et al., 1995). Levels of noradrenaline were elevated in the hippocampus, striatum, and cortex. Equimolar doses of amphetamine, MDMA, MDA, and MDE were inactive, supporting the idea that PMA, and probably PMMA, have a different molecular action. The levels of 5-HT were slightly elevated whereas those of the metabolite 5-HIAA were lowered (Hegadoren et al., 1995).

This finding is again consistent with a strong inhibition of MAO-A by PMA. The high intrinsic potency of PMA against 5-HT oxidation by MAO-A was demonstrated in mice under in vivo conditions (Green and ait., 1980). The authors estimated that 0.5 mg/kg PMA inhibited 50 % of enzyme activity. This dose is only about one quarter of the equipotent dose of the irreversible MAO-A inhibitor, phenelzine. Whereas inhibition by phenelzine persists for several days, the high level of inhibition by PMA is maintained only for a short time, and the extent of inhibition declines rapidly after one hour.

A recent report compared the in vivo effects of PMA and MDMA on serotonergic and dopaminergic neurones (Daws et al., 2000). In vivo chronoamperometry was used to measure the effects of PMA and MDMA in anaesthetised rats. MDMA induced the release of dopamine and inhibited uptake of both dopamine and 5-HT. In contrast, PMA was a relatively weak releasing agent and did not inhibit dopamine uptake. However, PMA potently inhibited uptake of 5-HT. It can be concluded from these findings that the acute effects of PMA (and probably PMMA) are more likely to be associated with alterations in serotonergic rather than dopaminergic neurotransmission.

Effects on the cardiovascular system: PMMA produces cardiovascular and other sympathomimetic effects by what is believed to be an indirect mechanism (Cession-Fossion et al., 1966). A 0.2 mg/kg dose showed prolonged cardiovascular effects in the dog (Cheng et al., 1974).

The cardiovascular effects of PMA have been investigated in conscious rats, by radiotelemetry. The effects of PMA were compared with those of MDMA. The influence of ambient temperature on these responses was also investigated (Irvine et al., 2001). In contrast to MDMA, which releases both dopamine and 5-HT, PMA appeared to be more selective in releasing only 5-HT, not dopamine or noradrenaline. This may account for their markedly different cardiovascular profiles. PMA (10, 15, and 20 mg/kg) lowered, rather than increased, heart rate. The bradycardia produced by PMA was of considerable magnitude and was sustained at 20 °C ambient temperature but not at 30 °C. MDMA produced a minor increase in heart rate, which was only evident at the lowest dose. Furthermore, bradycardia after PMA administration was not a result of increased BP. PMA and MDMA (10 and 20 mg/kg) decreased both systolic and diastolic BP. This effect was sustained for PMA, whereas in MDMA-treated animals the BP returned to normal at about 45 minutes. At 30 °C, systolic and diastolic BPs were significantly increased for both drugs at 10 and 20 mg/kg.

The effects of PMMA and PMA on respiratory, gastrointestinal, and genito-urinary systems, as well as on liver and kidneys, have not been investigated.

Behavioural studies: In order to determine the physiological nature of a given compound (entactogenic, hallucinogenic, soporific, etc.) without exposing human subjects to unknown consequences, drug discrimination studies are often used. Briefly, drug discrimination studies are conducted by training test animals to differentiate the effect(s) of a ‘training’ drug from those of a saline (control, vehicle) solution. When the test animal can reliably differentiate or discriminate the training drug from a saline solution, they may then determine if the effects of a new compound mirror the effects of the training drug. If the animals’ response to the new drug correlates with their response to the training drug, the tested compound is said to ‘generalise’ (resemble) the training drug (Dal Cason, 2001).

Unexpectedly, PMMA has previously been shown to lack amphetamine-like or hallucinogen-like stimulus properties in animals in drug discrimination studies. For example, in tests of stimulus generalisation, neither a (+)amphetamine stimulus nor a DOM stimulus generalised to PMMA. Similarly, it has been shown that stimulus generalisations do not occur in animals trained to discriminate MDMA from vehicle. In order to further characterise this unique agent, six rats were trained to discriminate 1.25 mg/kg of PMMA (ED50=0.44 mg/kg) from saline vehicle. The PMMA stimulus failed to generalise to (+)amphetamine or the hallucinogen DOM. Stimulus generalisation occurred to (±) MDMA (ED50=1.32 mg/kg) and S(+)MDMA (ED50=0.48 mg/kg). Partial generalisation occurred with R(-)MDMA, PMA, 3,4 DMA and fenfluramine. The PMMA stimulus also generalised to the
-ethyl homologue of PMMA (ED50=1.29 mg/kg). Taken together, these findings suggest that PMMA is an MDMA-like agent that lacks the amphetamine-like stimulant character of MDMA (Glennon et al., 1997).

Researchers have investigated whether the stimulant effects in drug discrimination experiments are stereoselective (Young et al., 1999). S(+)PMMA (ED50=0.32 mg/kg) was found to be at least as potent as racemic PMMA (ED50=0.41 mg/kg), whereas R(-)PMMA failed to result in complete stimulus generalisation. The results support the concept that PMMA and MDMA share considerable similarity with respect to their stimulant properties in animals except that PMMA lacks the amphetaminergic stimulant component of action associated with MDMA. These findings suggest that the S(+) enantiomer of PMMA is the active compound.

Based on the Sidman avoidance schedule and the Bovet-Gatti profiles, Smythies and colleagues have developed an animal test which predicts the hallucinogenic effect of a drug on man (1967). The authors reported that PMA proved the most potent hallucinogen they have so far tested (with the exception of LSD). This statement is based on findings in only two rats. At a dose of 3.1 mg/kg, it produced a typical ‘low dose hallucinogenic’ Bovet-Gatti profile quite distinct from amphetamine. Doses of 6.2 mg/kg PMA induced bizarre behaviour in both rats tested. Although the rat could walk about normally, and appeared to be able to eat and drink normally, it frequently walked backwards — a typical mescaline effect. It would show exaggerated startled responses in the absence of external stimuli and would frequently engage in strange behaviour reminiscent of shadow boxing — rearing and pawing in the air. If placed on a table, it would walk, apparently normally, towards the edge and fall off, and would do this repeatedly if replaced on the table. This period of abnormal behaviour lasted until the rat died (after one day and one week, respectively; Smythies et al., 1967). This report had a strong impact on the drugs ‘scene’ in the 1970s. It contributed greatly to the abuse of PMA.

With respect to the locomotor stimulating effect of PMA in rats, a comparative study investigated equimolar effects of five amphetamines (32 μmol/kg). PMA did not differ from vehicle (Hegadoren et al., 1995). MDMA (10 and 20 μg/kg) increased locomotor activity in rats in contrast to PMA (10 μg/kg) which was without effect (Irvine et al., 2001).

Pharmacokinetics in animals

There are no published reports on the pharmacokinetics of PMMA in animals. There is one report that compares equimolar doses of five amphetamines in rats 3h post-injection. The level of PMA in the brain was about six times lower than that of amphetamine and 10 times lower than that of MDMA (Figure 7; Hegadoren et al., 1995). These findings suggest a poor penetration of PMA into the brain. Because MDA levels were approximately 50 % higher than those of MDMA, PMMA might penetrate the bloodbrain barrier to a lesser extent.

Becket and Midha (1974) have examined the metabolism of PMA by liver preparations of rabbit, guinea pig, and rat. Four side-chain oxidation products, the N-hydroxy derivative, oxime, phenyl-2-propanone, and phenyl-2-propanol were characterised. Further findings are reported under in vitro studies (see above). O-demethylation is the major metabolic reaction of the drug in the rat, dog, and monkey.

Human pharmacology

Laboratory studies in volunteers

Effects on cognition and behaviour

PMMA: There is a report of PMMA use by Shulgin (Shulgin and Shulgin 1991) in which he took 110 mg PMMA. He states:

I was compulsively yawning. There was some eye muscle disturbance, a little like the physical side of MDMA, but there was none of its central effects. But all the hints of the cardiovascular (effects) are there. By the fourth hour, I am pretty much back to baseline, but the yawning is still very much part of it. I might repeat this, at the same level, but with continuous close monitoring of the body.’ Later he wrote I tried it and I didn’t like it.

Shulgin commented in the same report:

N-methylhomologues of primary amines maintain the stimulant component, but the ‘psychedelic’ contribution is generally much reduced. And as PMA is a pretty pushy stimulant with little if any sensory sparkle, why bother with the N-methyl compound?

The report by Shulgin of no stimulatory activity with PMMA, in contrast to a weak stimulatory action with PMA, agrees well with observations in animals. There might be pharmacokinetic reasons for the lack of central effects with this specific dose of PMMA. Although there are no specific investigations, the distinct cardiovascular effects which are caused by peripheral activation of 5-HT mechanisms (Irvine et al., 2001) support this notion. Further human experiences with PMMA are reported below.

PMA: PMA was ingested by five normal subjects in a dose range of 10–65 mg (PMA HCl). No psychotic or other behavioural changes were reported (Schweitzer et al., 1971). However,

With 60 mg, I found the effects reminiscent of DET (N,N-diethyltryptamine), distinct after-images, and some paraesthesia. I was without any residue after 5 hours.

Shulgin (1978) observed,

With 70 mg it hit quite suddenly. I had a feeling of druggedness, almost an alcohol-like intoxication, and I never was high in the psychedelic sense.

He also reported that,

A major metabolite of amphetamine is 4-hydroxyamphetamine. It has been long known that with chronic amphetamine usage there is the generation of tolerance. When the daily load gets up around one or two hundred milligrams, the subject can become quite psychotic. The question was asked: might the chronic amphetamine user be methylating his endogenously produced 4-hydroxyamphetamine to produce PMA, and maybe this is the agent that promotes the psychosis? To address this question, several studies were done with normal
subjects, about 20 years ago, to see if 4-MA might produce a psychotic state. It produced excitation and other central effects, it produced adrenergic pressure effects, and it consistently produced measurable quantities of 4-MA in the urine, but it produced no amphetamine-like crazies (dose range 10–75 mg PMA). And since the administration of up to 629 mg of amphetamine over a period of 51 h (5–10 mg/h) produced no detectable PMA in the urine, this theory of psychotomimesis is not valid (Angrist et al., 1969) (Shulgin, 1978).

From these studies, Shulgin (1978) concluded that PMA is a treacherous drug to study in human subjects. The compound has an unusually steep dose-response curve in man. At dosages of 40 mg or less, it is without either peripheral or central effects. Yet at dosages of 60–80 mg, the effective dose for induction of a psychotomimetic syndrome (Shulgin et al., 1969), there have been incidents of precipitous hypertension and cardiovascular stimulation (Angrist, personal communication). The psychotomimetic state occurs quite suddenly about an hour after ingestion of the drug, and a plateau of central intoxication occurs within the second hour (Shulgin, 1978).

The report of Shulgin et al. (1969) has been quoted in connection with the psychotomimetic effect of PMA. Mescaline was selected as the initial compound for this study. Although it is less active than most psychotomimetics, it has a close structural relationship to compounds known to be naturally present in humans. No psychotic symptoms were observed in this study. In contrast to what was reported by Smythies and co-workers for rats (1967), PMA was a weak psychotomimetic in humans (5 mescaline units compared with LSD’s 4 600 mescaline units in humans). The three-carbon side chain seems to provide optimal activity. This is presumably because such molecules are poor substrates for MAO, the enzyme which deaminates alpha-unsubstituted phenethylamine.

Cardiovascular effects

PMMA: One hour after taking 110 mg PMMA orally, Shulgin (Shulgin and Shulgin, 1991) reported that his pulse was over 100 beats/minute. All indications of the cardiovascular effects of MDMA were there.

PMMA: The somatic effects can persist for over two hours, together with BP elevation. Paraesthesia can still be observed four hours after administration (Shulgin, 1978).

With 60 mg at just over an hour, there was a sudden blood pressure rise, with the systolic going up 55 mm. This was maintained for another hour (Shulgin, 1978).

The delay in the cardiovascular effects cannot be explained. As already discussed, the cardiovascular effects of medium doses of PMA are caused by activation of peripheral serotonergic mechanisms.

Effects of overdose

Blood concentrations of PMA greater than 0.5 mg/l seemed likely to be associated with toxic effects. Post mortem PMA concentrations were 0.24 to 4.9 mg/l (mean 2.3 mg/l) for femoral blood and 1.4 to 21 mg/kg (mean 8.9 mg/kg) for liver.

Pharmacokinetics in humans

There are no pharmacokinetic reports of human use of PMMA in the literature. From studies on PMA, it can be concluded that demethylation of the 4-methoxygroup is the major metabolic inactivation step. Oxidation of the side chain probably occurs slowly because MAO-A, the enzyme involved, oxidises phenylpropylamines much more slowly than phenylethylamines, despite the high affinity of PMA (and probably PMMA) for the enzyme.

PMMA is demethylated in the liver by the cytochrome P450 2D6 isoenzyme (see in vitro studies and PMA for details). Repeated intake of PMMA might cause inhibition of the isoenzyme due to a so-called mechanism-based inhibition (see below for details).

Three adult male volunteers of known oxidation phenotype (2 extensive oxidisers, 1 poor oxidiser) each took a single oral dose of 5 mg of 4-methoxy [14C] amphetamine (a form of PMA). Urine was collected over 24 hours. 82.6, 76.8, and 49.0 % of the ingested radioactivity was detected in the urine of each of the volunteers, respectively. PMA is metabolised by O-demethylation and by side-chain oxidation. Marked intersubject variations were observed. The 2 extensive oxidisers excreted mainly 4-hydroxyamphetamine (63 and 49 %, respectively) together with smaller amounts of 1-(4‘-methoxyphenyl) propan 2-one oxime (4.5 and 5.5 %, respectively) and 4-hydroxynorephedrine (6.1 and 4.6 %). The poor oxidiser excreted unchanged PMA (28 %) together with products of side chain oxidation, namely 1-(4‘methoxyphenyl) propan-2-one oxime (9.9 %), 1-(4‘-methoxyphenyl)propan-2-one (1 %) and 4-methoxybenzoic acid (0–2 %). About 9 % of caucasians are characterised by this oxidation defect, which is genetically determined and inherited as a recessive trait. The authors speculated that individuals who carry the defective oxidative trait could be poor demethylators and therefore de-activators of O-methylated psychotoxins (Kitchen et al., 1979).

Phenylisopropylamines interact with the cytochrome isoenzyme CYP 2D6 as substrates and/or inhibitors. The apparent Ki-values of PMA (24 μM), (+)methamphetamine (25 μM) and (+)amphetamine (26.5 μM) were equal. PMMA was not investigated
(Wu et al., 1997).

Repeated intakes of PMMA and PMA might cause inhibition of the isoenzyme due to a so-called mechanism-based inactivation. This has been demonstrated in rats with a model compound, allyloxymethamphetamine. The aromatic ring oxidation seems to be a prerequisite for the inhibition (Lin et al., 1996). Both PMA and PMMA fulfil this criterion. The relevance of the inactive CYP 2D6 isoenzyme for the reduced metabolism of amphetamines has been demonstrated in vivo in the Dark Agouti model. Female rats metabolise substrates of the isoenzyme more slowly (Colado et al., 1995). The hyperthermic response following MDMA was enhanced, and the plasma concentrations were 57 % higher than in controls. The hyperthermic response was higher in rats pre-treated with a substance which competes selectively for the isoenzyme (quinine) suggesting that other substrates of the isoenzyme reduce the inactivation of the amphetamines if combined (see below).

Excretion

In man, PMA is extensively metabolised, since the average excretion of PMA was 6.7 % of the administered dose with a range of 0.3 to 15 % (Schweitzer et al., 1971). After oral ingestion of PMA, about 80 % of the dose is excreted in the urine within 24 hours with more than 15 % unchanged, 18 to 25 % free 4-hydroxyamphetamine and 50 % conjugated (containing 21 % 4-hydroxy-amphetamine and 7 % N-hydroxy-PMA), and 5 % 4-hydroxynorephedrine (EMCDDA, 2001a).

No calculation of the elimination half-life of PMMA and PMA has been reported.

Pharmacokinetic interactions
The use of PMMA and PMA may cause metabolic interactions with other drugs that are CYP 2D6 substrates and the potential for polymorphic oxidation via CYP 2D6 may be a source of interindividual variation in their abuse liability and toxicity. Interacting medical drugs would be: inhibitors of the neuronal transport mechanism of serotonin (e.g. fluoxetine), tricyclic antidepressants (e.g. imipramine), b-adrenoceptor blockers (e.g. metoprolol), deprenyl (N-propargyl methamphetamine), inhibitors of MAO-B; and methoxymorphinans.

The interaction with fluoxetine might be of special importance because some MDMA users take fluoxetine to prevent neurotoxic damage. Fluoxetine has been detected in the urine samples of some PMA/PMMA users.

Clinical experience

Studies of street users (Table 5)

In the early 1970s, the illicit use of PMA was first identified in the USA and Canada.

Canada

Between March and August 1973, there were nine deaths of young people in Ontario that were attributed to PMA (Cimbura, 1974).

PMA was the only chemical toxin found in significant amounts. Low levels of alcohol were present in four cases and, in one case, traces of MDA were found in the bile and urine but none were detected in the blood.

These deaths indicate that PMA is more toxic than MDA. This is supported by the fact that the range of PMA concentrations found in the blood of the victims was considerably lower than that of MDA.

USA

With respect to fatalities in the USA in the early 1970s, Shulgin et al. (1991) reported that PMA became widely distributed in the USA as the sulphate salt and in Canada as the hydrochloride. This usage was perhaps inspired by some studies in rats which reported that PMA was second only to LSD in potency as a hallucinogen (Smythies et al., 1967). Several deaths occurred, probably following overdose. It was clear that PMA was involved as it was isolated from both urine and tissue during post mortem.

Comments collected in association with 10 deaths implied that the quantities ingested were of the order of hundreds of milligrams.

The causes of the deaths are not clear. Common symptoms were hyperthermia (~42 °C), possibly dehydration, and cardiac problems (e.g. BP 180/130 mmHg, pulse 140 beats/min). It is noteworthy that chronic dosing of MDMA produced sensitisation to both hyperthermic and hyperkinetic responses in rats. Furthermore, high ambient temperature and water deprivation augmented the hyperthermia (Dafters, 1995). These findings suggest that individuals who regularly use ‘ecstasy’ have a higher risk of developing hyperthermia. Whether there is a cross-sensitivity with PMMA is not known.

Other reasons might be metabolic defects and mechanism-based inactivation of CYP 2D6 isoenzyme, which might cause delayed inactivation of PMMA.

Australia

PMA has only been available in Australia since late 1994. Between June 1996 and January 1997, there was a sudden increase in the number of patients in Adelaide suffering from amphetamine toxicity. Among a total of 16 admissions, 14 patients were found to have PMA in their urine.

Since 1995, 10 PMA deaths have been reported in Australia. Behaviours that were observed before death were ‘thrashing around’, extreme agitation, convulsions, jaw rigidity and sweating. Features of rhabdomyolysis and renal failure were found at autopsy, including disseminated intravascular coagulation and hyperkalaemia in several cases. The authors (Felgate et al., 1998; Byard et al., 1998) commented that MDMA was of significance in two of the cases and amphetamine and methamphetamine in one case each; the significant factor in each case was the toxic effects of PMA. PMA would appear to be more toxic than other common amphetamine derivatives. All the PMA-related deaths involved oral administration.

The PMA levels were considerably lower in the Canadian deaths (Cimbura, 1974), being in the range of 0.3–1.9 mg/l for the blood samples.

Spain

A paper was published that compiled the toxicology data from all the fatalities investigated from 1993 to 1995 by the Instituto Nacional de Toxicologia in Madrid, in which at least one amphetamine derivative was found in the blood (Lora-Tamayo et al., 1997). In 1995, one case had high PMA levels in the blood (5.7 mg/l). Other amphetamines detected were p-OHAMP and a metabolite of PMA (0.35 mg/l); no other amphetamines, MDMA, MDEA, or MDA were found. A second case found PMMA (1.15 mg/l) and 2.00 mg/l MDEA, 0.3 mg/ml MDM and ethanol (0.2 g/l) in the blood. The authors commented that, ‘the meaningful interpretation of the contribution of the amphetamine derivative to the death in those cases is problematic.’

Austria

The Austrian Reitox national focal point reported on the death of a 17-year-old man in July 2000. Forensic analysis confirmed that PMA and PMMA were involved in this death. The concentrations found in the blood were 1 mg PMA/l and 0.4 mg PMMA/l.

Denmark

The Danish Reitox national focal point notified three deaths associated with PMA/PMMA which occurred between July and September 2000. It was concluded from forensic analysis that two deaths at the beginning of July were caused by PMA and PMMA poisoning. In the first case, the poisoning was caused by PMA and PMMA as well as MDMA, whereas the second and third case were caused by poisoning with PMA and PMMA alone.

Germany

Europol reported that PMA was implicated in two deaths in 2000.

Belgium

The Belgian Reitox national focal point reported on the following fatal cases: the first death in which PMA was involved occurred in February 2001. Forensic analysis of a blood sample revealed MDA (0.39 mg/ml), amphetamine (0.22 mg/ml) and PMA (1.43 mg/ml). The report concluded that the subject died due to the effects of a cocktail of several amphetamines.

According to his friends, a young man from the region of Leuven used ‘ecstasy’ regularly and had ingested seven tablets on the evening of his death (July, 2001). The analysis of the blood revealed MDMA, MDA, amphetamine and PMA. Traces of cannabis, codeine (possibly due to medical treatment with Dafalgan codeine), and alcohol were detected as well.

Two deaths were reported from the region of Antwerp in July 2001. Analysis of the blood samples yielded PMA (1.7 mg/ml blood) and traces of norephedrine in the first case, and PMA (3.4 mg/ml blood), and MDMA (0.4 mg/ml blood) in the second case.

Potential for dependence in humans

• Users are misled by the logo which suggests to them that the tablet contains MDMA.

• Reports of drug-experienced users of PMMA and the findings from animal studies suggest a low risk for PMMA dependence. The users of PMMA reported mental stimulation after the intake of high doses (e.g. 215 mg PMMA). Other pleasant effects encountered with MDMA were not reported (i.e. euphoria, a general sense of well-being, emotional warmth, and closeness and empathy for others). In contrast to the effects of MDMA, the users reported reduced motivation to talk and to get involved with others. They suffered from unwanted physical effects such as transpiration, severe nystagmus, body stiffness, and pain in the stomach and head. They did not feel out of control.

• The results of animal experiments suggest that PMMA does not activate mesolimbic/mesocortical dopaminergic neurones, a prerequisite for the induction of drug seeking behaviour in animals. There is evidence for a reduction of the activity of dopaminergic neurones in vivo (catalepsy in cats and rats).

Clinical safety

Based on experience with MDMA, a major concern with PMA and PMMA is the neurotoxic potential. An interesting hypothesis for the possible mechanisms of MDMA neurotoxicity is the formation of thioether adducts. One of the hydroxyl groups of dihydroxymethamphetamine, the main metabolite of MDMA, reacts with the SH group of either glutathione or cysteine. The main metabolite of PMA is 4-hydroxyamphetamine. Demethylation of the 4-methoxygroup is probably the major inactivation step for PMMA metabolism as well. When such amphetamine adducts are administered to the striatum or cortex, they are able to reduce serotonin concentrations, to produce longterm depletion (seven days), and to induce neurodegeneration of serotonergic neurones similar to that observed after systemic MDMA administration (Bai et al., 1999; Miller et al., 1996 and 1997).

Most of the psychotropic actions of MDMA, such as euphoria, emotional warmth, empathy for others, mental stimulation and a general sense of well-being are not reported with PMA and PMMA. The user expecting these effects probably assumes that the dose is too low and takes more tablets. The therapeutic index of PMMA and PMA is much lower than that of MDMA and reaches toxic doses almost within the range at which psychotropic effects occur. PMMA is less effective than PMA. Animal experiments suggest that PMMA is less toxic than PMA (see Table 4). The reason for both observations might be that PMMA penetrates the blood-brain barrier less easily than PMA. The acute toxicity of PMA and PMMA is caused by the increased extraneuronal serotonin due to exchange diffusion and the inhibition of MAO-A which prevents the breakdown of serotonin. A hyperthermia-rhabdomyolysis syndrome then develops (Table 6). The hyperthermia reported in PMA fatalities was in the range of 42–46.1°C. The body temperature in volunteers taking MDMA in a dose range of 18–125 mg/70 kg changed by –0.17 to 0.65 °C (de la Torre et al., 2001). The hyperthermia may cause a perturbation of the cellular metabolism of calcium and cyclic AMP within the muscle fibres. In the case of a mitochondrial myopathy, the risk to develop hyperthermia increases (Larner, 1993). This has been concluded from clinical experience which shows that intoxication with MDMA and MDA can be treated with dantrolene.

Psychological risk assessment

Acute effects — effects on cognitive functioning

There is a report on the Internet, dated 26 July 2000, of individual subjects ingesting certain amounts of PMMA (). While these are not scientifically controlled human trials, they are of certain evidential value. There are no other reports on the psychological effects of PMMA, besides the report of Shulgin and Shulgin (1991). The individual experiences described on the Internet are reported below.

Subject 1 (dose undefined): The subject was a female who suffered from insomnia, ’head noise’ and temperature control problems.

Subject 2: The subject described the dehydrating actions of PMMA, which could affect his neuropsycholological status. A further point to consider is the anorectic action of the amphetamines. The subsequent poor nutrition, with diminished absorption of vitamins, would affect the actions of any drug. The subject concluded from his own experience that the symptoms described by others in the Internet report ‘are actually caused by the malnutrition and dehydration that one puts their (sic.) bodies through during these extended periods of heavy use, and not so much (by) the drug’.

The subject found that if he avoided poor nutrition and hydration, he did not get any of the unpleasant side effects (e.g. nystagmus, stiffness of the body, cardiovascular stimulation, lack of sleep). He adds, ‘One other thing, if you start noticing some of the edginess or any of the jumpiness, pop a xanax, not a lot, about 0.25–0.50 usually does the trick. Within 20 minutes everything is just fine.’

Subject 3 (initial dose 50 mg): The subject describes the following experiences after a trial ingestion: after 15 to 45 minutes he experienced a ‘mildly speedy onrush, similar giddiness experienced when dosed with LSD mildly.’ After 1 to 1.5 hours he reported ‘some rolling of the eyes … stimulated and yet relaxed to the point of not really wanting to do much but chill.’ At two hours he took 50 mg more PMMA and reported, ‘eye rolling increased and the desire to remain inactive increased.’ At four hours, sleep occurred automatically. On awakening, he wondered how and when he had got into bed.

In a second trial, this subject took 90 mg PMMA, with other people around for stimulation. He reported:

• Strange audiostimulation in which it seemed that sounds were all emanating from within his own head.

• The intent behind the words seemed more clear.

• He grew tired of idle, insignificant conversations and went to bed.

In a third trial, he ingested 110 mg PMMA. The initial stimulation lasted about one hour, turning into a ’who needs to work’ attitude which was fairly persistent. He noticed his skin crawled with strange cold tingling sensations which were rather pleasant. His mental ‘wheels’ turned very slowly. He experienced no anxiety whatsoever, and felt ‘almost too calm’.

He concludes, ‘at the <50 mg level, PMMA serves as a nice stimulant similar to ginseng. It also seems to blur out emotional turmoil. Motivation seems a bit diminished. In comparison with MDMA, PMMA seems to lack the super rush of MDMA in the initial onset. The feeling of being out of control and at the mercy of the drug was not present. The down time is nowhere near that of MDMA.’

Subject 4 (215 mg dose): This subject reports ‘After 45 min I returned to rolling, hard. My jaw went into total lockdown and my eyes began to cross, weird as hell. Euphoria was there. The experience was very similar to MDMA. (Six hours later) I am in a stupor.’

The next day he took the same dose with the same experience. The day after he was a little disoriented. He found himself much more introspective and emotional than for previous post-dosage days (e.g. crying for very little reason). He also noticed a jumpiness of a reflex-type nature.

He considered that PMMA was active in a psychedelic way at these dosages. An amphetamine component was not really present. It was very difficult on the body as recovery was very slow.

Subject 5: This subject observed that the dose response curve for PMMA can, in some subjects, be very steep. At 100 mg, the subject experienced very mild, relaxing, euphoric effects that were physically pleasant. But when 150 mg was ingested some weeks later, there were severe physical ill effects. The acute effects were transpiration, tremor, severe nystagmus, the subject’s body became very stiff, and his head and stomach hurt badly. There was no anxiety and the pulse did not rise. The head and neck turned very red. The jaw felt locked but there was no clenching as with MDMA.There was a great pressure over the chest and some nausea. After two hours, the physical terror had begun to decline. The subject reported of PMMA that ‘it is not psychedelic.’

Shulgin and Shulgin (1991) reported that, after an oral dose of 110 mg, there was none of the central effects of MDMA. He comments, ‘The active components are primary amines and the N-methyl homologues might have, in general, the stimulant component maintained, but the psychedelic contribution is generally much reduced. MDMA is, of course, an exception.’

The psychological effects of PMA have been described by Shulgin as follows: ‘I found the effects of 60 mg reminiscent of N,N-diethyltryptamine, distinct after-images, and some paraesthesia. I was without any residue after five hours. With 70 mg it hit suddenly. I had a feeling of druggedness (sic.), almost an alcohol-like intoxication, and I never was really high in a psychedelic sense.’

Shulgin wrote that, in human trials conducted 20 years ago in which the mechanism of the psychosis-inducing action of dexamphetamine was explored, PMA did not produce a psychotic state at the highest dose used (75 mg). He added, ‘PMA produced excitation and other central effects, it produced adrenergic pressor effects, and it consistently produced measurable quantities of PMA in the urine, but no amphetamine-like crazies.’

There are no other reports available concerning the psychological risk assessment of PMMA.

(14) This report was written by Prof. Dr Hans Rommelspacher of the Free University of Berlin, Germany.

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