PMMA

Para-methoxymethamphetamine (PMMA) is a synthetic amphetamine derivative related to MDMA and PMA. It has a methoxy group at the para position of the phenyl ring and a methyl group attached to the nitrogen. PMMA has often been sold as ecstasy or mixed into tablets marketed as MDMA. Its effects develop more slowly than those of MDMA, while its toxicity can be severe, with documented cases of serotonin syndrome, hyperthermia, multiorgan failure and death.

Chemistry and history

PMMA is the N-methyl analogue of PMA. It is structurally related to methamphetamine, but carries a methoxy group at the para position of the aromatic ring. PMA is also formed as a metabolite of PMMA.

PMMA appeared on illicit markets in the 1980s, initially as a powder and later in tablets sold as ecstasy. Its presence in counterfeit products has been associated with outbreaks of severe poisoning, particularly in Europe and Canada. The WHO reviewed PMMA because of its public-health risks and lack of recognised therapeutic use (WHO critical review of PMMA, 2015).

Pharmacology

PMMA acts mainly on the serotonergic system. Animal studies indicate that it promotes serotonin release more strongly than dopamine or norepinephrine release. It can produce MDMA-like effects in drug-discrimination tests, but its stimulant effects are weaker and slower to emerge. PMMA has also been proposed to inhibit monoamine oxidase A (MAO-A), although the contribution of this mechanism to human toxicity is not fully established.

The WHO review noted that PMMA’s slow onset can encourage repeated intake when users mistake the delay for a weak or inactive product. This pattern has been reported in fatal intoxications and is an important difference from the faster subjective onset commonly associated with MDMA.

Reported effects

At lower levels of exposure, PMMA may produce stimulant and MDMA-like subjective effects, including increased energy and euphoria. These effects can be delayed and may be less pronounced than expected. The absence of a strong early effect does not mean that the substance has not been absorbed.

Physical and neurological effects

Severe intoxication has involved hyperthermia, tachycardia, sweating, tremor, seizures, breathing difficulties and cardiovascular collapse. Serotonin syndrome is a recurring feature in clinical reports. Severe cases may also involve rhabdomyolysis, acute kidney injury, liver injury, coagulopathy and shock.

Clinical toxicity

A Canadian case series documented 27 PMMA-associated deaths over an 11-month period. Sixteen of the 17 patients who died in hospital showed clinical features consistent with serotonin syndrome. Multiorgan dysfunction was common, including acute kidney injury, rhabdomyolysis, liver injury and cardiac ischaemia. Other drugs were detected in all cases, so the findings reflect complex exposures, but PMMA was considered a principal toxic agent (Deaths from PMMA exposure in Alberta and British Columbia, 2015).

Earlier Danish forensic work described three fatal cases involving PMA and PMMA, including deaths after consumption of tablets sold as ecstasy (Three fatal cases of PMA and PMMA poisoning, 2003).

Related compounds

PMMA is related to PMA, its N-desmethyl analogue, and to MDMA. PMA is an active metabolite of PMMA, so both compounds may be found in biological samples after PMMA exposure.