Please review the presentation and treatment of patients who have used
MPTP-contaminated designer drugs.
DESIGNER DRUGS are analogs of known pharmacological agents, synthesized
by underground chemists, for sale on the street.
The concept of designer drugs is to manipulate the chemical structure of
a narcotic, for example, and create a totally new compound. The
"underground" chemist has two goals. First, is the belief that the
nature and duration of the "high"
experienced can be changed through chemical manipulations. Although the
science of medicinal chemistry involves predictions of structure-activity
relationships regarding psychodynamic effects, associated toxicities are
Second, since there are no laws against newly formulated compounds, legal
ramifications are bypassed. Fortunately, emergency laws have been
implemented against such agents and new regulations are being processed
(Baum, 1985). This consult includes a brief overview of designer drugs and a
discussion of DESIGNER MEPERIDINE, proposed mechanisms of its toxicities and
some treatment possibilities.
There are at least three popular types of designer drugs: MDMA
(3,4-METHYLENEDIOXYMETHAMPHETAMINE), FENTANYL ANALOGS, and MEPERIDINE
ANALOGS. MDMA is not a true designer drug, as this agent is a schedule I
agent that was once used in psychiatry. Street names for MDMA include: MDA,
ADAM, ECSTASY and XTC. MDMA interacts with serotonergic neurons. MDMA
produces effects that are similar to those of LSD without hallucinatory
properties. These include increased self-awareness and decreased
communication barriers. Side effects consist of increased heart rate and
blood pressure, irregular heart beat, panic attacks, anxiety, sleep
disorders, drug craving, paranoia, and rebound depression.
Fentanyl analogs include the following: alpha-methyl-p-fluoro-3-methyl
and alpha-methyl-acetylfentanyl. In 1979 the alpha-methyl analog was found
in users of "CHINA WHITE". The effects of these compounds are
similar to heroin in terms of the nature of the "high" and its
duration of action. However, these analogs can be up to 40 times more potent
than heroin. This potency makes overdose a serious risk. The drug-induced
respiratory depression can be fatal (Baum, 1985). Adverse Drug Reactions of
Designer Meperidine Designer meperidine is sold as SYNTHETIC HEROIN. The
primary street analog of meperidine is MPPP
(1-methyl-4-phenyl-4-propionpiperidine). Very specific chemical reaction
conditions are required to produce MPPP. In the event of sloppy synthesis,
where the pH is too low or the temperature is too high, a contaminant, MPTP
(1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine) is formed. MPTP is a known
industrial toxin which affects the dopaminergic neurons of the substantia
nigra. Cases of PARKINSON'S DISEASE caused by MPTP have been reported (Baum,
The proposed biochemical mechanism of action of MPTP involves the rapid
oxidation of MPTP to MPP+ after systemic administration. This conversion
takes place in all tissues studied (brain and systemic), except for the eye,
and is necessary for MPTP to exert its toxic effects (Irwin & Langston,
1985). Monoamine oxidase catalyzes this reaction. Highly reactive
intermediates may also be formed in the conversion. MPP+ is then taken up by
neurons in the substantia nigra where it destroys dopaminergic neurons in
this area. Although the formation of MPP+ occurs in many parts of the brain,
it remains unclear as to why it selectively accumulates in the substantia
nigra and not in other dopaminergic areas of the brain such as the striatum
(Langston, 1985). These biochemical mechanisms are undergoing further
MPTP exposure is suspected if the patient answers "yes" to the
following questions on initial presentation: 1. Did the pure form of the
drug resemble brown sugar? 2. Was there a burning sensation on intravenous
injection at the injection site and up through the vein? 3. Was the
"high" more "spacey and giddy" than that of heroin?
These questions can help identify MPTP exposures (Latimer, 1985). Other
symptoms of MPTP toxicity are discussed below.
Three phases of MPTP toxicity have been identified (Langston, 1985a). The
first is an acute phase which occurs on initial exposure to MPTP. Symptoms
include disorientation, hallucinations, blurred vision, "nodding
off" (a slow downward drifting of the head, and drooping and closure of
the eyelids), difficulties in speech and swallowing, intermittent jerking of
the limbs, slow movement, and tremor at rest. The second phase is a subacute
event which occurs after exposure to the drug.
Two to three days post-exposure there are reports of increased
bradykinesia and rigidity of extremities, abrupt onset of "freezing
up" and inability to move. Up to three weeks after exposure, awkward
posture, progressive slowness of movement and "freezing up" have
been reported. Finally, if there is no recovery from the above two phases, a
chronic syndrome results.
A permanent Parkinsonian syndrome evolves consisting of classical
Parkinsonian symptoms such as bradykinesia, rigidity, resting tremor, fixed
stare, and loss of postural reflexes. Recovery from the acute or subacute
phase may occur, but it is unlikely once the chronic phase has been reached.
Several mechanisms have been proposed to explain the manifestations of
each of the three phases. Possible mechanisms regarding the acute phase
include an opiate receptor interaction with MPTP, serotonergic effects of
the substance, and a slight dopaminergic deficiency caused by MPTP. Because
MPTP is a meperidine analog, an opiate receptor interaction is probably
responsible for the "nodding off" which takes place. This
phenomenon is typical of exposure to heroin and is due to the same type of
opiate receptor interaction. An initial suppression of serotonin in the
central nervous system by MPTP is the suggested cause for the hallucinations
and retropulsions which occur (Ballard et al, 1985). Motor symptoms are
attributed to MPTP's effect on the dopaminergic neurons in the substantia
nigra, but the dopamine deficiency is not yet substantial.
The subacute phase is thought to occur once MPTP accumulation reaches a
critical threshold before killing cells in the substantia nigra. This theory
thus offers an explanation for the delayed onset of symptoms and for the
continuation of symptoms after exposure. Metabolic damage, such as impaired
dopamine synthesis, is also suggested as a cause of dopamine depletion.
Further study of this delayed phase is in progress. The likely cause of the
chronic phase is actual nigral cell death. This, in turn, leads to a
permanent hypodopaminergic state, and thus permanent Parkinsonism.
Recovery from the acute and subacute phases has two possible
explanations. A critical toxic threshold of MPTP may not be reached
intracellularly in the substantia nigra, thus the cells can return to normal
once exposure is stopped. Or, perhaps less than a critical number of
dopaminergic neurons are lost and the remaining cells are able to compensate
by overproduction of dopamine, therefore resolving the clinical symptoms.
Typical Parkinsonian treatment modalities are employed in patients who
present with MPTP toxicity. Anticholinergic agents only help to reduce the
tremor, and thus are of little benefit. CARBIDOPA and LEVODOPA therapy, with
or without dopamine agonists, such as BROMOCRIPTINE, are helpful, but
complications typical of this therapy have resulted. These problems include
dyskinesias, end of dose deterioration, and on-off swings between
choreathetosis and Parkinson's symptoms. Studies with monoamine oxidase type
B inhibitors, such as PARGYLINE and SELEGILINE, suggest a possible
alternative treatment (Tetrud & Langston, 1989; Langston et al, 1984;
Fuller & Hemrick-Lueck, 1985). If monoamine oxidase (MAO) is inhibited,
the conversion of MPTP to MPP+ is prevented. Thus, MAO inhibitor drugs may
provide a protecting effect if given prior to MPTP and may be effective in
retarding the progression of symptoms if given after MPTP. Further research
is underway concerning drug therapy for MPTP toxicities.
Several significant points can be noted regarding MPTP contamination.
First, the risks of designer drugs are great due to the lack of purification
after synthesis, the lack of knowledge about what is actually being created,
and the presence of possible adulterants. Secondly, MPTP is a very specific
neurotoxin which can induce irreversible Parkinson's symptoms at any age.
Finally, MPTP administration to laboratory animals, provides scientists an
opportunity to study the function of dopamine on the nervous system, the
effects of chronic dopamine deficiency, and the effects of chronic dopamine
agonist therapy, and other areas of interest. It is hopeful that
understanding the mechanisms of MPTP will provide further understanding of
Parkinsonism and offer new insights to the understanding and management of
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9. Tetrud JW & Langston JW: The effect of deprenyl (selegiline) on the natural history of Parkinson's disease. Science 1989; 245:519-522.