Using  MDMA in the Treatment of Schizophrenia

Julie Holland, M.D.

 The purpose of this chapter is to familiarize the reader with schizophrenia, and what is currently known about its symptoms, their chemical basis, and their management.  Also included in this chapter are multiple reports from schizophrenics who have used MDMA.  I am presenting this anecdotal evidence to support the idea that MDMA may help some schizophrenics to deal with the issues that arise when confronting the presence of this disease.  It is possible that the effects of MDMA can temporarily reduce some of the acute symptoms of this illness, or may help to equip schizophrenics with the power to fight their illness chronically.  It is not clear whether MDMA may or may not help a majority of people with schizophrenia.  What is clear, is that good clinical research is necessary to explore the effects of single oral dose MDMA-assisted psychotherapy in these patients.  Whether the results of this proposed research are miraculous or lackluster, they will nevertheless shed more light on this disease and its pharmalogical management.
 

     I have met all kinds of people with schizophrenia.  Since my college days, I have been fascinated by the disease.  I remember noticing people on the street, usually homeless and acting bizarrely, that I thought might be ill.  My main reason for going to medical school and becoming a psychiatrist was to try and help these particular patients.
     One percent of the world's population has this diagnosis, or perhaps you should say suffers with this illness.  Schizophrenia is a chronic mental illness characterized by a waxing and waning level of psychosis.  Contrary to a widespread misunderstanding, schizophrenia does not mean multiple personalities.  It is the split between thoughts and affect, between one's inner world and outer behavior that earned the disease its name.  The hallmark features of schizophrenia are divided into two categories: positive symptoms and negative symptoms.  Among the positive symptoms are auditory hallucinations (i.e. "hearing voices"), disorganized thoughts and speech, and paranoid delusions.
    Imagine that you believe you  are being monitored by the FBI, poisoned by your family, or perhaps that those around you have been replaced with imposters.  It is common for you to have ideas of referenceó thinking that everything that is happening around you has something to do with you, that everything is a clue for you to interpret, or a secret code for you to translate.  You are convinced that the purpose of a televised newscast or a song on the radio is specifically to send you a message.  Other experiences that you may have are audible thoughts, or the belief that others can hear what you are thinking, as well as believing you can read people's minds and they yours.  The voices in your head may keep up a running commentary of what is going on around you, or they may call you derogatory names, or may command you to do things.
      Over the last fifty years, antipsychotic medications have been developed to help ease the symptoms of schizophrenia.  Auditory hallucinations usually respond first to this treatment; the voices typically become quieter, although they do not always vanish.  Speech then becomes more organized and less fragmented, perhaps because there is no longer competition from the voices while trying to speak. Paranoid delusions usually stick around a bit longer, as they are stubborn beliefs that take some time for people to abandon, but eventually they diminish in intensity as well.
     After the positive symptoms have been adequately treated, the negative symptoms often remain.  Although less disruptive, these can be quite debilitating, and are much more difficult to eradicate with typical antipsychotic medication.  The deficit side of schizophrenia shows itself as amotivation, social isolation, talking less, and thinking less (known in psychiatry as poverty of speech and thought).  Also present are some abberations in attention and concentration, usually referred to as cognitive deficits.  Some schizophrenics have more negative symptoms than positive symptoms.  Negative symptom-laden schizophrenics are at times reminiscent of people with autism.  Emotionally withdrawn, they stay to themselves and may make rocking or other repeptitive motions, seeming quite disconnected from their environment.  Also observed is affective blunting or flattening; if emotion is felt at all, it is not conveyed in their faces or voices.
     Contrast this syndrome of paranoia, social withdrawal, decreased speech, motivation, and emotional expression with the syndrome seen during MDMA use: enhanced sociability, enthusiasm, euphoria, an increased desire to speak with and connect to others and a sense of openness and trust.  It is easy to see why some people with schizophrenia have been drawn to MDMA use, and why they, and I, am eager for scientific research to move forward in this area.  Because MDMA targets the very components of behavior that are affected in schizophrenia, and because MDMA enhances the function of the two brain chemicals that are implicated in the disease, these are two compelling reasons to explore the connection between this medication and this illness.  It is quite possible that we may learn more about the biological basis of schizophrenia , its symptoms and its treatment, by learning more about MDMA.

The Dopamine Theory of Schizophrenia

     In the early phases of schizophrenia research, the dopamine theory dominated the scientific literature.  This hypothesis stated that the disease reflected a state in the brain where there was too much dopamine, or an overactivity of the transmission of dopamine (Meltzer, 1976).  To support this, it was pointed out that the most effective antipsychotics were those which blocked dopamine receptors the most potently (Creese, 1976; Seeman, 1976).  This receptor blockade is known as dopamine antagonism.  For many years, it was felt that schizophrenia simply reflected a state of too much dopamine, and its effective treatment was to antagonize the dopamine transmission.  More recent theories about dopamine and schizophrenia posit that there may be an imbalance of dopaminergic activity, with the positive symptoms (hallucinations and delusions) reflecting a "hyperdopaminergic" state in certain parts of the brain (the subcortical regions) and negative symptoms reflecting a "hypodopaminergic" state in the cortical, or prefrontal, region (Deutch, 1992; Knable, 1997; Dworkin, 1992).
     Another theory is that the negative symptoms may reflect actual structural changes in the brain (neuropathology) (Crow, 1980).  Supporting this theory is the observation that people with frontal lobe injuries, for example those who have undergone frontal lobotomies or strokes, tend to have problems with initiating behaviors, showing emotion, and interacting appropriately with others (Neylan,1999).  Interestingly, some stroke patients have been given amphetamine in order to enhance their motivation and hasten their recovery (Goldstein, 1999).  Also seen in schizophrenia is a decreased rate of blood flow to the front part of the brain (Gur, 1989), while MDMA has been shown to enhance blood flow to some of  the same areas often mentioned as abnormal in schizophrenics. In healthy normal volunteers given a single oral dose of MDMA (1.7 mg/kg), blood flow was increased bilaterally in the ventromedial prefrontal cortex, the ventral anterior cingulate, the inferior temporal lobe, the medial occipital lobe and in the entire cerebellum (Gamma,2000).
 
Clinical Studies: Giving Dopamine Agonists to Schizophrenics

    What has become clear over time is that while the classical antipsychotics which block dopamine receptors can quiet the voices, organize the speech, and diminish the paranoia, they do not adequately treat the deficit state or negative symptoms which remain.  Some researchers have stated that despite over twenty years of negative symptom research, there is still no proven pharmacologic treatment for primary negative symptoms (Carpenter, 1995).  And so continues the search for medications to ameliorate the negative symptoms.  Some medications which have been tried are dopamine agonists (enhancers) such as amphetamine.  Amphetamine has been used in psychiatry as early as 1936 (Meyerson, 1936).  It is widely accepted that chronic use of high dose amphetamine, sometimes called a psycho-stimulant, can yield a paranoid psychosis in non-psychiatric patients (Angrist, 1994); at one time, this was part of the basis of the dopamine theory of schizophrenia (Snyder, 1973; Ellison, 1994).  Amphetamine, and other psychostimulants such as ritalin and ephedrine, have been used in schizophrenia research as "probes," or provocative tests.  (see Lieberman, 1987 for a review)  The idea behind provocative tests is to give a drug which causes an effect, any measureable effect at all in the schizophrenic population.  Knowing how the probe works chemically and observing its effect on the research patients yields important information about the pharmacologic basis of the symptoms and their treatment.
      One theory of negative symptoms involves a failure of dopamine activation to the prefrontal cortex (an area of the brain felt to be involved in executive decision making) to explain some of the cognitive deficits seen in this syndrome (Dworkin, 1992).  Therefore, it is felt that in smaller doses, psychostimulants such as the dopamine agonist amphetamine might be helpful in treating the deficit state of schizophrenia. There have been some studies showing that amphetamine can worsen a psychotic episode in schizophrenics (Guttman and Sargant, 1937; Angrist, 1980; Van Kammen, 1982). However, there were several other studies of schizophrenics which mentioned some decrease in negative symptoms with the administration of amphetmine (Angrist, 1982; Cesarec, 1985; Goldberg, 1991;Matthew , 1989; Van Kammen, 1988).
     One study using schizotypal personality disordered patients, who tend to show similar affective flattening and cognitive deficits as schizophrenics, demonstrated amphetamine-associated improvement on a card sorting test typically affected in schizophrenia (Siegel,1996).  Most amphetamine studies in negative-symptom laden schizophrenics qualify the statistically significant results seen as partial, but not complete. Although the results of these studies were not robust, one paper does caution that "amphetamine may modestly improve negative symptoms in those schizohprenics in whom this symptomatology is more severe." (Sanfilipo, 1996)
 In reviewing the psychostimulant studies, a few trends are apparent: patients are less likely to become psychotic if the drugs are given orally, instead of intravenously, and if the patient is not acutely psychotic, but rather is showing residual, attenuated positive symptoms of schizophrenia.  Methylphenidate (Ritalin) is reportedly more likely to bring on a psychotic episode than is amphetamine (Lieberman, 1987).
     Important in the consideration to use MDMA in the treatment or study of schizophrenia is the following fact: the level of activity of the serotonergic system affects the response seen with amphetamine challenges.  In animals, the results of a variety of tests in which serotonin was depleted or cells were lesioned showed a more robust repsonse to amphetamine challenges. Likewise, when serotonin availability was enhanced, there was an attenuation in amphetamine-elicited activation (Gerson, 1980).  In schizophrenic subjects, when a serotonin precursor, 5-hydroxytryptophan, was given in conjunction with amphetamine, it prevented the induction of acute psychotic symptoms sometimes seen with amphetamine challenges (Irwin, 1987).  Because MDMA acutely raises levels of serotonin and dopamine in the brain, this may prevent an increase in psychotic symptoms in schizohrenics.
 

Serotonin and Schizophrenia

     Support for the involvement of the serotonergic system in schizophrenia has been gathering in the literature since it was first observed that lysergic acid diethylamide (LSD) caused a syndrome evocative of schizophrenia in normal controls, and that the structure of LSD shared  similarities with serotonin (Gaddum, 1954).  Although the dopamine hypothesis dominated the literature for the next three decades, further evidence to re-assert serotonergic abnormalities in schizophrenics came as clozapine, the first antipsychotic in forty years to demonstrate clinical superiority to chlorpromazine (Thorazine, a dopamine antagonist), was found to have potent serotonin receptor antagonism (Meltzer, 1989;Canton, 1990).
     Because the serotonergic system is functionally interactive (Kelland, 1990) and anatomically closely connected (Tork, 1991) with the dopaminergic system, there is good reason to view these two neurotransmitter systems in tandem, as opposed to each in isolation.  The serotonin system inhibits dopaminergic function at both its origin in the midbrain and its termination in the forebrain (Kapur, 1996).  Thus, it may be desirable to augment the dopamine antagonist treatment that is seen in classical antipsychotics with a serotonin agonist.  Serotonin modulation may be beneficial in reducing the negative symptoms of schizophrenia  (Leysen, 1993).  It should be noted, however, that many of the newer antipsychotics are serotonin antgonists.  This is a complex area of study.  There are many different receptor subtypes of both serotonin and dopamine, and there are likely multiple modes of interaction between these two systems (Kapur, 1996).  Also confounding, are the long term changes that take place in the brain when given chronic doses of serotonin and dopamine antagonists (e.g., antipsychotics) versus immediate effects seen with acute agonists of these same neurotransmitter systems, as is seen with MDMA.
     The co-existing presence of illnesses known to respond to serotonin reuptake inhibitors  (SSRIs like Prozac) lends support to the idea that serotonin is involved in the pathophysiology of schizophrenia.  The prevalence of depression in schizophrenics is quite high and is seen throughout the course of the disease. Approximately 25% of schizophrenics experience depression following an acute psychotic episode ("post psychotic depression") and as many as 60% suffer a major depressive episode during the course of their illness (Bartels, 1988).  One study found the incidence of depression to be twenty-two percent (22%) at baseline, and 26% over a five year follow up period (Koreen, 1993).  The suicide rate for schizophrenics, ten to thirteen percent, is ten times the national average (1%) and is the leading cause of premature death in schizophrenia (Caldwell, 1990). A general population study showed that people with schizophrenia have the highest relative risk for attempted suicide, with a risk ratio of 23:1 (Dyck, 1988).  Mann (1987) notes that a low level of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) measured in the cerebrospinal fluid (CSF) correlates with suicidal behavior in depression and in schizophrenia.  One CSF 5-HIAA study noted low levels in schizophrenic patients, with a further reduction seen in those schizophrenics who had attempted suicide (Cooper, 1992).  Clozapine treatment of neuroleptic resistant patients resulted in markedly less suicidality, and was accompanied by improvements in depression and hopelessness (Meltzer, 1995).
 Schizophrenia and obsessive compulsive disorder show a high co-morbidity, perhaps reflecting the involvement of the serotonergic system in both of these psychiatric diseases.  One study listed the occurrence of significant obsessive compulsive symptoms in schizophrenics as twenty five percent (Berman, 1995). Schizophrenia and Autism,too, share similar features (withdrawn behavior, self stimulation stereotypies, inappropriate or flattened affecct, poor eye contact).  Some of these features of autism have been shown to respond to treatment with fenfluramine (Geller et al., 1982; Ritvo et al., 1983), a halogenated amphetamine with serotonin-agonist actions in behavioral models and serotonin-depleting actions in biochemical models (Clineschmidt, 1978) similar to MDMA.

Altered  Markers of 5-HT function
 
     Studies of platelet serotonin levels and receptor sites have further implicated the role of serotonin in schizophrenia.  Increased levels of serotonin measured in platelets of schizophrenic and depressed research subjects were found to correlate with presence of psychotic symptoms. (Muck-Seler, 1991).  Increased number of platelet serotonin binding sites were measured in drug-free schizophrenics (Pandey, 1993).  Cerebrospinal fluid levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) have been shown to be reduced in schizophrenics in a number of studies (Potkin, 1983).
      Several postmortem studies have demonstrated altered serotonin uptake site binding in schizophrenic brains (Joyce, 1993).  This is the receptor site where SSRIs bind, and also where MDMA binds.   The prefrontal cortex, frequently implicated in the neuropathology of schizophrenia, was shown to have selective abnormalities of serotonergic receptors in a post mortem study of schizophrenic patients. (Laruelle 1993)  The findings of decreased binding sites in the frontal cortex and increased binding sites in the striatum lend support for the hypothesis that in schizophrenia there is an imbalance, cortical  relative to subcortical, of serotonergic transmission, with the prefrontal cortex having a low or hyposerotonergic state, correlating with negative symptoms, and the subcortical structures exhibiting a high or a hyperserotonergic state, correlating with psychotic symptoms. (Breier, 1995)

Clinical Studies: Giving Serotonin Agonists to Schizophrenics

     Several studies have used serotonin reuptake inhibitors, particularly fluoxetine (Prozac), as an adjunctive treatment in medicated schizophrenics.  Fluoxetine has been shown to significantly improve negative symptoms without worsening extra-pyramidal side effects, although blood levels of neuroleptics were significantly elevated. (Goff, 1995; Spina, 1994); fluvoxamine (Luvox) has also been shown to ameliorate negative symptoms. (Silver, 1992).  In a recent study comparing fluvoxamine with maprotiline (a non-serotonergic antidepressant) in medicated schizophrenics, those given fluvoxamine showed significant improvement in motor retardation, emotional withdrawal, and affective blunting as compared with the group given maprotiline (Silver, 1998).  This effectively factors out the possibility that it is merely an antidepressant effect, and suggests that it is the serotonergic effect specifically, which may be responsible for the improvement seen in negative symptoms.
    In one study in which medicated schizophrenics received fenfluramine, three out of eight subjects showed statistically significant within-subject improvement in negative symptoms, and three other patients showed significant improvement in positive symptoms (Stahl, 1985).  Fenfluramine has properties similar to MDMA, and rats trained to discriminate fenfluramine and placebo, tended to equate it with MDMA 90% of the time (Schecter,1997).  However, another study using chronic fenfluramine treatment showed that it  worsened negative symptoms in schizophrenic patients. (Soper, 1990). An open (unblind) trial of sertraline (Zoloft) administered to patients stabilized on antipsychotics noted some amelioration of both positive and negative symptoms (Thakore, 1996), while a double blind study found no statistically significant improvement (Lee, 1998).
     Studies utilizing the serotonin agonist meta-chlorophenylpiperazine (mCPP) as a challenge test (single dose) in schizophrenic patients have been performed in an effort to test the assumption of serotonergic involvement in schizophrenia.  They have produced mixed results.  In normal subjects, mCPP infusion leads to increased body temperature, anxiety, and release of growth hormone, cortisol, ACTH and prolactin.(Murphy, 1991 and 1986) In a 1993 Yale study of neuroleptic-free schizophrenics, mCPP caused a larger anxious  response in patients than in controls. Furthermore, it was shown to exacerbate psychotic symptoms in the patient group (Krystal, 1991).  Iqbal (1991) corroborated the finding of psychotogenesis in schizophrenics exposed to an mCPP challenge (.25 mg/kg, pO), but Kahn (1991) actually measured an  improvement in the symptoms (as measured by the Brief Psychiatric Rating Scale, or BPRS) of those schizophrenics undergoing an mcpp challenge  (.35 mg/kg, pO).
 
     What can be understood from all of the above results?  Clearly, there is no simple answer.  What was once a theory of too much dopamine or serotonin is now a theory of imbalance: too much in some areas, not enough in others.  A few theorists go one step further to match the levels of neurotransmitters with symptomatology.  Positive symptoms represent an abundance of dopamine turnover and negative symptoms represent the opposite (Rao, 1994).  Because some people with schizophrenia have more positive or negative symptoms, some do better with certain medications, and some respond to others.       There are many researchers who think that schizophrenia is a syndrome, or a group of illnesses, and not simply one disease.  This may mean that if you are doing research on large groups of subjects, that you may not be studying the same phenomenon.  Many studies now try to focus on positive-symptom or negative-symptom-predominant populations.
     About the only thing that can be generalized from all this data is this:  decreasing available dopamine and serotonin in the synapse seem to improve positive symptoms, and it's possible, though not nearly as certain, that enhancing available serotonin and dopamine in the synapse may  improve negative symptoms.
 

Pre-Pulse Inhibition

     There is one more interesting piece to the puzzle.  Schizophrenics are known to have deficits in the way they process the outside world.  Typically, people get used to a repeptitive stimulus (habituation) and would have less of a response to second and third presentations of the same thing.  Also, there is a phenomenon known as sensory gating, which is demonstrated well by a tehnique known as pre-pulse inhibition (PPI).  If a smaller stimulus is given before a larger one, say two tones of escalating volume, typically someone would be less startled by the second, louder tone, having been prepared by the first, quieter tone.  In schizophrenia this is not the case, and this is known as a deficit in sensory gating, or a disruption in PPI.  There are many medicines and drugs which make this deficit worse, but there are few substances which have been shown to enhance the inhibition of the first pulse.  Nicotine is one drug which does enhance pre-pulse inhibition, which may explain why so many schizophrenics smoke cigarettes heavily.
     Recently, Swiss researchers have discovered that MDMA has the capacity to enhance PPI (Vollenweider, 1999).  This may be the most compelling reason to give single oral dose MDMA to people with schizophrenia.  If MDMA can enhance pre-pulse inhibition in the general population, it is possible it can enhance PPI in schizophrenia.  Any medicine we can give that will ameliorate any symptom or syndrome is worth studying, if for no reason than to help us learn what the pharmacological basis of that symptom is, so better medications can be created.  In the past, schizophrenics have been given LSD, DMT, PCP, amphetamine, ritalin, and ketamine in order to observe what effect these medications had on their symptoms. (Stol,1947; Boszormenyi,1958;, Itil,1967; Angrist,1980 and 1982; Lieberman,1987; Malhotra,1997; Lahti,1995) Many of these drugs worsened their symptoms for a short time.  The rationale in performing these studies was that any observable change in symptomatology yields valuable information about the illness.
      Given what we know about MDMA, which is that it increases the availability of serotonin and dopamine in the synapse, that it strengthens pre-pulse inhibition in humans, and that it does seem to reliably enhance sociality and motivation, it does seem reasonable to ask the question:  Could it help people with schizophrenia?  Connecting to and communicating with others is severely impaired in negative-symptom schizophrenics; it is markedly enhanced when taking MDMA in the rest of the population.  Attention, concentration, and insight are all compromised in schizophrenics, yet augmented in someone experiencing MDMA.  In the same way that amphetamine and fenfluramine have been used to try to ameliorate negative symptoms, so should the ring-substituted amphetamine MDMA.

 
     The following "testimonials" are from people who have been diagnosed with schizophrenia, and have found, on their own, some benefit from their MDMA use.  These are excerpts taken directly from their e mails to me describing their experiences.

Robert

Robert was diagnosed as paranoid schizophrenic in his early twenties.  He had auditory and visual hallucinations, ideas of reference and paranoid ideation, and was  treated with olanzepine.

    "I strongly believe MDMA has huge potential for the treatment of schizophrenia..."
"another commonality is a sense of well-being, not just in a personal sense, but also in a communal sense, a kind of belonging which can maqnifest itself as more "connected" conversations with people, or perhaps just more talking for those of few words.  For me, this was a key factor in breaking down my own cycle of desocialization.  On MDMA, I found myself more able to talk with almost anyone about almost anything, and felt rather freed of most (formerly unrealized or at least unadmitted) neuroses/psychoses that normally plague me."  "Just this visceral experience of sharing thoughts and feelings with people, even if only for a few hours, did have a lasting effect on my own self-  view and world-view.  In some sense, it gives me something of a role-model for what sort of personality I would like to achieve without the use of external chemicals, and also gives direct proof that there is a lot of psychological flexibility in my own mind."
 

John

      John was diagnosed with schizohrenia in his late teens. History of being treated with clozapine, olanzepine. Currently has been "de-diagnosed" and no longer takes any antipsychotic medication.  (may have been misdiagnosed, though he did have a history of referential ideation and paranoia, never heard voices.)

     "I have used MDMA quite successfully in combating my psychosis....With the very first use MDMA completely changed my life....The paranoia that I was experiencing was temporarily halted and replaced with an immense sense of love, compassion, intimacy and closeness.  Please note that MDMA only reduced my paranoia temporarily, the paranoia came back later. But the insight that I gained from these precious few hours of clarity proved to be invaluable.... For one, I had now learned how to truly love, as the schizophrenia had removed that ability from me.  I became closer to my friends and family. ...Secondly, I became a much more open, outgoing, and positive person.  Again, schizophrenia had lobotomized these critical qualities from me. ...Finally, MDMA instilled in me an unrelenting will to live.  A will to keep pushing on through my road to recovery no mattter what obstacles presented themselves. ... Through the positive MDMA effects, carefully titrated antipsychotic drugs, and having a lot of people who cared about me, I slowly began to turn the tide on my disease.  Over time, I gradually worked my way to the point where I could live outside a psychiatric treatment facility.  In fact, it's been over two and a half years since I left the hospital.  the way I see it is that I will never have to go back, ever."

James

     James' first signs of schizophrenia began around age 14 or 15. He has a history of persistent auditory hallucinations, paranoia, delusions, ideas of reference, one suicide attempt,and a psychiatric hospitalization.

     "I felt as is if my mental problems had washed away.  All of my paranoia, all of my reservations about people, all of the pent up anger and frustration, the bitterness towards my family, all of it had been flushed out with a single dose.  I felt like a real person.  I remember reflecting on my life in disgust at how I behave on a day to day basis, I wanted to initiate change, to make myself more like I was when I was on E, because I thought it was beautiful, and right.  when I came down I wasn't disappointed that it was over, and I  didn't crave more, but I did remember the changes I wanted to make."  "My whole outlook on life changed that night."   "It has given me freedom from a disease that has plagued me for years, and a bit of that freedom continues on even after the drug wears off."  "I do not think this is a cure for anything, only a new perspective, that should be used wisely."

     I also had an interesting telephone call with a young man with schizophrenia whose symptoms were much more severe than the other men I had spoken with.  On a subsequent phone call he was acutely paranoid, and he was eventually lost to follw up, but he told me that when he took MDMA for the first time, he felt like he was cured for a few hours, and he felt it was important that doctors and scientists do reseach on why that had happened.
 And I couldn't agree more.
 
 
 

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