My Medwatch report to the FDA:

Trazodone ==> mCPP may induce psychosis;
Trazodone should have a warning label

Submitted on December 30, 2002

- Bonze Anne Rose Blayk

(F/K/A "Kevin Eric Saunders a/k/a bonze blayk")

Kevin Eric Saunders a/k/a bonze blayk

Describe event or problem  up to a total of 6400 characters allowed

NOTE... my GP is Dr. Breiman of Family Medicine Associates, 209 W. State 
St., Ithaca, NY  14850.  The psychiatrist who prescribed the drugs which 
caused the adverse reactions was the (now-deceased) Dr. Robert Hamlisch.  
If you would please provide me with an email contact address, I  can also 
submit research citations in RTF format which support this analysis.

SUMMARY:  Concurrent use of fluoxetine (Prozac, 20mg/day in the morning 
as an antidepressant) and Trazodone (50 mg/day at bedtime as a "sleep 
aid") over 6 days led to peripheral numbness, heart palpitations, urinary 
retention, visual distortions, and eventually paranoia and delusions.  
Discontinuation of Trazodone after 6 days and later substitution of 
Hydroxyzine Pamoate (25 mg) as a "sleep aid" further complicated the 
adverse reaction, eventuating in frank psychosis with prominent auditory 
hallucinations (2/5/97).  

Fluoxetine was initiated 12/28/96, followed by Trazodone (taken at 
bedtime) on 1/4/97.

On an ER visit on 1/11/97 physical symptoms listed above were dismissed 
by the ER examiner as effects of "agitated depression."  (Fluoxetine had 
been used 8/96 - 10/96 at 10mg/day, but had been discontinued due to 
mildly unpleasant side effects.)

I discontinued Trazodone, since according to the Trazodone insert it 
might be a possible cause of the heart palpitations I had felt; on 
1/16/97 Hydroxyzine Pamoate (Vistaril) was prescribed as an alternative 
"sleep aid," resulting in extreme anticholinergic side effects and 
worsening of paranoia.  

I believed I was suffering from a serious neurological disorder, and 
resumed smoking cannabis for about two weeks (through 1/28/97) in the 
hope I would experience some relief of the symptoms.  (NB:  I had never 
experienced any significant negative side affects from smoking marijuana 
over 20 years of fairly regular use, which had been discontinued more 
than one month prior to going on fluoxetine ... nor, prior to this 
incident, psychosis from any cause.)  Use of cannabis was discontinued in 
the expectation that I would soon be undergoing an NCV test for the 
presence of neurological problems (since use of cannabis could 
conceivably be reducing inflammation or affecting other neuropathic 

For some period during this interval, I completely lost all sensations of 
appetite, and lost 20 pounds.

On 2/6/97 I suffered a major psychotic episode involving delusions and 
auditory hallucinations.

Since the psychosis wound up resulting in serious criminal charges, 
consequently resulting in an acquittal under New York State law as "Not 
Responsible for Reason of Mental Disease or Defect," the cause of the 
psychosis was considered by a number of psychiatrists, neurologists, and 
psychologists.  No signs of brain abnormalities were found in an MRI 
(5/12/97).  The possibility of a neurological disorder was dismissed 
after subsequent 3-day sleep-deprived EEG testing showed no abnormalities 
(2/98).  The diagnosis of Cannabis-Induced Psychotic Disorder was also 
considered and dismissed.

Psychiatric and psychological examiners made varying diagnoses, including 
some questioning the presence of psychosis during the criminal offense 
(particularly since I'd been consistently found to be rational in 
numerous examinations).  No doctor or other examiner ever considered the 
possibility of side effects from Prozac, Trazodone, or Hydroxyzine as a 

Around May 2000, I finally identified the underlying cause(s) of my 
physical illness in January 1997 (and subsequent psychosis) when I found 
research which identified both Fluoxetine and Trazodone as sodium channel 
blockers capable of inducing paresthesias.  My suspicions having been 
heightened, I did more research on Trazodone, and discovered that 
Trazodone has an anxiogenic byproduct with hallucinogenic properties:  
the serotinergic agonist mCPP (meta-chlorophenylpiperazine).  The 
anxiogenic properties of mCPP are widely used in clinical research; the 
hallucinogenic properties have gone largely unrecognized (though note 
"The subjective effects of MDMA and mCPP in moderate MDMA users", Tancer 
& Johanson, PMID 11714594, and reports of delirium induced by Trazodone 
where these effects were probably caused by mCPP, e.g., 
"Trazodone-induced delirium in bulimic patients," Damlouji & Ferguson, 
PMID 6584039).

Also, mCPP is a powerful anorectic agent, accounting for my loss of 

Moreover, I found that research has clearly established that Fluoxetine 
impairs clearance of substances metabolized by the P450IID6 enzyme (and 
indeed there is a warning noting this effect in the Prozac monograph)... 
which includes mCPP, as well as Hydroxyzine.  (It is not known whether I 
have a defective allelle at CYPIID6 causing impaired P450IID6 metabolism 
-- present in about 7.5% of the Caucasian population -- since I have been 
unable to find a doctor or lab performing dextromethorphan/dextrorphan 
ratio or other tests of P450IID6 functioning.)

Thus, the "rare" CNS side effects of paranoia, delusions, and 
hallucinations listed in the Trazodone monograph are statistically 
predictable disasters:  Trazodone has tranquilizing, antipsychotic 
properties which ordinarily mask the anxiogenic, psychotogenic properties 
of mCPP... but the vagaries of metabolism may result in Trazodone 
clearing relatively unimpaired P450IIIA4 channels while mCPP accumulates 
as a result of P450IID6 blockade.

CONCLUSION:  I strongly believe that the labelling of Trazodone (and, 
likewise, of Serzone) should clearly indicate that it produces mCPP, a 
panic-inducing hallucinogenic byproduct, and that clearance of this 
byproduct may be impaired by use of other drugs or by genetic variations 
affecting the P450IID6 enzyme.  

6. Relevant tests/laboratory data, including dates
    up to a total of 1000 characters allowed

Cayuga Medical Center:  ER 1/11/97 for complaints of heart palpitations, 
peripheral numbness, urinary retention, etc.  No tests directly relevant 
to the question of plasma levels of Fluoxetine, Trazodone, mCPP, or 
Hydroxyzine Pamoate were performed.  Other tests were normal (EKG, chest 
X-ray, lab work).

Dr. Jody Stackman (neurologist):   neurological exam 1/20/97, NCV 
(negative) 3/26/97, MRI (negative) 4/8/97

Strong Memorial Hospital, Rochester:  2/11/98, 3-Day sleep-deprived EEG 
(negative for epilepsy)

7. Other relevant history, including preexisting medical conditions, 
(e.g. allergies, race, pregnancy, smoking and alcohol use, hepatic/renal 
dysfunction, etc.) up to a total of 500 characters allowed

Discussed in Section B5.  

1. Name 
(Product Name) (Label Strength) (Mfr/Labeler) 
#1      Trazodone   50mg    
#2      Prozac      20mg    Eli Lilly

2. Dose/Frequency/Route used 
#1 50mg / nightly  / op   
#2 10mg / morning  / op   [sic 4/23/11:  should be 20mg]

3. Therapy Dates (or best estimate)
         If necessary, use Section B5 to explain or clarify dates. 
From To 
#1 1/4/97   -  1/10/97        
#2 12/31/96  - 6/30/97       

4. Diagnosis for use (separate indications with commas)
#1  Insomnia
#2  Depression

5. Event abated after use stopped or dose reduced 
#1  Yes  (No)  Doesn't Apply 
#2  Yes  (No)  Doesn't Apply 

6. Lot # If known 

7. Exp. Date If known.
   If necessary, use Section B5 to explain or clarify dates. 

8. Event reappeared after reintroduction 
#1  Yes  No  (Doesn't Apply)
#2  Yes  No  (Doesn't Apply)

9. NDC #(for product problems only) 
10. Concomitant medical products and therapy dates (exclude treatment of 
Vistaril 25mg / 1-2 prn for insomnia / 1/16/97 - ?  precise dosages 

Subject: Thank you for your submission
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Updated 11/6/10, 1/7/10, 2/1/10