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A New Treatment for HPPD?

September 19th, 2012 Leave a comment Go to comments

The following new treatment study was presented at the Annual Meeting of the Biological Psychiatry Society in 2012. A shortened form of the report is below. It describes a beneficial response in some patients with HPPD to drugs which augment the dopaminergic system of brain chemicals. This study is NOT the gold standard of proof that this approach works. But the use of two medications, tolcapone and Sinemet, improved HPPD in a third of the subjects. These medications are not approved for use in HPPD. Any interest in them should be discussed with your physician.

Catechol-O-Methyl Transferase Inhibition Reduces Symptoms of Hallucinogen Persisting Perception Disorder
Henry David Abraham, M.D.
Department of Psychiatry

Tufts University School of Medicine


Hallucinogen persisting perception disorder (HPPD) is a poorly understood chronic disorder arising from the use of hallucinogenic drugs, classically associated with LSD (1). It is characterized by a variety of continuous visual disturbances including geometric pseudohallucinations, “visual snow,” trails of moving objects through the visual field halos around objects, and acquired dyslexia (2).

Illustrative Case

A 28 year old single male PhD in cell biology presented with a self-diagnosis of HPPD after consulting the Internet. Six years prior to presentation, he had used MDMA (“Ecstasy”) on 13 occasions. The morning after his last drug use he noticed an array of symptoms he had never experienced before. These included aeropsia (“visual snow”) in which the air appeared at all times to comprise moving dots too numerous to count. He could see trails of objects, such as the tail lights of moving cars as they passed before his eyes. There were afterimages of static objects, a distortion of the angles of a room, and difficulty reading because of the illusion that the printed page was vibrating. He denied anxiety, but reported “an absence of calmness” and a chronic feeling as if his head was “in a vise.” His past psychiatric history was negative, as was an MRI of the brain. Symptoms were palliated by clonazepam but have remained on a daily basis for six years.

This case shows common clinical features of HPPD, namely the onset of episodic or continual visual symptoms within the first month following drug use. Symptoms can be acutely exacerbated by marijuana, stimulants, alcohol withdrawal, anxiety, or extreme physical activity. Other somatic symptoms difficult to characterize such as “a head feeling” and “depersonalization” are also commonly described. The prevalence among hallucinogen users in one survey was 4.5% (3). Treatment is palliative (4). Benzodiazepines, olanzapine, sertraline, naltrexone, and clonidine have been anecdotally reported to help in selected cases (5-11). Blockade of the 5HT2A receptor with risperidone  exacerbate symptoms (12).

Episodic perceptual disturbances from LSD were originally called “flashbacks” (13). Anderson and O’Malley first observed that “flashback” is a misnomer, in that HPPD is continuous and in many cases permanent (14). A series of studies of HPPD patients showed that the visual symptoms in HPPD arise from chronic disinhibition of the visual apparatus (15-18), consistent with a neural network models of afterimage formation (19). Further support for hallucinogen-mediated disinhibition of neurobehavioral systems comes from animal data, in which the hallucinogenic 5-HT2A agonist 2,5-dimethoxy-4-iodamphetamine (DOI) has been shown to disrupt sensory gating (20).

Treatment has been palliative. If defective sensory gating is involved in the pathogenesis of HPPD, The reversible COMT inhibitor, tolcapone, which has been shown to improve sensory gating in COMT rs4818 GG homozygotes, could possibly benefit HPPD patients as well (21). Thus, the following clinical trial was conducted.


20 consecutive patients with HPPD were self-referred for a structured psychiatric evaluation. The mean age was 30.3 ± 10.0 years. 95% were Caucasian. One subject was East Indian. 85% were male. Inclusion criteria were applied using diagnostic criteria of Hallucinogen Persisting Perception Disorder, DSM-IV TM 292.89. The mean time of continual visual symptoms in the sample was 8.9 ± 9.4 years. Prior to the evaluation, each subject was required to have a normal MRI of the brain and a normal chemistry screen of liver function.

Each visual symptom was scored for occurrence at the time of the study on a Likert 0 to 7 scale, with zero being the absence of the symptom and the highest score being “the greatest intensity ever experienced.” The mean score for all symptoms was then calculated before and two hours after drug administration. Medication was given in an open label design. Each subject received tolcapone 200 mg, carbidopa 25 mg, and levodopa 100 mg by mouth. Pre-drug and post-drug visual disturbance scores were analyzed using a two-tailed paired T-test.


The frequency of specific drugs precipitating symptoms in this sample of 20 patients included LSD (70%), MDMA (65%), mushrooms (35%), Cannabis (30%), and ketamine (5%). As far as is known, this is the first report of MDMA and ketamine as pathogens in HPPD. Co-morbid illnesses included lifetime panic disorder (65%), current panic disorder (55%), lifetime major depressive disorder (50%), and current major depressive disorder (35%).

Inhibition of COMT and dopamine decarboxylation reduced intensity of visual symptoms in HPPD from 4.4 ± 2.4 to 3.4 ± 2.5 (mean ± SD, P < .001). See Figure 1.

Figure 2 shows a distribution of treatment responses by case suggesting subsets of cases which are highly responsive (59% symptom improvement in the six highest responders, compared to 2% in the lowest six). This is compatible with the finding that tolcapone affects sensory gating in a bimodal fashion, with  increases in rs4818 GG homozygotes.


1. An open-label treatment trial for HPPD using a combination of tolcapone, a COMT inhibitor, and levodopa augmentation resulted in a medication effect size of 0.2. This represents a novel treatment for this disorder.
2. The distribution of responses appears to be bimodal, and consistent with a genetically based sensitivity to tolcapone in the greatest responders.

3. MDMA use preceded the onset of HPPD in 65% of the sample.4. Current and lifetime major depression and panic disorder are important co-morbid features of HPPD.


1. El-Mallakh RS, Halpern JH, Abraham HD (2008): Substance Abuse: Hallucinogen- and MDMA-Related Disorders (Chapter 60). In: Tasman A, Maj M, First MB, Kay J, Lieberman JA, editors. Psychiatry. 3rd edition. London: John Wiley & Sons, pp. 1100-1126, 2008.
2. Abraham HD (1983): Visual phenomenology of the LSD flashback. Arch Gen Psychiatry; 40: 884 889, 1983.
3. Baggott MJ, Coyle JR, Erowid E, Erowid F, Robertson LC (2011): Abnormal visual experiences in individuals with histories of hallucinogen use: a Web-based questionnaire. Drug Alcohol Depend. 2011 Mar 1;114(1):61-7.
4. Abraham HD, Aldridge A, Gogia P (1996): Psychopharmacology of the hallucinogens.  Neuropsychopharmacology, 14:285-298.
5. Young CR (1997): Sertraline treatment of hallucinogen persisting perception disorder. J Clin Psychiatry. 1997 Feb;58(2):85.
6. Alcántara AG (1998): Is there a role for the alpha2 antagonism in the exacerbation of hallucinogen-persisting perception disorder with risperidone? J Clin Psychopharmacol. 1998 Dec;18(6):487-8.
7. Lauterbach EC, Abdelhamid A, Annandale JB (2000): Posthallucinogen-like visual
illusions (palinopsia) with risperidone in a patient without previous
hallucinogen exposure: possible relation to serotonin 5HT2a receptor blockade. Pharmacopsychiatry. Jan;33(1):38-41.
8. Aldurra G, Crayton JW (2001): Improvement of hallucinogen persisting perception disorder by treatment with a combination of fluoxetine and olanzapine: case report. J Clin Psychopharmacol. Jun;21(3):343-4.
9. Lerner AG, Gelkopf M, Skladman I, Oyffe I, Finkel B, Sigal M, Weizman A (2002): Flashback and Hallucinogen Persisting Perception Disorder: clinical aspects and pharmacological treatment approach. Isr J Psychiatry Relat Sci. 2002;39(2):92-9.
10. Halpern JH, Pope HG Jr (2003): Hallucinogen persisting perception disorder: what do we know after 50 years? Drug Alcohol Depend. Mar 1;69(2):109-19.
11. Lerner AG, Gelkopf M, Skladman I, Rudinski D, Nachshon H, Bleich A (2003): Clonazepam treatment of lysergic acid diethylamide-induced hallucinogen persisting perception disorder with anxiety features. Int Clin Psychopharmacol. Mar;18(2):101-5.
12. Abraham HD, Mamen A (1996): LSD-like panic from risperidone in post-LSD visual disorder.  J Clin Psychopharmacol, 16:238-241.
13. Rosenthal S (1964) Persistent hallucinosis following repeated administration of hallucinogenic drugs.  Am J Psychiatry 124, 238-244.
14. Anderson WH, O’Malley JE (1972): Trifluoperazine for the “trailing” phenomenon. JAMA. May 29;220(9):1244-5.
15. Abraham HD (1981): A chronic impairment of colour vision in users of LSD.  Brit J Psychiatry. 140: 518 520.
16. Abraham HD, Wolf E (1988): Visual function in past users of LSD: psychophysical findings. J Abnormal Psychology 97(4):443 447.
17. Abraham HD, Duffy FH (1996): Stable qEEG differences in post-LSD visual disorder by split half analyses:  Evidence for disinhibition.  Psychiatry Research:Neuroimaging, 67:173-187.
18. Abraham HD, Duffy, FH (2001): EEG coherence in post-LSD visual hallucinations. Psychiatry Research:Neuroimaging, 107:151-163.
19. Kilpatrick ZP, Ermentrout BG (2012): Hallucinogen persisting perception disorder in neuronal networks with adaptation. J Comput Neurosci. Feb;32(1):25-53.
20. Sipes TE, Geyer MA (1995): DOI disruption of prepulse inhibition of startle in the rat is mediated by 5-HT(2A) and not by 5-HT(2C) receptors. Behav Pharmacol. Dec;6(8):839-842.
21. Giakoumaki SG, Roussos P, Bitsios P (2008): Improvement of prepulse inhibition and executive function by the COMT inhibitor tolcapone depends on COMT Val158Met polymorphism. Neuropsychopharmacology. Dec;33(13):3058-68.
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