The Mysteries of HPPD
The clinical and scientific aspects of hallucinogen persisting perception disorder (HPPD) have been previously reviewed. (1-3) What follows is a summary of my 47 years’ experience to understand and treat patients with this disorder.
Human consumption of hallucinogens predates written history. One plausible theory regarding the discovery of these potent plants is that hunter-gatherer societies were omnivorous, and as plants were discovered that had profound psychological effects, they were incorporated into the realms of magic and religion.
Until 1938 all hallucinogenic drugs were of botanical origin, of low dose, and with an availability subject to the natural cycles of climate and weather. The synthesis of LSD by Albert Hofmann in that year resulted in profound changes in the cost, potency, and availability of such drugs. No longer were adventurers of the mind required to travel to exotic places to experience them. In America and Europe, markets of the young and curious were ripe for exploitation, soon to be helped by the American Central Intelligence Agency, or CIA.
In 1953 the Agency began Project MKULTRA, a twenty-year clandestine effort to study the effects of LSD and other drugs in humans. Funding involved universities and medical schools. Drugs were given to unwitting employees of the military and civilian government in ill-conceived scientific studies. It was in this climate that Timothy Leary, a lecturer in the psychology department at Harvard university, promoted the use of hallucinogens as a panacea. From that point students and others created a black market for LSD. It could be easily synthesized into millions of individual doses, sold locally and smuggled into countries around the world. What followed was a decade long pandemic of hallucinogen abuse and a half-century government blackout on their scientific study in humans.
My first exposure to patients arising from this epidemic of hallucinogenic drugs was as a first-year resident in the Department of Psychiatry of the Massachusetts General Hospital in Boston in 1971. A steady stream of self-described casualties of LSD captured my interest. They described a broad range of perceptual, cognitive, and affective symptoms. I chose to focus on the perceptual complaints of these patients for a variety of reasons. First and foremost, the symptoms the patient were describing to me seemed utterly distinct from the non-drug related patients in the clinic. Second, perceptual symptoms appeared to be more easily quantified, reliable and valid than measures of cognition and affect. And finally, the visual disturbances of HPPD suggested they could be keys to understanding psychotic disorders. It took me nearly half a century to realize every reason I found to study this problem was wrong. But I was young, unfettered, and unhampered by preexisting data.
What HPPD Looks Like
One advantage of studying a problem that no one else had much of an interest in was that one could create new language to describe what these patients were reporting. Nearly all the visual disturbances appeared to be pseudohallucinations, since virtually none of the patients believed what they were seeing were real. Also, reinforcing that the visual disturbances seemed unreal was that the vast majority of them comprised bizarre changes in normal imagery, the appearance of stereotyped geometric images, afterimages, halos, false perceptions of movement in the peripheral visual field, the illusion of seeing the trail of a moving object, and the perception of countless dots in the air. The most debilitating of these was afterimagery while driving at night or using a computer. The examples illustrated below are drawings that patients made months after their last use of LSD, the preeminent hallucinogen in use at the start of my studies. These drawings capture visual disturbances they reported to me at the time of their interviews.
An artist's rendition of one HPPD symptom, pareidolia, is shown in the painting below. Pareidolia is the imagined perception of objects imbedded in objects actually in the visual field.
"Hide-and-Seek", an oil painting by Pavel Tchelitchew, Medium: oil on canvas Painted between 1940 and 1942 The painting is in the collection of, and owned by, the Museum of Modern Art in NYC.
While Shick, Cohen, Rosenthal and others had described evanescent visual disturbances that occurred following LSD use, these visual and affective moments were transient, and were called ”flashbacks.” The patients that I was studying, on the other hand, described continuing visual disturbances that had lasted for many years from their last use of LSD. Either this was a condition that could slowly reverse in time, or HPPD, which had yet to be named, was permanent.
In 1983, with the generous mentoring of Sheldon Eisenthal over many months, I published the first case-controlled study comparing LSD users with non-LSD experienced psychiatric outpatients. (4) The first surprise was that HPPD occurred without any correlation to how much a person ingested over a lifetime. Recovery could happen, but only in half of the sample, and then taking a matter of years. These observations served as the diagnostic criteria of HPPD in the Diagnostic and Statistical Manual of the American Psychiatric Association the following year. Because the study was based entirely on self-reports, I began to look for a measure of visual disturbance to test this population objectively.
The White Dot Experiment
None of a panel of conventional ophthalmologic tests yielded any discriminating findings in LSD users. These included measures of near and far visual acuity, Ishihara color plates, the Farnsworth-Munsell 100 hue test of color vision, confrontational visual fields, intraocular pressure, fundoscopy, and fluorescein angiography. One evening as I was working with an LSD patient, I tested his perception of a variety of colors and shapes that were readily available in the examining room. One such object was the cover of a 1972 South Boston phone book that showed a silhouetted hunter in front of a setting sun. I asked my patient to describe each of the objects he saw and their colors. When he came to the sun he said it was yellow. Clearly to my eye the circular sun was white. Perhaps he was confusing the yellow glow around the sun with the object in the center, and so I asked him to describe the color of the sun, and not the glow around it. He was sure. ”Yellow.” “Get closer,” I said. He continued to see yellow until he was about a meter from the object. Then he saw white. In 1981 I found my test object. It looked like this:
Controlling for visual acuity and ambient light, I found that subjects with LSD related HPPD needed to get closest to see “white.” See below. Better were LSD users without visual disturbances. Performing the best were LSD abstinent subjects. HPPD, it appeared, was something more than simply the madness of crowds. (5)
This finding was verified by the following experiment. HPPD subjects and non- HPPD controls were compared on the intensity of an afterimage from a bright light over time. The graph below shows how the intensity of the afterimage was high, and persisted for fifteen minutes, ten minutes longer than in the controls. (11)
This is admittedly unorthodox experiment did not have a ready explanation. One theory was that as the observer’s eye moved back-and-forth across the white sun, the eye inadvertently saw the yellow aura as well, which it could not shut off. LSD somehow had chronically disinhibited the perception of color. I shared my data with Dr. Ernst Wolf, chief of the psychophysics laboratory at the Massachusetts Eye and Ear Infirmary. Wolf was the senior psychophysicist there and remembered experimenting with mescaline as a student with Heinrich Klüver in Germany in the 1920s. In that work Klüver had described seeing geometric figures of spirals, checkerboards, and cobwebs under the effect of the drug which he called “form constants.” Documenting that these images persistent was important, both to the sufferers of HPPD, and what they might teach us about the brain’s visual system. Wolf was pleased I had come along. He proposed that we do a series of classical psychophysical studies in LSD users and controls. These included dark adaptation, critical flicker fusion perimetry, and visual thresholds across the retina.
We discovered the first quantified measures in HPPD subjects that set them apart from non-HPPD, non-LSD experienced controls. The HPPD subjects required on the average three times more light to see a test subject in the dark compared to controls. In testing flicker-fusion points we found that the LSD group compared to controls could only see pulsations at two-thirds the normal frequency. That is, when normal controls saw a flicker go off, the HPPD subjects continued to see the same flickering off of the light as “on.” (6)
How could we explain these findings? The dark adaptation study was preceded by a period of controlled illumination. Like the yellow aura in the previous study, it could be that in the LSD user a stimulated visual system, compared to controls, could not shut itself off. Instead, the test object was lost in a background of visual static, like a TV screen on but tuned to nothing. This theory would also explain the difficulty LSD subjects had in shutting off a pulsating light in the dark phase of the flicker–fusion test. In HPPD appeared to be a disorder of visual disinhibition.
Neurophysiological Studies of HPPD
There were occasional clues that HPPD was a disorder of the central nervous system, and not simply the eye. Pressing gently on one closed eye with a finger, the Ladd-Franklin maneuver, could occasionally elicit a variety of visual disturbances in that eye. But in the rare individual, imagery could spread to the other eye. Did that mean that a disinhibited visual cortex in HPPD was spreading information beyond its usual confines?
I had searched for anatomical abnormalities in MRIs of the brain and conventional EEGs and found little of significance. I shared my findings with Dr. Frank Duffy, Chief of Neurophysiology at the Children’s Hospital of Boston, who proposed a series of studies using a new technology of quantified electrophysiology, qEEG.
This system digitizes conventional EEG data, which then permits statistical and topographic comparisons between groups. While the EEGs that we acquired in HPPD subjects were conventionally unremarkable, that was not the case once the data has been digitized and mapped over the cerebral cortex of users and controls. Duffy and I found clear-cut differences between the two groups. First, when we measured how sensory information was processed in the brains of HPPD subjects, the information was increased in the LSD group. Second, they tended to be involved most frequently in the posterior brain where sensory processing occurs. And third, there was increased coherence of brain waves, a measure of connectivity between brain regions in LSD users, most commonly found in the occipital and temporal cortices. (7, 8)
A study of qEEG coherence in a 24-year-old HPPD patient. The nose is symbolized by a triangle at the top of the brain map. The white and red notations show abnormally increased connections in the occipital and temporal parts of the brain, which deal with visual perception.
Thus, qEEG showed that HPPD involves the cerebral cortex, especially the posterior regions of the brain, and that disinhibition appears to occur there.
The Drug Etiologies of HPPD
Agents reported to be associated with HPPD include LSD, mescaline, psilocybin, Ecstasy (MDMA). We have reported a single case from ketamine. An eight-year- old boy with no other drug history than treatment with methylphenidate (Ritalin) also presented with HPPD symptoms (author’s unpublished data). Also seen by not published were cases of HPPD from substituted phenethylamines such as “N- Bomb”. “N-Bomb” is dangerous. 19 deaths have been reported by the US Drug Enforcement Agency, including one with chemical identification at autopsy. (9, 10) The ease with which indoles and phenylethylamines can be modified raises the likelihood that this list of agents linked to HPPD will grow in the future.
Treatment of HPPD
There is no known treatment which results in the total remission of HPPD. Symptoms can be vexatious to treat, and not uncommonly are permanent. The most studied, and most helpful, medication for HPPD are benzodiazepines with long serum half-lives, such as clonazepam or diazepam. Benefits include the reduction of anxiety, panic attacks, and a reduction in the intensity of visual disturbances. However, in any population with a history of drug abuse clinical judgment is indicated.
In a laboratory setting, the ultra-short acting benzodiazepine midazolam intravenously reduced experimentally induced afterimagery in a dose-response fashion to control levels in a small HPPD sample. (11) The reader should note that this is not a proven treatment for HPPD, and should not be employed as a treatment under any circumstance. The experiment does show, however, that there is a good correlation between the symptoms of HPPD and the use of a benzodiazepine drug.
A controlled study used tolcapone and carbidopa, a drug combination with little abuse potential, in twenty cases, and found symptomatic relief in a third of the sample. A placebo reaction was not ruled out. (12) Transdermal clonidine has also been found to be helpful. (13) Self-medication with any of these agents is dangerous, and so not recommended without close supervision by a medical doctor.
Several drug classes are contraindicated in HPPD. These include benzodiazepines with short half-lives (e.g., alprazolam and lorazepam), because of reduced effectiveness in symptom control, and greater liability for abuse. Dopamine-2 blockers commonly used to treat psychosis may exacerbate HPPD. (14) Approximately 20% of HPPD patients suffer a comorbid psychosis. In such cases, the risk to benefit ratio of using dopamine blockers usually favors treatment of the psychosis as a priority.
Other treatments have a theoretical rationale but are untested. The antiseizure medication, levetiracetam, has been touted on the Internet as beneficial. The choline supplement, phosphatidylcholine, has been shown to improve sensory gating, a theoretical vulnerability in HPPD patients. (15)
Treatments without strong empirical evidence for their support include pergolide, amantadine, pramipexole, aripiprazole, methylfolate, SAMe, antiseizure medications, modafinil, buspirone, selegiline, other dopamine agonists, and norepinephrine agonists. The absence of safe and effective treatments for HPPD is a source of frustration for patients and clinicians alike. Desperation should not drive patients to self-experiment. Working carefully with a compassionate and knowledgeable clinician over time is the best treatment I can recommend until something better comes along.
Certain factors tend to indicate a good prognosis. These include drug abstinence, employment, relationships, psychological denial, a philosophical outlook, and patience. Poor prognostic indicators include the use of alcohol, marijuana, hallucinogens, or ketamine. The obsessive patient, given to a compulsive check of his visual symptoms from moment to moment, needs behavioral psychotherapy, especially since intentionality is one of the disorder’s sources of exacerbation.
HPPD patients also suffer from comorbid alcohol use disorders. Because alcohol has similar effects as the benzodiazepines in the short run, the HPPD patient is at risk to drink to alleviate symptoms. But the short half-life of alcohol results in a rebound of visual and anxiety symptoms, leading to more self-medication with alcohol, and eventually, alcohol dependence.
At least half of the time HPPD patients also suffer with major depression, panic disorder, and generalized anxiety disorder. This, perhaps, is where the clinician can do the greatest good. Our tools for treating substance abuse, depression, and anxiety are strong. Using them in the service of treating HPPD patients is almost always gratifying, despite the refractory nature of their visual symptoms.
What Does the Future Hold for Hallucinogens?
Albert Hoffmann who first synthesized LSD in 1938 called it his problem child. Society’s ambivalence has apparent since then, with initial excitement of its psychological and psychiatric promise only to lead to epidemic abuse and decades of governmental suppression of legitimate research.
A review shown above of favorable and unfavorable scientific reports from 1960 to 1994 illustrates attitudes towards Hoffmann’s problem child. (11) In the 1960s hope rose that LSD could help with depression, autism, alcoholism, and other disorders. As these drugs lost favor as a treatment and gained notoriety for their abuse, negative reports predominated. This curve appears to reflect not only scientific attitudes towards a specific drug, but a common human process throughout all of history in which a rising hope of new idea (treatment, religion, political movement) are dashed by sober reconsideration after a negative consequence, yet another warning to be careful what you wish for.
That said, it may be the curve is about to bound upwards once more as enthusiasm grows for this class of drugs to treat patients with depression, pain, PTSD, and those facing terminal illness. Stakeholders who advocate for a loosening of social controls over hallucinogens include a growing coalition of adventurers of the mind and more traditional voices calling for scientific research and clinical care. The bedrock principles in taking these drugs off the shelf and giving them to human beings are efficacy and safety. Do they work reliably? Are the claims scientifically valid and reproducible? Are there significant side effects that would ethically prevent their use? These are the tests that science and society must apply if hallucinogens can legitimately take their place in the modern pharmacopeia.
For many this class of drugs is also simply fun. A free society must constantly grapple with a citizen’s right to dictate what happens to his own mind and body, balancing this against the genuine risk of social harm. It is one thing for someone to enjoy feeling high, and another to feel high while flying a plane. This is a step beyond science, and more a question of social values, and ultimately one about the evolution of society.
Many important questions remain to be answered.
What is the biological basis for HPPD?
Is there a genetic vulnerability that predisposes people to HPPD?
Given the prevalence of drug use, what percent of users actually get HPPD?
What are the adverse functional effects of HPPD over time?
What are safe and effective treatments for HPPD?
Do hallucinogens play a role as a trigger to psychosis and other psychiatric disorders?
What are the psychological benefits to their use, and are such benefits sustained?
Can hallucinogens be used to treat psychiatric disorders? If so, which ones?
Can hallucinogens be modified which maximize their benefits while reducing their liabilities?
Compared to addictive substances, why is it that users tend to stop taking hallucinogens after a period of time?
Can hallucinogens serve as haptens which then lead to antibodies eventually blocking drug effects over time?
Governmental relaxation of controls over these drugs must occur if we are to answer these questions. The growing community of those supporting these changes in policy must also be more willing to deal with the scientific evidence about HPPD than simply denying it exists.
I am often asked why I spent so much time studying this problem, compared to other disorders of psychiatry. There are many reasons, chiefly among them that HPPD sufferers have been for too long disregarded by clinicians and others. There is also the process of disinhibition in the central nervous system that seems to be at the heart of HPPD. The fact that HPPD patients often report depression, anxiety, and panic disorders as well raises the intriguing question of whether these pervasive problems can be conceptualized as ones of brain disinhibition as well. For what are unwanted feelings, perceptions, and thoughts but a breakdown in the brain’s ability to keep them at bay through the vast inhibitory apparatus that it contains? In that light, the study of HPPD may lead to benefits to humankind that now are only dimly perceived.
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