Effects of Psilocybin in Obsessive-Compulsive DisorderPrincipal Investigators: Francisco A. Moreno,
MD, Pedro Delgado, MD, Alan J. Gelenberg, MD
University of Arizona
PURPOSE AND OBJECTIVES
The purpose of this project is to evaluate the effects of oral administration of psilocybin on the symptoms of obsessive compulsive disorder (OCD) in 10 subjects with this condition. The long-term objective is to evaluate the safety and therapeutic potential of serotonin (5-HT)-2A/2C receptor agonist treatment of OCD. Two important questions will be addressed in this protocol: 1) do potent 5-HT 2A/2C agonist hallucinogens lead to an acute decrease in the symptoms of OCD; 2) is a full hallucinogenic dose required to demonstrate significant reduction in the symptoms of OCD.
BRIEF RATIONALE AND BACKGROUND
Obsessive compulsive disorder (OCD) is a chronic and debilitating condition with a life time prevalence of 2 to 3 % worldwide. Some researchers estimate that OCD represents up to 10% of the population in outpatients psychiatric clinics, making it the fourth most common diagnosis after phobias, substance abuse, and major depression. OCD can have its onset in childhood and adolescence, sometimes as early as 2 years old. Males have an earlier onset than females, but in adulthood the incidence is similar in both genders. Mean age of onset is about 20 years (males 19 y/o, female 22 y/o). Most OCD patients developed the disorder by age 25 with only 15% presenting after the age of 35. Patients with OCD are commonly affected by other mental disorders. The lifetime prevalence of depression is 67%, phobias is 25%, other frequently encountered comorbid disorders include specific phobias, alcohol use disorders, and eating disorders. Most patients with OCD have abrupt onset, and most of them develop symptoms in response to a stressful event. OCD symptoms are commonly kept secret, delaying psychiatric treatment for about 5 to 10 years. Once treated, about 20 to 30% of OCD patients have a significant symptom improvement, 40 to 50% have partial improvement, and up to 40% of patients may not improve or worsen despite treatment. Common complications include: delusions, suicidality, panic, substance abuse, depression, and interpersonal difficulties, affecting productivity, and morbidity.
Although its etiology remains elusive, pharmacological challenge studies, as well as pharmacotherapy trials support the hypothesis that a dysregulation of serotonin (5-HT) is involved in OCD symptom formation. Nevertheless, peripheral and central markers of 5-HT activity (platelet binding studies, and CSF metabolite measurements) have given mixed results. Functional PET imaging studies have shown increases in metabolic rate activity in the frontal cortex, basal ganglia, and the cingulum of OCD patients. These changes are reversible after improvement with both pharmacological as well as by cognitive behavioral therapy. Structural brain studies like CT and MRI, also show decreased caudate size bilaterally.
It is now well established that 5-HT reuptake inhibitors, such as fluvoxamine, fluoxetine, paroxetine, and sertraline are effective in obsessive compulsive disorder (OCD). For example, in a 10-week, placebo-controlled, double-blind study carried out in 160 patients with OCD (Goodman et al., 1996), fluvoxamine (100-300 mg/day) was significantly more effective than placebo as assessed by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the National Institute of Mental Health Obsessive- Compulsive (NIMH-OC) scale and the Global Improvement item of the Clinical Global Impression (CGI) scale. The percentage of patients classified as "responders" (much or very much improved according to the Global Improvement item) was also significantly higher in the fluvoxamine group. In contrast, drugs such as desipramine which are primarily noradrenaline uptake inhibitors, are not effective (Goodman et al., 1990).
In spite of the established efficacy of potent 5-HT reuptake inhibitors in the treatment of OCD, these treatments are sub-optimal. The length of time required for improvement of patients undergoing treatment with 5-HT reuptake inhibitors appears to be quite long. Most patients that will ultimately improve do not show significant effects until at least 4 and up to 8 weeks of continuous treatment and the percentage of patients having satisfactory responses may only approach 50%, and most patients that do improve only have a 30 to 50% decrease in symptoms (Goodman et al., 1990).
Common treatments generally include pharmacotherapy, cognitive behavioral psychotherapy, or both. When these treatments fail, a series of atypical drug combination strategies may be tried with the hope of diminishing symptoms severity. ECT has limited efficacy as well. In cases where these interventions fail, such extreme measures as psychosurgery may be indicated. Psychosurgery is a dramatic, irreversible procedure with some risk of morbidity and mortality and limited clinical success rate.
Developing drugs that are more effective and faster acting for the treatment of OCD is of utmost importance and until recently, little hope was in hand. A new potential avenue of treatment may exist. There are several reported cases concerning the beneficial effects of hallucinogenic drugs (psilocybin and LSD), potent stimulators of 5-HT2A and 5-HT2C receptors, in patients with OCD (Brandrup and Vanggaard, 1977, Rapoport, 1987, Moreno and Delgado, 1997) and related disorders such as body dysmorphic disorder (Hanes, 1996). For example, a 34 year-old male had suffered from OCD symptoms (e.g., checking compulsions, counting compulsions, having to do things a certain number of times and a variety of other rituals) since the age of 14 years. However, he had abused hallucinogens recreationally from the age of 18 and found that, during the time that he was intoxicated, he had no obsessions or compulsions. He then began chronic use of hallucinogens and found that the obsessions and compulsions actually went into remission for periods of several months after he stopped using them (Moreno and Delgado, 1997).
Another patient with body dysmorphic disorder showed similar responses after the use of psilocybin. Her concerns about facial asymmetry were relieved within four or five hours after ingestion of this drug (Hanes, 1996).
These findings may be considered to support the 5-HT hypothesis, suggesting that enhancement of neurotransmission through 5-HT2A or 5-HT2C receptors may be the a common feature of drugs with therapeutic effects in the treatment of OCD. Irrespective of the actual mechanism of action of hallucinogenic drugs in OCD, if it can be established that this class of drug can indeed lead to rapid and substantial reduction in OCD symptoms, then it opens the way for a variety of future studies with new drugs that might possibly have the anti-OCD but not the psychedelic effects. Drugs that potently block serotonin (5-HT) reuptake lead to time-delayed therapeutic effects in OCD, often taking 8 to 12 weeks.
Psilocybin, LSD, and mescaline are extremely potent agonists at 5-HT2A and 5-HT2C receptors and their binding potency to these receptors is correlated with their human potency as hallucinogens (Glennon et al., 1984). The acute improvement in symptoms described in the published case reports (Brandrup and Vanggaard, 1977, Rapoport, 1987, Moreno and Delgado, 1997) suggests that interactions with 5-HT2A and 5-HT2C receptors may be an essential component of anti-OCD drug action. The observations that administration of the non-selective 5-HT antagonists metergoline or ritanserin exacerbate OCD symptoms further supports this view.
The use of hallucinogens in psychiatry was greatly favored during the late 1950s and 1960s. The controversy and stigma about their illegal use, and the negative outcome of alcoholic treatment studies facilitated the loss of popularity of these drugs. Most of the large studies about long term safety of hallucinogens date back to the 1960s and 1970s. In 1971 McGlothlin and Arnold published a ten year follow study of medical LSD use. The results from surveying 247 subjects who had used LSD found little evidence that measurable, lasting personality, belief, value, attitude, or behavior changes were produced in the sample as a whole. LSD also showed to be less attractive in continued use, and almost always self limiting in the long term. McGlothlin et al., 1969 reported lack of generalized evidence of organicity following repeated LSD ingestion. Two other studies in the effects of LSD use (Blacker et al., 1968, and Cohen and Eduards, 1971) agree with these findings.
Only a fraction of hallucinogen research is accounted for by psilocybin. Although much of the information about LSD and other psychedelic drugs can be generalized to psilocybin, this drug has some specific qualities briefly described below. Sandoz pharmaceuticals first produced synthetic psilocybin. A vast review of the literature including 101 scientific publications dating back to 1950s was made available for us from Sandoz pharmaceuticals. A selected review of those publications suggest that the doses of psilocybin proposed in this protocol (100 to 300 mcg/Kg), are safe and able to induce a psychedelic experience. That is, a potentially severe distortion of perception and thinking which can include visual, auditory, somatic, olfactory and gustatory illusions or hallucinations, and synesthesias an unusual mixing of sensations where for example sounds may be perceived as pictures, images or colors may be perceived as tastes. These experiences are usually accompanied by intense mood swings, or exaggeration of the emotional state existing at the time of ingestion of the drug. This can include elation or euphoria, depression, anxiety and panic feelings. While these experiences are described by many people as pleasant or profound, to some it may be frightening and confusing. The symptoms listed above usually begin within the first hour after taking the psilocybin and can last for up to 12 hours, although they generally resolve 6 hours after ingestion.
Psilocybin can also cause dizziness, nausea, vomiting, headaches, increased pulse and blood pressure, dilated pupils, slightly elevated temperature, raising of skin-hair, and increased reflexes. These symptoms usually can begin 20 to 30 minutes after taking the drug and can last up to 6 hours.
At times psychedelic sensations or memories of these sensations may be re-experienced in the future. These are called "flashbacks", it is not well established how often they occur. Studies done in LSD users (McGlothin and Arnold 1971) suggest that subjects with less than 10 exposures report flashbacks at a rate of 12%, and they were less common in the medically controlled used when compared to street users. Psychosis has been associated with the use of hallucinogens, and studies on psilocybin are limited. Cohen 1960 estimated the incidence of LSD related psychosis to be about 0.8/1000 experimental subjects. McGlothin and Arnold in 1971 reported 1 case in 247 LSD users surveyed. Other complications such as prolonged, suicide, or homicide have been attributed to use of hallucinogenic drugs. It is unclear to what extent this effects can be caused by hallucinogenic drugs, but it is clear that if psychosis or exaggerated mood conditions occur, individuals may be at higher risk for these complications. Addiction to psychedelic drugs is for the most part considered unlikely
POPULATION AND SAMPLE
1. Estimated number of subjects: A maximum of 10 subjects will be Tested.
2. Description of population to be recruited and rationale for their participation (indicate age range):
Ten subjects (ideally 5 males and 5 females) between the ages of 21-60 with moderate to severe and refractory OCD (DSM-IV), but no concurrent medical or psychiatric (AXIS-I) disorders, and no past personal or family history of psychosis will be enrolled. Subjects must have failed at least one adequate trial of usual care treatment. They must have had prior experience with psychedelic drugs including at least one but no more than twenty experiences with any of the following: (LSD, psilocybin, mescaline or other related compounds. The use of these substances should have occurred as far as ten years back, and not closer than one month prior to enrollment. Non-related compounds like MDMA and marijuana do not qualify as previous experience).
3. Source of subjects and method of recruitment (if a "captive" population, i.e., students, is being involved, please LEFT [submit a copy of advertisement for approval]): Newspaper advertisements, referral from local physicians, community mental health agencies, and word-of-mouth. A copy of the advertisement is included.
4. Criteria for exclusion of potential subjects:
Subjects will be admitted if after diagnostic interview using the Structured Clinical Interview for DSM-IV (SCID) they are found to have no comorbid mental disorder, substance abuse problem, or a personal or family history of psychosis. Healthy subjects must also be free of any medical illness based on physical examination and routine blood testing. They should not require any prescription or over the counter medications on a regular basis, and any medication they may have taken, should have been stopped long enough in the past to allow for their elimination prior to start the administration of the study drug. Women who are pregnant, lactating, or unwilling/unable to practice medically acceptable birth control during the study, will also be excluded.
5. What (if anything) is planned to encourage the recruitment of minorities and women: Due to the small size of this pilot study, we suspect that the population characteristics could be skewed compared to the ethnic mixture of Southern Arizona. However, vigorous attempts will be made to insure that as much as is possible, the study population does represent of the population in the Southern Arizona region and is composed of an ethnic breakdown of 60% non-Hispanic Anglo American, 30% Mexican American, 3% African American and 2-3% Native American. We will attempt to recruit 5 males and 5 females.
METHODOLOGY AND RESEARCH PROTOCOL
6. Where will the project be conducted (room number or area):
Research area of the Department of Psychiatry in the 7th floor, and the inpatient unit (UMC 2-East) at the Arizona Health Sciences Center.
7. General description of procedures:
This project will administrate oral psilocybin to 10 subjects who have severe OCD and are treatment resistant. It will assess the safety and therapeutic effects of psilocybin at decreasing the amount and severity of obsessions and compulsions in those patients.
If subjects are found to be suitable for the study, after written informed consent is obtained, they will be scheduled for one to four testing sessions as described below, with different doses each session administered in a double-blind randomized procedure.
Testing: Each test occurs over a 24-hour period. Subjects will arrive to the outpatient research clinic at 8:00 AM, and will receive clinician and self ratings. At 8:30 AM subjects will receive their dose of psilocybin by mouth. Subjects will be asked to remain in the study room at the outpatient clinic until 6:00 PM. During this time, subjects will not be allowed to sleep but can move about, eat or drink fluids at leisure, and go to the bathroom. Questionnaires regarding OCD symptoms, and psychedelic experiences will be obtained at 1,4, and 8 hours after taking psilocybin. Subjects will be continuously monitored by study personal during those first 8 hours and at 6:00 PM they will be placed in a private room at the psychiatric unit of the University Medical Center, where they will spend the night. The next day, subjects will return to the outpatient psychiatry clinic where they will once again complete clinician- and self- ratings and be interviewed by one of the study investigators. Subjects feeling well enough to go home, will be allowed to leave the hospital. If subjects are not feeling well enough, or in the opinion of one of the investigators the subjects is felt to be unsafe to go home, subjects may be asked to remain in the hospital. Subjects will only be discharged from the hospital when the investigators are assured of the subjects safety.
If no beneficial or adverse effects are observed, subjects will be asked to return for up to three additional tests. Each testing session will be separated by about two weeks. The protocol will be identical for all four tests when necessary. If subjects have a dramatic improvement in OCD symptoms further testing will be unnecessary. Conversely, if serious adverse effects are observed, testing will be discontinued.
In order to monitor for safety, study personnel will contact all subjects weekly for one month and monthly for six months, or more frequently if considered necessary by the investigators. Subjects will also be encouraged to call the investigators if adverse events occur.
The table below describes the timing of psilocybin administration and subsequent assessment.
Table 1. Schedule for Psilocybin Test Sessions
8:00 AM Arrive at the Research Clinic, obtain clinician and self-ratings, vital signs
8:30 AM Administration of psilocybin
9:30 AM Clinician- and self-ratings, vital signs
12:30 PM Clinician- and self-ratings, vital signs
4:30 PM Clinician- and self-ratings, vital signs
6:00 PM Transfer to a private inpatient psychiatric room at our inpatient unit
8:00 AM (Next day) Clinician- and self-ratings, vital signs. In the absence of side effects, or indicators of high risk subjects will be allowed to leave.
8. Measurements to be conducted:
Initial screening will involve brief, focused review of inclusion and exclusion criteria and medical and psychiatric history. Subsequent evaluation for all subjects will involve a complete medical and psychiatric history and a complete physical (including EKG and routine laboratory studies) and neurological exam. The routine laboratory studies will include a CBC, FBS, BUN, Creatinine, Electrolytes, LFTs, substance of abuse screen, and urine pregnancy test for women of childbearing potential. Urine pregnancy test will be repeated on the day of each drug administration session. Behavioral ratings will include the Yale Brown Obsessive-Compulsive Scale (Y- BOCS) (Goodman et al. 1986), Structured Clinical Interview of DSM-IV patient version (SCID-P), SCID-II interview, and the Hallucinogen Rating Scale (HRS) (Strassman et al., 1994).
9. Approved drugs and dosage:
a. Dose range approved for clinical use: NA
b. Dose to be administered in this project: NA
10. Experimental drugs/devices:
a. Not approved by FDA: Psilocybin
b. Approved by FDA but not approved for use for this experimental procedure: NA
c. Doses reported in previous human clinical trials (as reported in IND application): 2 to 30 mg.
11. Special instruments, technical equipment, radioisotopes, or investigational devices (approval of Biomedical Engineering or Clinical Radioisotope Committee): NA
12. Tissue, blood, or other fluid collections (amount and frequency):
Blood and urine samples for routine medical safety testing will be obtained prior to beginning the study (CBC, BUN, Creatinine, electrolytes, Liver Function Tests, urinalysis). This will require approximately 20 cc (approx. 2/3 oz). Urine samples (approx. 1 oz) for pregnancy test will be obtained from women of child- bearing potential on the day of each test session.
NOTE: The use of human blood, sera, bone, tissues, fluids, and excreta in laboratory research requires Biosafety Level 2 practices as well as the use of Standard Precautions (formerly Universal Precautions) as required by OSHA. Biosafety Level 2 practices are described in the CDC-NIH Handbook for Biomedical and Microbiological Laboratories, 3rd Edition. Please contact the Institutional Biosafety Committee at 621-3441 for a copy of this handbook.
13. Diet modification or restriction:
Subjects will be asked to refrain from the use of alcohol, drugs of abuse, and medicinal natural products for the duration of the study.
14. Injections (route, frequency, and quantity): None
15. Physical activity (nature and extent): None
16. Special tests or procedures not included in above:
Several special procedures will be performed in order to minimize risk to patients who participate in this study. During testing each subject will be under constant observation, they will be kept in the hospital overnight, and will be assessed by the investigator prior to leaving the next day. If subjects are found to be suffering or at risk of complications from testing at the projected time of discharge, they will be kept in the hospital until they are felt to be safe. If complications should result during testing, the investigators will be available to treat them as they arise (i.e.: panic attacks, abnormal mood states, psychosis, and others). If adverse events are observed such as anxiety or panic they will be treated with therapeutic techniques, if necessary for cases of extreme agitation or seizures IV Diazepam will be utilized. Subjects experiencing difficult emotions will be talked through the experience by trained clinicians, or given risperidone or olanzepine (5-HT 2a/2c blockers) as antidotes if considered necessary. Possible medical complications will be treated at the Emergency Department of the Health Sciences Center.
Subjects will be debriefed from the hallucinogen experience prior to their transfer to the inpatient psychiatric unit.
17. Is hospitalization required specifically for the proposed research, and if so, extent: As mentioned above, overnight hospitalization has been included in our protocol for safety reasons. The rational behind it is to extend the period of supervised observation to a minimum of 24 hours.
18. Estimated total costs to human subjects for all of the above: None
19. Will monetary or other compensation be offered to the human subject: Subjects will not receive compensation monetary or otherwise for participation in the study.
POSSIBLE REACTIONS OR COMPLICATIONS
(List only those due to the experimental procedure)
20. To approved drug(s) or radiation therapy: NA
21. To experimental drug(s) (as listed in IND application): None
a. Most common complications (list incidence, if known): At the higher doses, psilocybin will cause a psychedelic experience, a potentially severe distortion of perception and thinking. This can include visual, auditory, somatic, olfactory and gustatory illusions or hallucinations, and synesthesias an unusual mixing of sensations where for example sounds may be perceived as pictures, images or colors may be perceived as tastes. These experiences are usually accompanied by intense mood swings, or exaggeration of the emotional state existing at the time of ingestion of the drug. This can include elation or euphoria, depression, anxiety and panic feelings. While these experiences are described by many people as pleasant or profound, to some it may be frightening and confusing. The symptoms listed above usually begin within the first hour after taking the psilocybin and can last for up to 12 hours, although they generally resolve 6 hours after ingestion.
b. Possible, but less common complications (list incidence, if known): At times psychedelic sensations or memories of these sensations may be re- experienced in the future. These are called "flashbacks", it is not well established how often they occur. Studies done in LSD users (McGlothin and Arnold 1971) suggest that subjects with less than 10 exposures report flashbacks at a rate of 12%, and they were less common in the medically controlled used when compared to street users. Psychosis has been associated with the use of hallucinogens, and studies on psilocybin are limited. Cohen 1960 estimated the incidence of LSD related psychosis to be about 0.8/1000 experimental subjects. McGlothin and Arnold in 1971 reported 1 case in 247 LSD users surveyed. Other complications such as prolonged, suicide, or homicide have been attributed to use of hallucinogenic drugs. It is unclear to what extent these effects can be caused by hallucinogenic drugs, but it is clear that if psychosis or exaggerated mood conditions occur, individuals may be at higher risk for these complications. Addiction to psychedelic drugs is for the most part considered unlikely.
22. To physical activity involved: None
23. To other tests, measurements, or procedural requirements: None
24. Major risks of injury most likely to be encountered under the conditions of this protocol:
The most important risks are those derived from the experimental drug as described above.
25. Risks of secondary importance, or those least likely to occur under the conditions of this protocol:
Subjects will have tests resulting in more blood drawing than usual. Blood drawing will be done in the standard clinical fashion. Bruising and infection are always potential risks and will be treated appropriately if they occur.
26. Identify persons who will have access to specimens, results, and data:
Francisco Moreno, MD, and Pedro L. Delgado, MD
27. To what extent and to whom will identity of human subjects be revealed:
Unless required by law, only the investigators listed above, other study personnel, and the US Food and Drug administration will have access to confidential data identifying subjects by name.
28. Will a certificate of confidentiality be utilized: YES
29. Where will the signed subject consent forms be stored so that they will be easily accessible in the event of on-site visits from authorities (include administrative office and room number):
A copy of the consent form will be filed in room 7402 of the Psychiatry Research Program in the Arizona Health Sciences Center.
PRECAUTIONS AND SAFEGUARDS TO BE USED
30. For medical emergency: Patients in this study will be monitored closely for change in behavior or in medical condition. During the testing phase a nurse clinician will be present at all times and one of the investigators will be physically available. If a medical emergency were to occur during testing this would be handled by calling an audible code or transporting the patient to the emergency room. This decision will be made by the senior on site physician. If an emergency were to occur during the week the study patient would contact the investigator on call for the week. A weekly call schedule will be developed designating a specific physician responsible for emergency after hours calls. The UMC operator will be given a copy of the Psychiatry Research On Call Schedule on a monthly basis. Emergency calls during the day will be received the responsible study staff. Study staff will be available 24 hours/day at the following numbers:
Francisco Moreno, MD Pedro Delgado, MD
Office: 626-6509 Office 626-6509
Or Pager #3118 Or Pager #2786
31. Availability of consulting coverage: The Staff Physicians of the University Medical Center will be available.
32. Surveillance by technical personnel: During the testing phase patients will be under constant supervision by a nurse clinician.
33. Surveillance of equipment used: Not applicable
34. Other factors (environmental, social, psychological)
35. Protection of privacy and confidentiality of data (ultimate means of disposal of data): Privacy and confidentiality will be maintained through the use of the procedures outline in sections #26 - 29. The data obtained from this study will be kept by the investigators indefinitely. If data is to be destroyed it will be destroyed through the document shredder in the medical records area of the Department of Psychiatry.
SIGNIFICANCE OF PROJECT
36. Potential benefits to the human subjects (if any): Subjects in this study will receive a careful physical, neurological and psychiatric examination, and a series of blood examinations.
37. Potential benefits of the study to society and possibility for future expansion:
This test will evaluate the use of 5-HT agonists for OCD. A greater understanding of the neurochemical systems involved in OCD and the mechanism of antiobsessive action could provide an impetus for development of more effective and rapid treatments for this disorder.
38. Give your evaluation of the extent to which the possible benefits to be derived outweigh the likelihood of injury and risk to which the human subject is exposed: The patients would be exposed to the risks of psilocybin, and more frequent blood drawing. In addition they would have the inconvenience of participating in the studies. The benefit balancing this would be the possibility of gaining a more complete picture of the biochemical nature of OCD, facilitating the development of novel therapeutic options. The impact of this on the treatment of OCD could be enormous and would balance off the negative risks.
39. What alternative procedure could be considered to conduct this study which would reduce the physical, psychological, or social risk factors (explain why they were not proposed or included originally for this study): There is no other available forms of therapy that will acutely and dramatically improve such a disabling condition as OCD. Other 5-HT agonist agents without hallucinogenic properties are not available at this point for this study.
40. What may be revealed that is not currently known: The importance of this study is that it will for the first time confirm in a controlled environment that 5-HT 2a and 2c antagonists have significant therapeutic value in the population described above. The use of psychedelic drugs in psychiatry has a long and complex history. This study may facilitate the development of agents that may affect the same receptor system but lacking some of the adverse events.