Conditions: Nicotine Dependence
Keywords: Psilocybin Smoking cessation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 82
Healthy volunteers: yes

Brief summary:
One of the most promising lines of investigation for the therapeutic use of hallucinogens in the 1960s and 1970s was in the treatment of drug dependence. The investigators propose to examine psilocybin administration combined with a structured smoking cessation treatment program in nicotine dependent individuals in order to provide preliminary data on the efficacy of this combined treatment for smoking cessation. Prior work in the investigators laboratory has shown that under carefully prepared and supportive conditions, psilocybin administration can facilitate highly salient experiences with enduring personal meaning and spiritual significance. It is plausible that embedding such highly meaningful experiences into a drug dependence cessation attempt may provide an enduring motivation for remaining abstinent. Cigarette smoking is a good model system for studying drug dependence because users are less likely to be challenged by the many social and economic impairments that often accompany dependence on other drugs such as cocaine, heroin, or alcohol. More specifically, the investigators propose to conduct a randomized controlled comparative efficacy study in which either psilocybin or transdermal nicotine patch are administered under highly supportive conditions to individuals who are nicotine-dependent cigarette smokers, who have had multiple unsuccessful quit attempts, and who continue to desire to quit smoking. Other than nicotine dependence, participants will be healthy. Fifteen participants have already completed a preliminary open-label pilot-study with no control condition. Eighty additional participants will be enrolled and randomized to either psilocybin (n=40), or nicotine patch (n=40) treatment. Participants will receive a 13-week course of cognitive behavioral therapy for smoking cessation, with Target Quit Date set for week 5. After several preparation meetings with study monitors, participants will have either a single day-long psilocybin session using a high dose (30 mg/70 kg), or a standard 8 to 10-week course of nicotine patch treatment. Participant smoking status will be assessed repeatedly for 8 weeks after the Target Quit Date, including biological verification of smoking status through breath and urine samples. Smoking status will also be assessed at three follow up sessions approximately 3, 6, and 12 months after the Target Quit Date. Additionally, 50 of these participants (25 per treatment condition) will undergo MRI scanning before and after Target Quit Date to assess the brain-based mechanisms associated with these treatments. Individuals assigned to the nicotine patch study treatment condition will be eligible to undergo an optional high dose psilocybin session after completing the 6-month follow-up meeting.

Detailed description:

Arms:
arm 1: Participants will receive a 13-week cognitive behavioral intervention for smoking cessation, with a high dose of psilocybin (30mg / 70kg) to be administered on the Target Quit Date in week 5. arm 2: Participants will receive a 13-week cognitive behavioral intervention for smoking cessation, with a standard 8 to 10-week regimen of NRT to be administered beginning on the Target Quit Date in week 5. NRT for this study will be a transdermal nicotine patch administered according to recommended label usage (For individuals who smoke more than 10 cigarettes per day: 21mg daily weeks 1-6, 14mg daily weeks 7-8, 7mg daily weeks 9-10. For individuals who smoke 10 or less cigarettes per day: 14mg daily for weeks 1-6, 7mg daily for weeks 7-8).

Interventions: intervention 1: Psilocybin-assisted treatment intervention 2: Nicotine Replacement Therapy (NRT)
Intervention descriptions: intervention 1: Participants will be administered 30 mg/70 kg psilocybin. Preliminary evidence from our ongoing psilocybin dose-effects study suggests that this dose is associated with mystical-type experiences. intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
Date: April 15, 2024  
Principal Investigator: Matthew W. Johnson 
Application Number: NA_00016166 
 
JHMIRB eFormA 01 
Version 3 Dated: 06/2007 
 
Page 1 of 44 
 
 
 
 
 
Psilocybin-Facilitated Smoking Cessation Treatment: A Pilot Study 
 
NCT01943994 
 
April 15, 2024 
 
 


Date: April 15, 2024  
Principal Investigator: Matthew W. Johnson 
Application Number: NA_00016166 
 
JHMIRB eFormA 01 
Version 3 Dated: 06/2007 
 
Page 2 of 44 
 
Johns Hopkins Medicine - eForm A 
• Use the section headings to write the eForm A, inserting the appropriate material in 
each. If a section is not applicable, leave heading in and insert N/A. 
• When submitting eForm A (new or revised), enter the date submitted to the field at 
the top of eForm A. 
****************************************************************************** 
1. Abstract 
a. Provide no more than a one page research abstract briefly stating the problem, the 
research hypothesis, and the importance of the research. 
 
One of the most promising lines of investigation for the therapeutic use of hallucinogens in the 
1960s and 1970s was in the treatment of drug dependence. However, these studies did not 
involve the rigor and controls expected of modern clinical psychopharmacology research, 
making the efficacy of this approach difficult to judge. We propose to examine psilocybin 
administration combined with a structured smoking cessation program in nicotine dependent 
individuals to provide preliminary data on the efficacy of this combined treatment in smoking 
cessation. Prior work in our laboratory has shown that under carefully prepared and supportive 
conditions, psilocybin administration can facilitate highly salient experiences with enduring 
personal meaning and spiritual significance (Griffiths et al., 2006, 2008, 2011). It is plausible 
that embedding such highly meaningful experiences into a drug dependence cessation attempt 
may provide an enduring motivation for remaining abstinent. Cigarette smoking is a good model 
system for studying drug dependence because users are less likely to be challenged by the many 
social and economic impairments that often accompany dependence on other drugs such as 
cocaine, heroin, or alcohol. More specifically, we propose to conduct a pilot study in which 
psilocybin is administered under highly supportive conditions to individuals who are nicotine-
dependent cigarette smokers, who have had multiple unsuccessful quit attempts, and who 
continue to desire to quit smoking. Other than nicotine dependence, participants will be healthy.  
 
In total, 115 participants will complete this pilot study. Fifteen individuals have already 
undergone the initially approved protocol with no clinically significant adverse events. A further 
100 participants will be randomized to a psilocybin condition or a nicotine replacement therapy 
(NRT; i.e., transdermal nicotine patch) condition, 60 of whom will be studied with functional 
neuroimaging procedures. The NRT condition will serve as an important control for evaluating 
relative efficacy of the psilocybin condition, as well as examining differences in neuroimaging 
results. After screening and enrollment, individuals who are eligible for MRI scanning (n=60) 
will be invited to complete an optional preliminary sub-study protocol consisting of a 6-8 hour 
MRI scan, blood draw, and questionnaire assessment at the National Institute on Drug Abuse 
(NIDA) Intramural Research Program on the Johns Hopkins Bayview Campus. After completing 
the sub-study protocol, or opting out, participants will begin a 13-week cognitive-behavioral 
smoking cessation intervention, with Target Quit Date (TQD) set in approximately week 5. 
Participants who are eligible for and willing to participate in MRI scanning (n=60), will have 
MRI scans conducted in weeks 2 and 5, and at 3-month follow-up for those participants who 
have maintained smoking abstinence to that point. Individuals who do not meet MRI scanning 
inclusion criteria, but are otherwise eligible to enroll (n=40), will complete only the treatment-
related portions of the study. 
 
During the third treatment meeting in week 3, participants will be randomized into one of 
two treatment conditions (i.e., psilocybin or NRT). In one condition a single high-dose 


Date: April 15, 2024  
Principal Investigator: Matthew W. Johnson 
Application Number: NA_00016166 
 
JHMIRB eFormA 01 
Version 3 Dated: 06/2007 
 
Page 3 of 44 
(30mg/70kg) of psilocybin will be administered in the context of a 13-week smoking cessation 
treatment protocol. In the other condition an 8 to 10 week regimen of NRT (patch) will be 
administered within the same 13-week treatment protocol. Participants in both conditions will 
meet weekly with study staff during weeks 1-7, and at two-week intervals during weeks 8-13 
(i.e., in weeks 9, 11, and 13) of the 13-week treatment period. All participants will be asked to 
complete follow-up meetings at 3, 6, and 12 months post-TQD to assess smoking status and 
complete questionnaires. Additionally, in order to prevent differential dropout driven by 
individuals who hope to receive the novel psilocybin treatment, participants randomized to the 
NRT condition will be offered an optional psilocybin (30 mg/70 kg) session after completing 
their 6-month follow-up. 
 
A number of measures that assess the psychological process of smoking cessation will be 
utilized at intake and repeatedly after the psilocybin session or initiation of NRT. In order to 
explore the contribution of spiritual experience to smoking cessation success in the psilocybin 
treatment condition, questionnaires that assess the spiritual nature of the psilocybin session 
experiences will be given after the psilocybin session. In order to assess the hypothesis that 
spiritual experience or smoking cessation is associated with changes in immune function or 
stress hormones, blood samples at baseline and 1-week post-TQD will be collected from both 
groups for cytokine and hormonal analyses when possible. Diurnal saliva samples of cortisol will 
also be assessed at baseline, and 1-week post-TQD. In order to examine neural mechanisms 
associated with psilocybin-facilitated smoking cessation, MRI data will be compared within-
subjects and between treatment groups in a subset of up to 60 participants who complete MRI 
scanning procedures.  
 
2. Objectives (include all primary and secondary objectives) 
Primary objective: This is a pilot study to provide preliminary evidence on the efficacy of 
psilocybin administration combined with a structured smoking cessation program for the 
treatment of nicotine dependence. In order to differentiate the role of psilocybin from the role of 
cognitive-behavioral therapy and support from study staff, a randomized control group will be 
utilized. Participants in the control condition will receive a matched cognitive-behavioral 
intervention in conjunction with NRT. The results should also provide information about clinical 
trends that may be compared with previously published smoking cessation research that utilized 
cognitive-behavioral therapy or NRT (e.g., Fiore et al., 1994; Stapleton et al., 2013; Sykes & 
Marks, 2004). Such trends will indicate whether a larger-scale, rigorously controlled 
experimental study is warranted.  
 
Secondary objective: In addition to providing preliminary information on efficacy, the proposed 
pilot study will also provide valuable clinical experience for us to continue developing a 
psilocybin-based clinical intervention for treatment of drug dependence (e.g., smoking 
cessation). Such clinical experience will consist of both qualitative data from participant 
interviews and a battery of quantitative outcome measures, most of which are well-validated 
instruments with demonstrated clinical relevance. These measures will provide data that indicate 
which factors are theoretically relevant to the proposed intervention, and may assist in the design 
of further controlled trials if follow up investigation is warranted. In addition to the assessment 
of mystical-type experience (implicated as important to the attribution of behavioral change in 
previous research; Garcia-Romeu et al., 2015; Griffiths et al., 2006), relevant factors to be 
studied include self-efficacy, personal values, temporal perspective, and mood, (which are 
known to relate to nicotine dependence or smoking cessation). Outcome measures also include 
blood and saliva hormonal markers of stress. Blood samples will additionally allow for the 


Date: April 15, 2024  
Principal Investigator: Matthew W. Johnson 
Application Number: NA_00016166 
 
JHMIRB eFormA 01 
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assessment of cytokine markers of immune function, which will provide an opportunity to 
examine the hypothesized link between mystical-type experience and improved immune function 
(Roberts, 2006). Finally, the collection of MRI data will allow for a preliminary examination of 
underlying neural mechanisms that may play a role in psilocybin-facilitated smoking cessation, 
including the intermediate and persisting effects of psilocybin on resting state functional 
connectivity, and potential brain-based factors that may be useful predictors or mediators of 
treatment outcome. 
 
3. Study Procedures 
a. Study design, including the sequence and timing of study procedures (distinguish 
research procedures from those that are part of routine care). 
Study design: For this revised study protocol we will randomize 80 participants to complete a 
13-week cognitive-behavioral therapy treatment protocol involving either a single high-dose 
(30mg/70kg) administration of psilocybin, or an 8 to 10 week course of NRT (transdermal 
nicotine patch) for smoking cessation. Participants will be nicotine-dependent cigarette smokers, 
who have had multiple unsuccessful quit attempts, and who continue to desire to quit smoking. 
Other than nicotine dependence, participants will be physically and psychologically healthy. In 
total, 95 participants will complete the study, including 15 individuals who have already 
completed psilocybin-facilitated treatment before the current protocol modifications, and 80 
further individuals to be recruited for the revised study design including NRT control arm. Fifty 
participants will also undergo MRI data collection before and after treatment to inform 
neurobiological mechanisms of action. After screening and enrollment, participants will 
complete several baseline measures, and those who have consented to participate in the MRI 
scanning component will be invited to participate in an optional NIDA sub-study protocol. 
Participants will begin a 13-week cognitive-behavioral smoking cessation program consisting of 
weekly meetings with two trained study staff members for weeks 1-7 of study treatment, and 
meetings every other week thereafter (i.e., weeks 9, 11, and 13). For the revised study protocol 
up to 60 participants will undergo an MRI scan in week 2 of study treatment, and will be 
required to abstain from smoking for 24 hours before all MRI scans as verified by breath carbon 
monoxide measures. An additional 30 individuals who do not meet MRI scanning inclusion 
criteria (e.g., are left handed), but are otherwise eligible to enroll, will complete only the 
treatment-related portions of the study. During the third treatment meeting in week 3, 
participants will be randomized into one of two treatment conditions (i.e., psilocybin or NRT).  
 
After randomization, the 40 participants assigned to the psilocybin condition will receive 
specialized preparation for their psilocybin session in treatment meetings 3 and 4. They will then 
be administered 30mg/70kg psilocybin on their mutually agreed upon Target Quit Date (TQD) in 
approximately week 5. These participants will meet with study staff the day after their psilocybin 
session for debriefing, and 25 of these will additionally complete a 4-6 hour post-psilocybin MRI 
scan that day. Treatment meetings will continue weekly for two weeks after the psilocybin 
session, and at 2-week intervals from weeks 9 through 13 to discuss the session experience and 
to provide support for smoking cessation. Participant smoking status will be assessed repeatedly 
at five meetings after the psilocybin session using self-report and breath carbon monoxide (CO) 
samples. Smoking status will also be assessed at three follow up meetings approximately 3, 6, 
and 12 months after the psilocybin session using self-report, breath, and urine samples. All study 
meetings will have the option to be completed remotely using a secure online format, including 
remote breath CO monitoring and mailed in or at home urine sample tests, with the exception of 
physical examination during initial screening, psilocybin sessions, and MRI scan procedures.  


Date: April 15, 2024  
Principal Investigator: Matthew W. Johnson 
Application Number: NA_00016166 
 
JHMIRB eFormA 01 
Version 3 Dated: 06/2007 
 
Page 5 of 44 
 
After randomization, the 40 participants in the NRT condition (matched for age, sex, IQ, 
and smoking severity) will receive specialized preparation for NRT administration. In 
approximately week 5, these participants will begin a standard 8 to 10 week NRT treatment 
regimen according to recommended label usage (For individuals who smoke more than 10 
cigarettes per day: 21mg daily weeks 1-6, 14mg daily weeks 7-8, 7mg daily weeks 9-10. For 
individuals who smoke 10 or less cigarettes per day: 14mg daily for weeks 1-6, 7mg daily for 
weeks 7-8; FDA label, PDR.net). Participants in the NRT condition will have brief weekly 
counseling meetings and provide exhaled CO samples to test for smoking status in weeks 6, 7, 9, 
11, and 13. These individuals will also have follow-up meetings at approximately 3, 6, and 12 
months post target-quit date to assess smoking status. Participants randomized to the NRT 
condition who are also completing the MRI portion of the study (n=25) will complete their 
second MRI scan in week 5, immediately before initiating use of the nicotine patch. For both 
treatment conditions, MRI participating volunteers who provide biologically verified (i.e., breath 
CO), and self-report seven-day point prevalence abstinence at 3 months post-TQD will receive a 
final follow-up MRI scan. 
 
After completing the 6-month follow-up, participants initially randomized to the NRT 
condition (n=40) will be given the option to undergo a single high-dose (30mg/70kg) psilocybin 
session. If they choose to take part, they will receive two weekly preparation meetings, one 
psilocybin session and next-day integration meeting, and two weekly follow-up meetings. For 
individuals still smoking at that time, the session will serve as an additional quit attempt and 
provide further data on psilocybin-facilitated smoking cessation. For participants who are no 
longer smoking, the session will focus on promoting long-term abstinence. The rationale for 
offering an optional psilocybin session to all participants in the NRT condition is twofold. 
Firstly, we hope to reduce differential dropout among participants randomized to the NRT 
condition, and encourage them to complete study treatment through 6-month follow-up. 
Secondly, in offering this optional session to those who were both successful and unsuccessful in 
quitting smoking using NRT, we can avoid encouraging poor treatment compliance in the NRT 
condition (i.e., intentionally failing to quit smoking in order to receive additional treatment with 
psilocybin). For participants from the NRT condition who choose to take part in the optional 
psilocybin session, the remaining long-term follow-up meeting will be shifted to take place at 6 
months after their psilocybin session (in place of their original 12-month follow-up). For 
participants from the NRT condition who decline to take part in the optional psilocybin session, 
study follow-ups will proceed as originally planned at 12 months after their originally assigned 
Target-Quit Date. 
 
Volunteer Accrual and Screening: Potential participants will learn of the protocol by posted, 
and internet-posted notices, newspaper advertisements, and word of mouth referral. Volunteers 
will be screened via a secure online screening questionnaire hosted on a Johns Hopkins approved 
Qualtrics account and/or telephone to determine whether they meet major inclusion/exclusion 
criteria, and thus whether they are eligible for an in-person screening session. Individuals will 
not sign consent before telephone screening. It would not be practical to mail individuals a 
consent form for the telephone screen because we believe that individuals could find this 
inconvenient and would not respond, and also that some individuals might be unwilling to 
provide their mailing address. Individuals who do not pass online / telephone screening or 
choose not to participate will be asked whether they want us to keep their personal contact 
information. If the volunteer agrees, this information will be added to an existing approved 
research database established with application number: BPRU00-01-31-02. Identifiers for those 
individuals who do not want us to retain their information will be destroyed. The rationale for 


Date: April 15, 2024  
Principal Investigator: Matthew W. Johnson 
Application Number: NA_00016166 
 
JHMIRB eFormA 01 
Version 3 Dated: 06/2007 
 
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having the research database is that we want to be able to summarize the reasons that individuals 
failed screening or choose not to participate in this study, and we want to be able to contact 
individuals who might qualify for future studies. We anticipate that this protocol could be one of 
a set of studies with psilocybin and related hallucinogens that would continue for at least the next 
5 years. Because the inclusion/exclusion criteria may be changed in the future, it is possible that 
excluded volunteers may be eligible for studies in the future.  
 
Volunteers who do not fail online / telephone screening will be invited to the BPRU on 
the Johns Hopkins Bayview Campus for in-person screening. Individuals who complete an 
online / telephone screening and do not meet the following specific MRI-related study inclusion 
criteria, will still be eligible to screen and enroll in the treatment portion of the study. This 
includes individuals who: a) are left-handed; b) may have magnetic/metallic materials in their 
body; c) suffer from claustrophobia; d) are over 65 years of age; and e) indicate they do not have 
sufficient free time to complete the MRI related tasks, but would otherwise be available to 
complete the treatment portion of the study. 
 
Volunteers who fail screening at BPRU but who, in the judgment of the investigators, 
might be eligible for a future study will be asked to complete IRB-approved HIPAA-IRB Form 3 
“Authorization to contact you about future research studies.” Volunteers' files will be kept in a 
locked room and treated as confidential research material. All data will be collected using the 
unique identification code numbers assigned to each volunteer upon entry to the study. No 
individual identifiable information will be released without written authorization. These 
procedures have been used in the past to protect confidentiality of study data and no instance of 
loss of confidential information has occurred.  
Two hundred volunteers will sign consent to be screened to provide 130 participants who 
start the study, and 115 participants to participate until completion. Consent will be obtained at 
BPRU at a scheduled meeting after volunteers have passed telephone screening. Due to COVID-
19 space restrictions, participants and study staff may review the consent form remotely or onsite 
in separate rooms over a secure online platform (e.g., Zoom) to go over study procedures and 
answer questions before signing consent. Informed consent will be signed at BPRU in-person. 
Participants will be provided an information sheet about COVID-19 per JH SOM Research Visit 
Guidelines, as well as information about personal protective equipment (PPE) requirements for 
their upcoming visit. Participants will be encouraged to socially distance per national and 
regional guidelines. Written informed consent will be updated to reflect the measures described 
herein.  
Participants will complete a pre-visit COVID-19 symptom questionnaire within 24 hours 
of all in-person visits, and/or be screened with a symptom questionnaire upon arrival at the 
Behavioral Pharmacology Unit (BPRU). The screening questionnaire will assess for possible 
COVID-19 symptoms including: 
• Elevated body temperature 
• Presence of cough 
• Loss of smell or taste 
• Presence of fatigue or general malaise 
• Presence of headache 
• Presence of body aches 
• Adherence to social distancing guidelines  
• Known contact with an individual who tested positive for COVID-19 in the past 
14 days 


Date: April 15, 2024  
Principal Investigator: Matthew W. Johnson 
Application Number: NA_00016166 
 
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Version 3 Dated: 06/2007 
 
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• Engagement in high-risk behaviors (e.g. participation in large gatherings without 
social distancing or use of PPE) 
The screening questionnaire may be subject to change based on new information about COVID-
19. Body temperature measurement will also occur upon arrival at the BPRU.  
Participants will be allowed to take as much time as necessary to decide whether or not to 
sign consent. Study staff will discuss the consent form with the volunteer after they have read the 
consent form, as well as providing the recruitment materials for the optional NIDA sub-study 
protocol to be reviewed at the time of enrollment for individuals who are eligible for MRI 
scanning. Study staff will ask participants to read a paragraph from the consent form out loud to 
assess English literacy and will ask questions regarding basic study procedures to assess the 
individual’s understanding of the consent forms. Participants may take the consent forms home 
to review and return to sign consent if they wish. Non-English speakers and those with language 
or hearing impairments will not participate in the study. Participants will be physically and 
psychologically healthy adult volunteers (approximately equal numbers of males and females). 
Participants completing the MRI scanning portion of the protocol at NIDA must be between the 
ages of 21 and 65 years old. For those who will not be completing MRI scanning at NIDA 
(treatment only), volunteers ages 21 to 80 may participate. We expect to locate participants who 
are both qualified and motivated to adhere to the rigorous conditions of the study. Participants 
may or may not have used hallucinogens in the past. Our ongoing trial, as well as considerable 
data from prior studies, documents the safety of administering psilocybin at the proposed dose 
level to participants without histories of hallucinogen use. However, to attenuate the possibility 
of non-optimal response in individuals with higher body weight, this study will use an absolute 
maximum dosage of 50 mg, which is approximately equivalent to absolute doses we have 
administered safely to heavier participants in previous studies. 
Potential participants will be carefully screened to eliminate those with significant 
medical or psychiatric illnesses. Evaluation will include a history and physical examination, 
CBC, SMA-24 (or equivalent), ECG, and urine drug test. Participants will also be requested to 
refrain from illicit drug use during the course of the study and a urine test will be conducted 
before the administration of psilocybin. Left-handed individuals are ineligible for MRI scanning, 
but may otherwise complete the study treatment. Pregnant or nursing women are ineligible; 
female participants will receive a urine pregnancy test at intake and before psilocybin 
administration, and must use effective methods of contraception during the study. Other medical 
exclusion criteria are presented in section 5. With regard to psychiatric screening, based on 
clinical interviews and a structured psychiatric diagnostic interview, participants will be eligible 
if they are judged to be psychologically stable and do not meet any of the psychiatric exclusion 
criteria (as defined by DSM-IV) presented in section 5. Psychiatric screening interviews may 
take place remotely via secure online platform. 
 
Meetings Before and After TQD (Psilocybin Condition): Before the psilocybin session day 
participants in the psilocybin condition will meet with one or more of the study staff on at least 3 
occasions, for a minimum of 4 hours of contact time before the session day. Some flexibility in 
scheduling will be allowed to account for unexpected absences such as travel commitments or 
illnesses. The main purpose of the participant-staff meetings is to develop rapport and trust, 
which we believe helps minimize the risk of fear or anxiety reactions during the psilocybin 
session. Additional meetings and contact hours (up to 10 hours) will be scheduled if it is judged 
necessary to establish rapport and trust. The participant’s life history and current situation in life 
will be reviewed. 
  


Date: April 15, 2024  
Principal Investigator: Matthew W. Johnson 
Application Number: NA_00016166 
 
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Version 3 Dated: 06/2007 
 
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All standard study meetings, meeting content, and duration are summarized here: 
 
Timeline a 
Psilocybin condition meetings (duration) 
NRT condition meetings (duration) 
 
Screening Day 1/ Consent (6 hrs) 
 
Screening Day 2 (2-3 hrs) 
 
Optional NIDA sub-study protocol / MRI Scan 1 (6-8 hrs)* 
 
 
Week 1 
MRI task training at NIDA (2-3 hrs)* 
Treatment meeting 1 (1-2 hrs) 
Study orientation 
Assign Target Quit Date (TQD) 
Sign contract to quit / smoking diary introduction 
 
 
Week 2 
MRI scan 2 (4-5 hrs)* 
Treatment meeting 2 (1-2 hrs) 
Carbon monoxide demonstration 
Smoking financial costs 
Identifying motivation to quit 
 
 
Week 3 
Treatment meeting 3 (90 min) 
   Randomization to treatment condition 
   Discuss previous quit attempts 
   Weight gain and quitting smoking 
   Recovery symptoms 
   Discussing psilocybin effects 
Treatment meeting 3 (90 min) 
   Randomization to treatment condition 
   Discuss previous quit attempts 
   Weight gain and quitting smoking 
   Recovery symptoms 
   Discussing NRT effects 
 
 
Week 4 
Treatment meeting 4 (90 min) 
   Smoking diary discussion 
   Dealing with urges after TQD 
   Preparing to quit 
   What to expect in psilocybin session  
Treatment meeting 4 (90 min) 
   Smoking diary discussion 
   Dealing with urges after TQD 
   Preparing to quit 
   How to take NRT 
 
Week 5 
Psilocybin session / TQD (8 hrs) 
MRI scan 3 (4-6 hrs; Next day)* 
Treatment meeting 5 (1-2 hrs; Next day) 
   Participant Narrative of Session 
MRI scan 3 / TQD (4-6 hrs)* 
Treatment meeting 5 (1-2 hrs) 
   Initiation of NRT 
 
 
Week 6 
Treatment meeting 6 (45 min) 
   Identifying triggers 
   Overcoming urges to smoke 
Treatment meeting 6 / TQD (45 min) 
   Identifying triggers 
   Overcoming urges to smoke 
 
Week 7 
Treatment meeting 7 (45 min) 
   Supporting smoking abstinence 
Treatment meeting 7 (45 min) 
   Supporting smoking abstinence 
 
Week 9 
Treatment meeting 8 (45 min) 
   Supporting smoking abstinence 
Treatment meeting 8 (45 min) 
   Supporting smoking abstinence 
 
Week 11 
Treatment meeting 9 (45 min) 
   Supporting smoking abstinence 
Treatment meeting 9 (45 min) 
   Supporting smoking abstinence 
 
Week 13 
Treatment meeting 10 (45 min) 
    Clinical interview 
Treatment meeting 10 (45 min) 
   Clinical interview 
…3 months post-TQD 
Follow-up meeting (2-4 hrs) 
MRI Scan 4 b (4-6 hours)*  
Follow-up meeting (2-4 hrs) 
MRI Scan 4 b (4-6 hours)* 
…6 months post-TQD 
Follow-up meeting (2-4 hrs) 
Follow-up meeting (2-4 hrs) 
…12 months post-TQD 
Follow-up meeting (2-4 hrs) 
Follow-up meeting (2-4 hrs) 
* Indicates MRI procedures to be completed only by participants who are eligible for MRI scanning (n=60). 
a Times listed in the table are approximate. 
b MRI Scan 4 only for participants showing biologically verified abstinence at 3-month follow-up. 
 
Intentions and expectations for the psilocybin session will be discussed. Furthermore, a 
structured cognitive-behavioral smoking cessation intervention will be implemented throughout 
the course of these meetings to prepare participants for smoking abstinence and potential 
withdrawal. Throughout the preparatory meetings, participants will be encouraged to view the 
psilocybin session as providing an opportunity for deep reflection about the role of smoking in 
their lives. The purpose of the psilocybin session is to enhance motivation for initiating a quit 
attempt. Procedures for drug administration and the conduct of the session will be similar to 


Date: April 15, 2024  
Principal Investigator: Matthew W. Johnson 
Application Number: NA_00016166 
 
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procedures used in our previous (Griffiths et al., 2006, 2008, 2011) and ongoing studies with 
psilocybin (IRB # NA_00001390 in cancer patients; IRB # NA_00020767 in healthy adults), and 
are described below in the section “Conduct of Psilocybin Sessions.” 
 
Participants will meet with study staff for debriefing one or two days after the psilocybin 
session. Participants will then meet weekly with study staff for 2 weeks after their psilocybin 
session (i.e., in weeks 6 and 7), and at 2-week intervals until the end of the 13-week study 
treatment (i.e., in weeks 9, 11, and 13). The general purpose of the meetings following the 
session is to provide a context for discussing and integrating experiences from the psilocybin 
session, and to provide support for smoking cessation. Additional contact hours will be 
scheduled if it is judged that the participant would benefit from further meetings with study staff 
to discuss experiences from the session or provide additional support for smoking abstinence. 
Aside from the psilocybin session and MRI scan visits (if applicable), all meetings may be held 
remotely using a secure online platform, including use of remote CO monitoring and mailed in or 
at home urine sample testing. 
 
Meetings Before and After TQD (NRT Condition): Before the target-quit date participants in 
the NRT condition will meet with one or more of the study staff on at least 3 occasions, for a 
minimum of 4 hours of contact time before drug administration. Some flexibility in scheduling 
will be allowed to account for unexpected absences such as travel commitments or illnesses. The 
main purpose of the participant-staff meetings is to prepare participants for NRT transdermal 
patch administration, and to deliver a cognitive-behavioral smoking cessation intervention 
identical to that received by participants in the psilocybin condition. During these meetings study 
staff will answer any questions related to NRT, examine motivations to quit smoking, and 
encourage preparation for smoking cessation on the target-quit date. Participants in this condition 
will be provided with NRT patches and instructed how to use the patches, which may be mailed 
to participants to reduce unnecessary in-person visits. In week 5, participants in the NRT 
condition will begin a standard 8 to 10 week course of NRT for smoking cessation. For MRI 
participating volunteers, nicotine patches will be initiated directly after their week 5 MRI scan. 
All participants in the NRT condition will have five additional counseling meetings with study 
staff in weeks 6, 7, 9, 11, and 13, where they will provide self-report and breath samples to 
assess smoking status and complete study questionnaires. The study physician will be available 
during the study to discuss any potential side effects or medical issues. Participants will complete 
questionnaires and provide breath and urine samples to evaluate smoking status at approximately 
3, 6, and 12 months post-TQD.  
 
Optional Meetings / Psilocybin Session (NRT Condition): After completing the 6-month 
follow-up, participants initially randomized to the NRT condition will be eligible to undergo an 
optional high-dose (30mg/70kg) psilocybin session. If they choose to take part, they will receive 
two weekly preparation meetings, one high-dose psilocybin session and next-day integration 
meeting, and two weekly follow-up meetings. For individuals unsuccessful in their smoking 
cessation attempt using NRT, this session will serve as an additional quit attempt and provide 
further smoking cessation efficacy data on psilocybin pharmacotherapy in treatment-resistant 
populations. For participants who successfully quit smoking using NRT, this session will focus 
on promoting long-term abstinence. For participants from the NRT condition who choose to take 
part in the optional psilocybin session, their remaining follow-up meeting will be shifted to take 
place at 6 months after their optional psilocybin session (in place of their original 12-month 
follow-up). Participants who choose not to take part in this process will not be penalized, and 
will be asked to complete the study as originally planned through 12-month follow-up.  


Date: April 15, 2024  
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All optional study meetings, meeting content, and duration are summarized here (for 
participants in NRT condition only): 
 
Timeline 
Optional Meetings / Psilocybin Session 
Week 1B (after 6-
month follow-up) 
Psilocybin prep. Meeting 1 (90 min) 
Discuss previous quit attempt 
Discuss psilocybin effects 
Week 2B 
Psilocybin prep. Meeting 2 (90 min) 
What to expect in psilocybin session 
Week 3B 
Psilocybin session (8 hrs) 
Integration meeting 1 (45 min; Next day) 
Participant Narrative of Session 
Week 4B 
Integration meeting 2 (45 min) 
Supporting smoking abstinence 
Week 5B 
Integration meeting 3 (45 min) 
Supporting smoking abstinence 
…6 months post-
psilocybin 
Follow-up meeting (2-4 hrs) 
MRI Brain Scanning Sessions: For the revised study protocol, up to 60 participants in the 
psilocybin  and NRT conditions (n=30 per group) will undergo between two and four MRI brain 
scanning sessions (4-6 hours each), taking place at the NIDA intramural research program (IRP) 
on the Bayview campus under the supervision of Dr. Amy C. Janes. Dr. Amy C. Janes is Chief 
of the Neuroimaging Research Branch at the National Institute on Drug Abuse-Intramural 
Research Program (NIDA-IRP) and will serve as the Principal Investigator of the NIDA-IRP 
protocol addendum that covers all neuroimaging procedures performed in this study. Only 
participants demonstrating biologically verified seven-day point-prevalence smoking abstinence 
at the initial 3-month follow-up will be asked to undergo a final MRI scan at that time. All MRI 
participating volunteers will be financially compensated for their time on MRI scanning days 
with funding provided by NIDA IRP. Before MRI scanning, participants will provide a urine 
sample for a drug urine screen. MRI scanning will not proceed unless the drug screen results are 
negative, or unless participants pass a neuromotor evaluation showing they are not currently 
intoxicated, and are cleared to proceed by the NIDA study physician. NIDA IRP has resumed in-
person research, and instituted COVID-19 safety measures consistent with those described in the 
current protocol (i.e., physical distancing, PPE and mask use during all visits, pre-visit symptom 
checks, thorough equipment cleaning between participants), which will be used for participant 
and personnel safety at in-person MRI visits. Additionally, NIDA IRP will be providing point-
of-care COVID-19 testing for participants at in-person study visits. Only individuals with 
negative COVID-19 tests will be allowed to proceed with their scheduled visit. Otherwise they 
will be advised to quarantine according to CDC guidelines and required to provide negative 
COVID-19 test results before resuming in-person study visits as described below. 
 
The first (optional) MRI scan may occur as part of a voluntary NIDA approved sub-study 
protocol, which is a large-scale (N=2500) investigation of genetic polymorphisms associated 
with substance dependence. If participants agree to participate in this sub-study, the related MRI 
scan will be completed after study-screening, and will produce an MRI scan of clinical quality to 
be examined for incidental findings by a Johns Hopkins Hospital (JHH) neuroradiologist. 
Participants who decline to complete the NIDA sub-study will receive a clinical MRI scan at 
their first MRI scanning visit to be examined for incidental findings by a JHH neuroradiologist. 
The next (required) MRI scan will take place in approximately week 2 of treatment after an 
initial orientation meeting, and before randomization in week 3. The following (required) MRI 
scan will occur in approximately week 5 of treatment. For the psilocybin condition this scan will 


Date: April 15, 2024  
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occur one day after psilocybin administration. For the NRT condition this scan will occur 
immediately before initiating NRT administration. A final, conditional MRI scan will take place 
at 3-month follow-up only for participants demonstrating biologically verified seven-day point-
prevalence smoking abstinence at that time. After completing the 6-month follow-up all 
participants initially randomized to the NRT condition will be eligible to undergo additional 
(optional) meetings including a high-dose psilocybin session. However, no further MRI scanning 
will be conducted after the 3-month time point.   
 
Participants will be asked to abstain from smoking for 24 hours before all MRI scanning 
sessions, as verified by measures of exhaled breath CO. MRI scans will last roughly 4 to 6 hours, 
and be conducted at the NIDA IRP building adjacent to the BPRU by a trained MRI operator. A 
trained study staff member will be present during all MRI scanning sessions. Any incidental 
findings will be communicated by the JHH neuroradiologist to the NIDA IRP Medical Advisory 
Investigator, who will transmit incidental findings to Dr. Umbricht, the Hopkins study team 
physician. Dr. Umbricht will report any incidental findings to participants at an in-person 
meeting, over the phone, or via mail as deemed appropriate commensurate with the significance 
of the findings.  
 
Monitor Telephone Contact: In order to provide encouragement for smoking abstinence, and to 
monitor participant status after psilocybin or NRT administration, participants will receive a 
brief (<5 min.) telephone call or inquiry via text message from study staff every day (with the 
exception of days on which a monitor meeting is scheduled) for the first seven days after the 
TQD. An occasional day may be missed for unavoidable reasons, but efforts will be made to 
minimize this. Telephone discussions may continue up to 4 weeks after TQD on a less frequent 
basis (e.g., 3 times per week) if the study team judges that continuing daily support would be 
helpful. For all participants, the primary study staff member will be available 24 hours for 
telephone consultation, and in the case of side effects or medical issues, Dr. Annie Umbricht will 
be available by phone.  
 
Cognitive-Behavioral Therapy for Smoking Cessation: Starting with the first treatment 
meeting participants will be provided guidance and instructions on a variety of self-help 
cognitive-behavioral therapy (CBT) techniques shown to be effective in smoking cessation in 
controlled studies (Perkins et al., 2008; Sykes & Marks, 2001; Marks, 2005). These are easily 
understood techniques designed to raise the awareness of the individual about the motivations, 
antecedents, and consequences of smoking. Examples of these techniques include placing a 
rubber band around one’s pack of cigarettes to serve as a cue to reduce the automatic and 
habitual nature of smoking, the use of a score card to record when each cigarette is smoked, and 
the use of easily remembered acronyms to help highlight the unpleasant aspects of smoking each 
time a cigarette is smoked (e.g., that the cigarette is making the person feel rotten). This program 
fits nicely with the proposed design, in that it includes procedures to implement both before a 
target-quit date, and other procedures to implement after a target-quit date. Study staff will 
continue to discuss these techniques with the participant during staff-participant meetings 
throughout the study. For a summary of CBT modules, see the study timeline table in the study 
design section above. 
 
Conduct of Psilocybin Session: Participants in the psilocybin condition, as well as those in the 
NRT condition who elect to undergo an optional psilocybin session after the 6-month follow-up, 
will be instructed to consume a low-fat breakfast before reporting to the laboratory for the 
psilocybin session. Participants must refrain from smoking during the time of drug action on the 


Date: April 15, 2024  
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psilocybin session day. On the day of the psilocybin session, the last cigarette may be smoked 1 
hour before psilocybin administration. Participants will be instructed to abstain from smoking 
and drinking alcohol for at least the next 24 hours until the post-psilocybin MRI scan has been 
conducted (when applicable).  
 
Before drug administration, participants will provide a urine sample for a drug urine 
screen and, for females, for pregnancy testing. Sessions will not proceed unless drug tests are 
negative for illicit drug use, and pregnancy tests are negative. Psilocybin capsules will be 
administered with approximately 100 mL water. The study staff, under the supervision of the 
investigators, will be present in the room and available to respond to participants’ physical and 
emotional needs during the full course of the session (at least 7 hours). 
These sessions often require session facilitator(s) and the participant to be in a session 
room together for an extended period of time and may require periods of physical contact (e.g. 
for adjusting blood pressure cuff, therapeutic touch etc.). On session days, it is possible that 
participants may inadvertently remove PPE while under the influence of psilocybin. We will 
adhere to the following additional safety measures for these sessions: 
- 
COVID-19 testing will be available for participants and facilitators prior to these 
meetings if there is special concern raised about the possibility of exposure during the 
final preparation or drug administration day. The availability of testing will be discussed 
during preparation.  
- 
COVID-19 testing will be performed within 72 hours of each psilocybin session with a 
negative result, or written proof of such testing with negative result within 72 hours of 
each psilocybin session must be presented if the participant claims to have been tested. 
This will be required to move forward with a psilocybin administration session. 
Participants can alternatively bring proof of full COVID-19 vaccination being completed 
at least 2 weeks prior to their psilocybin session in lieu of COVID-19 testing. 
Vaccination status will be verified via official written documentation (e.g., CDC card or 
healthcare provider records) and copies will be kept on file. Study team members 
overseeing psilocybin sessions have presently been fully vaccinated.  
 
- 
Participants will be asked to maintain social distancing procedures and use PPE in public 
places between the baseline visit and the day after the drug administration session. 
- 
Session facilitators will wear a surgical mask at all times during these two visits. 
Facilitators will wear a face shield when there is less than 6 feet of space between any 
two individuals. Face shields may be omitted in cases where participants and staff have 
been vaccinated for COVID-19. 
- 
Session facilitators will wear gloves when touching the participant (adjusting blood 
pressure cuff, helping the participant to the bathroom, etc.). Gloves may be omitted in 
cases where participants and staff have been vaccinated for COVID-19. 
- 
The study team will monitor the data and guidelines on duration of vaccine effectiveness 
and correlate this to when the vaccine was administered to any given subject when 
potentially modifying COVID-19 related study safety procedures. 
- 
A washable couch cover will be used and cleaned between participants. 


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- 
Headphones will be sanitized between participants, or disposable headphone covers will 
be used. 
 
During the session, participants will lie on a couch, wear eyeshades, and listen to a 
program of music through headphones. The participant will be encouraged to focus her or his 
attention inward. The eyeshades and music are intended to encourage this inward reflection. 
Heart rate and blood pressure will be measured pre drug administration, at 30, 60, 90, 120 
minutes after drug administration, and then hourly until at least 6 hours after drug administration 
and until drug effects have subsided. Sessions are expected to last 7 to 10 hours. Baseline heart 
rate and blood pressure will be obtained after the participant has been recumbent for 5 minutes. 
Around the time of each physiological measurement, monitors will use questionnaires to rate the 
presence and intensity of behaviors, signs, and reported symptoms, including sleepiness, amount 
of speech, anxiety, stimulation/arousal, tearing/crying, nausea/vomiting, yawning, restlessness, 
feelings of unreality, visual changes, euphoria, and peacefulness. Video and audio recordings 
will be made throughout the session. At the end of the experimental session, participants will 
complete pencil-and-paper or computer-based instruments designed to assess acute subjective 
experiences associated with the psilocybin session (see section 7), and will be asked to write a 
narrative description of the experience of the psilocybin session that evening. On the first 
meeting with the monitor after the session (1 or 2 days after each session), the study staff will 
complete questionnaires retrospectively rating various behaviors and experiences observed on 
the session day and reported by the volunteer during the meeting (e.g. Next-Day Monitor rating). 
 
NRT Condition: Participants in the NRT condition will receive preparation and instructions 
from study staff on how to use the nicotine transdermal patch, which may be mailed to them to 
reduce in-person contact. Participants will receive detailed information on NRT and potential 
side effects prior to patch administration. On the day after their Target-Quit Date in week 5, they 
will be provided with a 2-week supply of medication, and instructed to begin a standard 8 to 10 
week transdermal nicotine patch regimen according to recommended label usage (For 
individuals who smoke more than 10 cigarettes per day: 21mg daily for weeks 1-6, 14mg daily 
for weeks 7-8, 7mg daily for weeks 9-10. For individuals who smoke 10 or less cigarettes per 
day: 14mg daily for weeks 1-6, 7mg daily for weeks 7-8; FDA label, PDR.net). For MRI 
participating volunteers receiving NRT (n=25), the Target-Quit Date will occur 24 hours prior to 
the MRI scanning day in week 5, and participants will begin using NRT immediately after that 
MRI scan is completed. To ensure matching treatment procedures, participants randomized to the 
NRT condition who are not MRI participating volunteers, and are completing only the treatment 
portion of the protocol (n=15), will also stop smoking 24 hours prior to their meeting in week 5 
(to be confirmed by breath CO). At this meeting they will receive their first 2-week supply of 
transdermal nicotine patches and initiate NRT use. Participants will receive additional supplies 
of appropriate dose patches at 2-week intervals around their regularly scheduled treatment 
meetings. Participants will be asked to notify study staff immediately in case of adverse events or 
side effects, and will determine with the study physician whether NRT dosage should be 
adjusted, or permanently discontinued. In the unlikely event of a severe side effect such as a 
myocardial infarction/arrhythmia, participants will be advised to immediately discontinue NRT 
use. Under these circumstances, participants will be asked to continue the study protocol 
meetings to completion. 
 
After completing the 6-month follow-up, participants initially randomized to the NRT 
condition will be eligible to undergo an optional high-dose (30mg/70kg) psilocybin session. If 
they choose to take part, they will receive two weekly preparation meetings, one high-dose 


Date: April 15, 2024  
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psilocybin session and next-day integration meeting, and two weekly follow-up meetings. For 
individuals who were unsuccessful in their smoking cessation attempt using NRT, this session 
will serve as an additional quit attempt and provide further smoking cessation efficacy data on 
psilocybin pharmacotherapy in treatment-resistant populations. For participants who successfully 
quit smoking using NRT, this session will focus on promoting long-term abstinence. For 
participants from the NRT condition who choose to take part in the optional psilocybin session, 
their remaining follow-up meeting will be shifted to take place at 6 months after their optional 
psilocybin session (in place of their original 12-month follow-up). Data collection at optional 
meetings, psilocybin session, and follow-ups will be identical to those in the psilocybin 
condition, including measures of breath CO and questionnaire assessments of smoking 
abstinence self-efficacy, craving, withdrawal, and subjective effects of psilocybin. Participants 
who choose not to take part in this process will not be penalized, and will be asked to complete 
the study as originally planned, by attending the remaining 12-month follow-up meeting. 
  
Baseline and Follow-up Data Collection: Baseline psychological data will be obtained on each 
volunteer at the time of enrollment. Smoking history will be collected, and several smoking 
related questionnaires will be administered. Psychiatric history (including family history), 
psychoactive drug-use history (including alcohol) and information about employment status and 
current functioning (including mood and psychological and psychosomatic symptoms) will be 
obtained using standard psychiatric instruments such as the SCID and the BSI. In addition, 
baseline assessments will be taken on a number of psychological variables that may be impacted 
by a psilocybin experience, e.g. psychiatric symptoms and mystical-type experience. Re-
assessment of several measures will be made throughout the study and at follow up visits. For 
MRI participating volunteers (N=60), functional neuroimaging (fMRI) data will also be collected 
in approximately weeks 2 and 5 weeks of treatment, and again at 3-month follow-up for 
participants demonstrating biologically verified 7 day point-prevalence smoking abstinence at 
that time point. A thorough description of measures and the time of their assessment is included 
in section 7. 
 
Assessment of Smoking Cessation: Participants will complete smoking assessments (including 
biological verification and other measures as shown in section 7) at 1 to 2 week intervals 
throughout the course of the study. These assessments will include biological verification of 
smoking status with breath carbon monoxide during the 13-week treatment period. Additionally, 
urine cotinine samples will be collected at screening, and at 3, 6, and 12-month follow-ups. 
Participants will have meetings in weeks 6, 7, 9, 11, and 13 after their initial TQD to provide 
self-report data on smoking behavior, exhaled breath samples, and to complete questionnaires. 
All participants will have follow-up meetings at 3, 6, and 12 months post-TQD, or at 3 and 6 
months post-TQD, and 6 months post-psilocybin administration for participants in the NRT 
condition who choose to undergo an optional psilocybin session. Breath samples may be taken 
remotely using an individually assigned mobile CO breath monitor device, and urine samples 
may be provided remotely by mail or tested at home. 
 
b. Study duration and number of study visits required of research participants. 
 
The pre-treatment phase of the study, including screening, enrollment, and sub-study protocol 
completion will require at least two full days (approx. 4-6 hours each) of meetings. Because of 
the large number of screening measures, screening and intake for either group may require 2 
appointments. The treatment phase of the study, including treatment meetings, psilocybin session 


Date: April 15, 2024  
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(when applicable), and MRI scans (when applicable) will require 11 meetings over 
approximately 13 weeks. For the post-treatment follow-up phase of the study, participants will 
have meetings at approximately 3, 6, and 12 months post-target quit date for follow-up 
assessment (2-4 hours each). Additionally, participants from the NRT group who choose to 
partake in an optional psilocybin session will undergo six supplementary meetings, including 
two weekly preparatory meetings, one high-dose psilocybin session and next-day integration 
meeting, and two weekly follow-up meetings to assess psychological and smoking status. 
However, participation in these optional meetings will not substantially affect overall study 
duration. Thus, the study will comprise a total of approximately 16-22 study meetings over the 
course of roughly 14 months. Participants who are not participating in MRI scanning (n=40) will 
have the same number of study visits as those who undergo NIDA MRI scanning (n=60), though 
study visits in weeks 1, 2, 5, and potentially 3-month follow-up will be approximately 4-5 hours 
shorter in duration.  
 
c. Blinding, including justification for blinding or not blinding the trial, if applicable. 
 
Because of the distinctive nature of the two treatment protocols, and the different preparation 
required for each (e.g., single day-long psilocybin session vs. 8 to 10 week daily nicotine 
transdermal patch use), blinding will not be utilized. 
 
d. Justification of why participants will not receive routine care or will have current 
therapy stopped. 
 
Participants will have multiple previous smoking cessation attempts, which may or may not 
include pharmacological (e.g., nicotine replacement, bupropion) or nonpharmacological 
therapies. Thus, participants will be those for whom routine care has proven unsuccessful to date. 
Participants who fail screening or decide not to participate after screening will be directed to 
American Lung Association and U.S. Department of Health and Human Services sponsored 
websites (http://www.lung.org/stop-smoking/; http://betobaccofree.hhs.gov/quit-now/) that 
provide information designed to help individuals quit smoking. Participants can discontinue 
participation in the study at any time. In the case of adverse events or side effects, participants 
will be instructed to contact their primary study staff member immediately. Adverse events will 
be documented, and participants will consult with the study physician before continuing with the 
study. Participants in the NRT condition reporting a severe side effect such as a myocardial 
infarction/arrhythmia will be advised to immediately discontinue NRT. However, in such cases, 
we will request that participants discontinuing NRT complete the study protocol meetings. 
 
e. Justification for inclusion of a placebo or non-treatment group. 
 
This is a proof-of-concept pilot study assessing the feasibility of the proposed intervention. 
Therefore, no placebo or non-treatment group is included. 
 
f. Definition of treatment failure or participant removal criteria. 
 
Treatment failure is defined by the inability to achieve 7-day point-prevalence abstinence at 6-
month follow-up, as confirmed by urine cotinine, breath carbon monoxide, and self-report data. 
However, all participants will be evaluated throughout the initial 12-month follow up regardless 


Date: April 15, 2024  
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if they have quit smoking. Participants will be removed from the study for non-compliance with 
study requirements.  
 
g. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely. 
 
Participants who fail screening or decide not to participate after screening will be directed to 
American Lung Association and U.S. Department of Health and Human Services sponsored 
websites (http://www.lung.org/stop-smoking/; http://betobaccofree.hhs.gov/quit-now/) that 
provide information designed to help individuals quit smoking. Participants who voluntarily 
discontinue the study protocol prior to drug administration will be directed to the same websites 
providing information on quitting smoking. Participants who experience adverse effects due to 
NRT will be asked to continue the study protocol meetings to completion, and will determine 
with the study physician on a case-by-case basis whether NRT should be permanently 
discontinued, or if a change in daily dosage may be appropriate. In the event of a severe side 
effect such as a myocardial infarction/arrhythmia participants will be advised to immediately 
discontinue NRT administration. In such cases, smoking cessation counseling meetings with 
study staff would continue as scheduled, and participants will continue to be encouraged to 
abstain from smoking without pharmacotherapy. 
 
4. Inclusion/Exclusion Criteria 
 
Inclusion criteria: 
• 21 to 80 years old 
• Have given written informed consent 
• Read, write, and speak English 
• Be a daily smoker with multiple unsuccessful previous quit attempts, and report a continued 
desire to quit smoking 
• Agree to abstain from smoking for the psilocybin session from 1 hour before psilocybin 
administration until at least 30 hours afterwards  
• Agree to consume approximately the same amount of caffeine-containing beverage (e.g., 
coffee, tea) that he/she consumes on a usual morning, before arriving at the research unit on 
the morning of drug session day. If the volunteer does not routinely consume caffeinated 
beverages, he or she must agree not to do so on session day 
• Agree to refrain from using any psychoactive drugs, including alcoholic beverages, within 24 
hours of psilocybin administration. Exceptions include caffeine and nicotine 
• Be healthy as determined by screening for medical problems via a personal interview, a 
medical questionnaire, a physical examination, an electrocardiogram (ECG), and routine 
medical blood and urinalysis laboratory tests 
• Agree to abstain from smoking for 24-hours prior to study visits in week 2 and 5  
 
Inclusion criteria for MRI scanning eligibility only: 
• 21 to 65 years old 
• Agree to abstain from smoking and alcohol for 24-hours, and caffeine for 12-hours prior to 
MRI scanning* 
• Be right-handed* 
 


Date: April 15, 2024  
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General medical exclusion criteria: 
• Women who are pregnant (positive pregnancy test) or nursing, or are not practicing an 
effective means of birth control 
• Cardiovascular conditions: uncontrolled hypertension with resting blood pressure systolic 
>150 or diastolic >95, angina, a clinically significant ECG abnormality (e.g., atrial 
fibrilation), TIA in the last 6 months stroke, peripheral or pulmonary vascular disease 
• Epilepsy with history of seizures 
• Insulin-dependent diabetes; if taking oral hypoglycemic agent, then no history of 
hypoglycemia 
• Currently taking psychoactive prescription medication on a regular basis 
• Currently taking on a regular (e.g., daily) basis any medications having a primary centrally-
acting pharmacological effect on serotonin neurons or medications that are MAO inhibitors. 
For individuals who have intermittent or PRN use of such medications, psilocybin sessions 
will not be conducted until at least 5 half-lives of the agent have elapsed after the last dose. 
• Have HIV or Syphilis. 
• Have any current neurological illnesses including, but not limited to, seizure disorders, 
frequent migraines or on prophylaxis, multiple sclerosis, movement disorders, history of 
significant head trauma, or CNS tumor. 
• Morbidly obese, or severely underweight as determined by medical examination. 
• Recent (within past 12 months) or extensive history of hallucinogen use (>20 lifetime uses). 
 
General medical exclusion criteria for MRI scanning eligibility only: 
• Not suitable to undergo an MRI session due to certain implanted devices (cardiac pacemaker 
or neurostimulator, some artificial joints, metal pins, surgical clips or other implanted metal 
parts), body morphology, or claustrophobia. 
 
Psychiatric Exclusion Criteria: 
• Current or past history of meeting DSM-IV criteria for Schizophrenia, Psychotic Disorder 
(unless substance-induced or due to a medical condition), or Bipolar I or II Disorder. 
• Current or past history within the last 5 years of meeting DSM-IV criteria for alcohol or drug 
dependence (excluding caffeine and nicotine) or severe major depression. 
• Have a first or second degree relative with schizophrenia, psychotic disorder (unless 
substance induced or due to a medical condition), or bipolar I or II disorder. 
• Currently meets DSM-IV criteria for Dissociative Disorder, Anorexia Nervosa, Bulimia 
Nervosa, Major Depression, or Post-traumatic Stress Disorder. 
 
Individuals who do not pass screening or choose not to participate will be asked whether they 
want us to keep their personal contact information using HIPAA-IRB Form 3. Identifiers for 
those individuals who do not want us to retain their information will be destroyed. We will retain 
information because we want to be able to summarize the reasons that individuals failed 
screening or choose not to participate in this study. Also, because the inclusion/exclusion criteria 
may be changed in our future studies with psilocybin and related compounds, it is possible that 
excluded volunteers may be eligible for studies in the future. 
 
5. Drugs/ Substances/ Devices 
a. The rationale for choosing the drug and dose or for choosing the device to be used. 
 


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Psilocybin dose: On the drug session day, participants will be administered 30mg/70kg 
psilocybin. Two previous studies in our laboratory on psilocybin suggest that this dose is 
associated with mystical-type experiences, with some variability across participants (Griffiths et 
al., 2006; Griffiths et al., 2011). This dose has been safely administered in our laboratory 
(Griffiths et al., 2006; Griffiths et al., 2011), is in the range of doses examined extensively in 
previous studies with hallucinogen-naïve individuals (Malitz et al. 1960 Metzner et al. 1965; 
Pahnke 1963, 1969; Pahnke et al. 1966; Leuner 1981), and is less than that (49mg/70kg) 
administered safely under a previously authorized IND (Strassman 1992, 1998). Furthermore, to 
attenuate the possibility of a non-optimal response in individuals with higher body weight, this 
study will use an absolute maximum dosage of 50 mg, which is approximately equivalent to 
absolute doses we have administered safely to heavier participants in previous studies with 
psilocybin. 
 
Transdermal nicotine patch dose: Nicotine replacement therapy (NRT) is widely considered a 
first-line smoking cessation treatment option that is available over the counter (Silagy et al., 
2000; Stead et al., 2012). As such, it was chosen to provide a proven control treatment with 
known efficacy. NRT patch doses will be administered according to recommended label usage. 
For individuals who smoke more than 10 cigarettes per day: 21mg daily for weeks 1-6, 14mg 
daily for weeks 7-8, 7mg daily for weeks 9-10; for individuals who smoke 10 or less cigarettes 
per day: 14mg daily for weeks 1-6, 7mg daily for weeks 7-8 (FDA label, PDR.net). Patch use 
will begin in week 5 of treatment, after 24-hours of smoking abstinence. 
  
b. Justification and safety information if FDA approved drugs will be administered for 
non-FDA approved indications or if doses or routes of administration or participant 
populations are changed. 
 
N/A; The transdermal nicotine patch is an FDA approved smoking cessation treatment.  
 
c. Justification and safety information if non-FDA approved drugs without an IND will be 
administered.  
 
N/A – We currently hold an IND for psilocybin and have amended the IND to include the 
present protocol. 
 
6. Study Statistics 
a. Primary outcome variable. 
 
The primary outcome variable will be between group differences of biologically verified (i.e., 
CO, cotinine) and self-reported smoking abstinence 6 months post-TQD, with a grace period for 
initiation of abstinence within 14 days of the TQD. This outcome meets success criteria used for 
FDA evaluation of smoking cessation medications. 
 
b. Secondary outcome variables. Descriptions of Outcome Measures 
Measure completed on a daily basis by participant at home (in the evening or at the same 
time each day, allowing 24 hours between completing measures): 
Smoking Diary: Participants will be asked to keep a smoking diary, in which they will record 
every cigarette smoked, and make a brief note about feelings, antecedents, or consequences of 
smoking. In the evening or at the same time each day (allowing 24 hours between each entry), 


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participants will review their daily smoking diary, and write a brief description of thought or 
feelings surrounding their smoking behavior on that day. 
 
Longitudinal measures (Smoking related): 
Carbon monoxide breath and cotinine urine samples as biological measures of smoking: 
These two measures are widely used in smoking cessation studies and provide advantages that 
complement each other. The carbon monoxide measure, assessed using expired air samples (e.g., 
Bedfont Smokerlyzer, Bedfont iCO mobile smokerlyzer) can detect very recent smoking and 
provides immediate results to study staff, but cannot detect smoking that occurred over 24 hours 
ago. The cotinine assay is collected with urine samples and will not provide results for several 
days because samples must be sent to an outside laboratory (e.g., Friends Research Institute). 
However, cotinine assays provide a larger time window of detection, with the ability to detect 
smoking that has occurred during approximately the last 6 days (SRNT Subcommittee on 
Biological Verification, 2002). Breath samples may be taken remotely using an individually 
assigned mobile CO breath monitor, and urine samples may be provided remotely by mail or 
tested at home. 
 
Fagerström Test for Nicotine Dependence (FTND): This 6-item questionnaire is widely used to 
characterize the level of dependence of cigarette smokers (Heatherton, Kozlowski, Frecker, & 
Fagerström, 1991). 
 
Smoking History Questionnaire (SHQ): This questionnaire permits collecting smoking data 
such as age of smoking initiation, parent and peer smoking behavior, history of quit attempts, 
and current level of smoking (DiClemente et al., 1991). 
 
Smoking Abstinence Self-Efficacy (SASE): This questionnaire provides a measure of a 
smoker’s confidence in his or her ability to not smoke in 20 challenging hypothetical situations 
(DiClemente et al., 1985). 
 
The Wisconsin Smoking Withdrawal Scale (WSWS): The WSWS is a 28-item questionnaire 
designed to assess withdrawal DSM-IV symptoms and other signs of withdrawal (Welsch et al., 
1999), and provides 7 construct subscales (anger, anxiety, sadness, concentration, craving, sleep, 
and hunger). The WSWS subscales have shown good reliability and have been validated in 
smoking abstinence and nicotine replacement therapy studies (Shiffman et al., 2004). 
 
Questionnaire on Smoking Urges (QSU): This 32-item questionnaire of smoking craving 
provides two dimensions (anticipation of pleasure from smoking, and anticipation of relief from 
negative affect and withdrawal), and has shown sensitivity to smoking cessation (Tiffany & 
Drobes, 1991). 
 
Smoking Cessation Contemplation Ladder: This single item measure is designed to assess an 
individual’s readiness to consider smoking cessation (Biener & Abrams, 1991). Participants are 
asked to rate their readiness to consider quitting smoking on a scale from 1 (i.e., no thought of 
quitting), to 10 (i.e., taking action to quit). 
 
Other measures: 
General Self-Efficacy Scale (GSES): This is a validated 17-item questionnaire which assesses 
general self-efficacy (Sherer et al., 1982). 


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Brief Symptom Inventory (BSI): This questionnaire is a well-validated measure of acute 
psychological distress (Derogatis, 1993). 
 
Positive and Negative Affect Schedule Expanded Form (PANAS-X): This is a well-validated 
questionnaire assessing positive and negative affect as two general factors (Watson and Clark 
1994, 1997). 
 
Beck Depression Inventory (BDI): The BDI is a well-validated 21-item self-report measure of 
depressive mood and symptoms (Beck et al., 1961).   
 
State-trait Anxiety Inventory (STAI): The STAI (Form Y; Spielberger, 1983) is a widely used 
self-report measure of state (temporary) and trait (recurring) anxiety consisting of 40 items 
assessing apprehension, tension, worry, and nervousness.  
 
Connectedness to Nature Scale (CNS): The CNS is a 14-item assessment of individuals’ 
general feelings of connection to the natural world and other (nonhuman) living organisms 
(Mayer & Frantz, 2004). 
 
Tellegen Absorption Scale (TAS): The TAS is a 34-item true-false questionnaire used to 
measure sensitivity to altered states of consciousness (Tellegen, 1982), which may be a marker 
for sensitivity to psilocybin (Studerus et al., 2012) and which may increase after psilocybin.  
 
Measure of Actualization of Potential (MAP): This questionnaire assesses the construct of self-
actualization, a process through which one’s potential is developed in congruence with one’s 
self-perception and experience (Lefrancois et al., 1997; Leclerc et al., 1998, 1999). 
 
TCI Self-transcendence subscale: The self-transcendence subscale of the Temperament and 
Character Inventory-Revised (Cloninger et al., 1993; Cloninger, 1999) is a 26-item self-report 
measure used to assess an individual’s sense of connectedness to their surroundings, a stable 
personality trait correlated with related personality constructs such as openness (McCrae, 2009). 
 
Five Facet Mindfulness Questionnaire (FFMQ): This is a questionnaire scale assessing 
mindfulness in daily activities (Baer et al., 2006). 
 
Schwartz Value Scale (SVS): This 57-item questionnaire is a multidimensional self-report 
measure assessing the relative importance of various life values (Schwartz, 1992, 1994). 
 
Purpose in Life Test (PIL): This 20-item questionnaire assesses a participant’s sense of 
meaningfulness in life (Crumbaugh and Maholick, 1964). 
 
Delay discounting: This measure assesses impulsivity by asking participants to make 
hypothetical choices between smaller immediate rewards and larger later rewards (e.g., would 
you rather receive $500 now or $1000 after waiting 1 year?). This measure has been found to 
relate to nicotine dependence in several studies (Bickel & Johnson, 2003). A delay discounting 
assessment based on health outcomes will also be administered (Baker et al., 2003). 
 
 


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Outcome measures to be assessed in the study are listed in the following table. 
 
Time of Measure (approximate) 
Measure 
Completed daily by participant at home from 2 weeks before the 
Target Quit Date until end of study treatment. 
• 
Smoking diary  
The morning of psilocybin session (before psilocybin 
administration) 
• 
Pre-Session Questionnaire 
• 
Staff Rating of Likely Experience 
 
Throughout psilocybin session (10 min. before capsule, and 30, 
60, 90, 120, 180, 240, 300 min. after capsule) 
• 
Within-session Monitor Rating Form 
• 
Heart rate / Blood pressure 
• 
Video and audio recordings 
 
About 7 hours after psilocybin administration 
• 
Mystical Experience Questionnaire (MEQ) 
• 
Hallucinogen Rating Scale (HRS) 
• 
Post-session Monitor Rating Form 
The day after psilocybin session 
• 
Next-day Monitor Rating / Headache Interview 
At End of Treatment (8 weeks after TQD) 
• 
COVID-19 Protocol Feedback 
Longitudinal measures (timing specified by superscripted number 
below) 
 
1 At baseline screening, at TQD, at all study treatment meetings, 
and at 3, 6, and 12 month follow ups 
 
2 At baseline screening, 8 weeks after TQD, and 3, 6, and 12 
month follow ups 
 
3 At baseline screening 
 
4 At baseline screening, and 3, 6, and 12 month follow ups 
 
5 At baseline screening and 1 week after TQD 
 
6 At 1 week after TQD 
 
7 At 8 weeks after TQD, 3, 6, and 12 month follow ups 
 
8 At baseline screening, at each treatment meeting, and at 3, 6, and 
12 month follow ups 
 
9 At baseline screening, week 2, week 5 of treatment, and 3-month 
follow-up* 
 
10 At baseline screening, 1 week after TQD, 8 weeks after TQD, 
and 6 month follow up 
 
11 At baseline screening, 8 weeks after TQD, 6 and 12 month 
follow up 
 
12 At baseline screening, at TQD, at 1 through 8 weeks after TQD, 
3, 6, and 12 month follow up 
 
13 At baseline screening, 1 week after TQD, and 6 month follow 
up 
 
14 At baseline screening, 6, and 12 month follow ups 
 
15 At baseline screening, 2 weeks after TQD, and 6 month follow 
up 
 
16 At baseline screening, 4 weeks after TQD 
Smoking related: 
• 
Carbon monoxide (CO) reading 8 
• 
Urine cotinine sample 4 
• 
Smoking History Questionnaire 4 
• 
Smoking Abstinence Self-Efficacy (SASE) 8 
• 
Wisconsin Smoking Withdrawal Scale (WSWS) 12 
• 
Questionnaire on Smoking Urges (QSU) (32 item) 8 
• 
Fagerström Test for Nicotine Dependence (FTND) 3 
• 
Smoking Cessation Contemplation Ladder 8 
• 
Timeline Follow-Back (TLFB) 1 
Other measures: 
• 
General Self-Efficacy Scale (GSES) 10 
• 
Brief Symptom Inventory (BSI) 2 
• 
PANAS-X 2 
• 
Beck Depression Inventory (BDI) 2 
• 
 State-Trait Anxiety Inventory (STAI) 2  
• 
Connectedness to Nature Scale (CNS) 10 
• 
Tellegen Absorption Scale 10 
• 
Toronto Alexithymia Scale 10 
• 
TCI Self-transcendence subscale 10 
• 
MAP (Measure of Actualization of Potential) 10 
• 
Five Facet Mindfulness Questionnaire 10 
• 
Schwartz Value Scale 10 
• 
Purpose In Life Test (PIL) 2 
• 
Delay / Health discounting & Elasticity of Demand 13 
• 
Zimbardo Time Perspective Inventory (ZTPI) 10 
• 
Future Time Perspective (FTP) 11 
• 
Visual Effects Questionnaire 4 
• 
Hood Mysticism Scale (lifetime) 14 
• 
Blood markers: Cortisol, ACTH, IL-4, IL-6, IL-10, 
INF-gamma, TNF-alpha, Gs-alpha 5 
• 
Persisting Effects 6 
• 
States of Consciousness Retrospective Questionnaire 7 
• 
Adverse Events form 1 
• 
Open-ended clinical Interview 7 
• 
Monitor Rating of Enduring Effects 7 
• 
Saliva samples for cortisol 5 
• 
Functional Neuroimaging: MRI scanning 9 † 
 
† MRI scanning procedures will occur only for those individuals who are deemed MRI eligible and consent to do so (n=60). 
*3-month follow-up MRI Scan 3 only for MRI participating volunteers showing biologically verified 7-day point-prevalent 
abstinence at that time. 


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Zimbardo Time Perspective Inventory (ZTPI): This validated questionnaire assess the 
construction of psychological time, and includes 56 questions scored on a 5-point scale with 
subscales assessing past negative, present hedonistic, future, past positive, and present fatalistic 
dimensions  (Zimbardo & Boyd, 1999). 
 
Future Time Perspective (FTP): Participants will complete task I from this questionnaire 
designed to assess future time orientation (Wallace, 1956; Petry et al., 1999). Participants are 
asked to list 10 events that may happen to the participants during the rest of their lives. After 
each written response, the participant is asked what age he or she might be when each event will 
occur. Unknown to the participant, the dependent measure is not the events listed, but the 
average number of years in the future in which the events will occur. Drug dependent individuals 
have been found to provide shorter distances into the future compared to non-drug dependent 
individuals on this task (Petry et al., 1999). 
 
Visual Effects Questionnaire: This form was used in our first psilocybin study (Griffiths et al., 
2006) to assess any persistent perceptual effects resulting from sessions (e.g., seeing auras). 
 
Hood Mysticism Scale (lifetime): This 32-item questionnaire was developed to assess primary 
mystical experiences. The Mysticism Scale has been extensively studied, demonstrates cross-
cultural generalizability, and is well-regarded in the field of the psychology of religion (Hood et 
al. 2001; Spilka et al. 2003). A total score and three factors are scored: Interpretation 
(corresponding to three mystical dimensions described by Stace [1960]: noetic quality, deeply 
felt positive mood, and sacredness); Introvertive Mysticism (corresponding to the Stace 
dimensions of internal unity, transcendence of time and space, and ineffability); Extrovertive 
Mysticism (corresponding to the dimension of the unity of all things/all things are alive). Items 
are rated on a 9-point scale. The lifetime version of the questionnaire instructs participants to 
answer questions with reference to their experiences over the course of their lifetime. This scale 
was shown sensitive to the effects of psilocybin in our previous study (Griffiths et al., 2006). 
 
Blood markers of stress/immune function: Cortisol, ACTH, IL-4, IL-6, IL-10, INF-gamma, 
TNF-alpha: To assess these markers 10 cc blood samples will be taken at baseline (a total of 30 
cc blood is taken at baseline, including 20 cc for general medical screening), and at 1 week after 
TQD. The blood draw at 1-week after TQD will be optionally completed if participants are able 
and willing to come to BPRU in person for blood draw procedures. It has been hypothesized that 
hallucinogen facilitated mystical experiences may be accompanied by decreased stress and may 
improve immune function (Roberts, 1999; Roberts, 2006), however smoking cessation may be a 
confounding factor. We have therefore included these easily obtained and inexpensive assays as 
an exploratory step to determine if changes are observed within subjects and between treatment 
conditions. 
 
Gs-alpha protein in blood: The Gs-alpha protein has been hypothesized to play a role in mood 
altering effects of drugs (Donati et al., 2015). Thus, from pre-post blood samples we will extract 
red blood cells (RBC) and platelets from cells and prepare membranes from both fractions. For 
RBC, we will determine the extent to which Gs-alpha is ensconced in lipid rafts pre- and post-
psilocybin treatment. For both RBC and platelets, we will determine the proportion of Gs-alpha 
that is palmitoylated. The former studies will be done by immunodetection and the latter by 
mass/spec analysis. 


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Saliva samples for cortisol assessment: In addition to blood cortisol collection as described 
above, we will also collect saliva samples for cortisol analysis (e.g., Lee et al., 2007; Varadhan et 
al., 2008). Diurnal amplitude of cortisol, which takes into account a morning and evening 
measure of cortisol within a 24 hour period, is known to to be a meaningful index of stress (e.g., 
Varadhan et al., 2008). Collecting these morning and evening levels via saliva allows the 
participant to collect samples at home, as has been successfully performed in previous research 
at Johns Hopkins (e.g., Varadhan et al., 2008). At baseline assessment, and 1 week after TQD, 
participants will be sent home with commercially available Salivette swabs (Sarstedt Inc, 
Newton, North Carolina). Participants will use these swabs to collect one sample in the evening 
before bedtime but at least 1 hour after eating, and another sample the next morning within 30 
minutes of waking but before brushing teeth. For each sample, the swab is chewed lightly for 45 
seconds and returned to its container. The two labeled samples will be returned to the laboratory 
on the next scheduled visit. Because identical procedures will be performed at baseline, and 1 
week after TQD, a total of 4 swabs (2 per occasion for evening and morning) will be obtained. 
 
Open Ended Clinical Interview: Brief interviews (approx. 60 min.) will be conducted during 
which participants will be asked to share any positive or negative effects from their study 
participation which have not been covered by other questionnaires. These interviews will be 
conducted by study team members during regularly scheduled counseling meetings, and may be 
audio recorded for purposes of qualitative data analysis.  
 
States of Consciousness Questionnaire: (Pahnke, 1969; Richards, 1975; Richards et al., 1977): 
This scale was designed to assess mystical experiences, was used as a primary outcome measure 
in the Good Friday Experiment (double blind study of psilocybin; Pahnke, 1963; Doblin, 1991), 
and has been shown to be sensitive to hallucinogens, including psilocybin in our previous study 
(Pahnke, 1969; Turek et al., 1974; Richards, 1975; Richards et al., 1977; Griffiths et al., 2006).  
 
Persisting Effects Questionnaire: This 145-item questionnaire was designed to measure changes 
in attitudes, moods, behavior, and spiritual experience, and has demonstrated sensitivity to the 
intermediate and long-term effects of psilocybin (Griffiths et al., 2006, 2011). The questionnaire 
has been modified for this study to additionally assess attributions volunteers make 
retrospectively to their treatment experience, and how it may have facilitated smoking cessation.  
 
Monitor Rating of Enduring Effects: This questionnaire will assess the monitor’s observations 
of persisting effects of study participation on participant attitudes and behaviors. 
 
States of Consciousness Retrospective Questionnaire: This questionnaire has been used in our 
previous psilocybin research (Griffiths et al., 2006) for purposes of long-term follow-up. Some 
items on this questionnaire comprise the States of Consciousness Questionnaire, and are 
completed retrospectively for the experience. Other items comprise the previously described 
Persisting Effects Questionnaire. For these items, volunteers are asked to rate any current 
persisting effects that they attribute to the experience. Within the Retrospective Questionnaire, 
volunteers are also asked to provide written descriptions of what was most memorable and what 
was most spiritually significant about the experience. 
 
Adverse Events Form: After TQD participants will be asked at each study treatment meeting to 
report on how they have been feeling since their last in-person meeting. In the case of any 
adverse events (AEs), these will be documented using an AE form, which assesses the nature of 


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AE, duration, severity, and what course of action was taken to address the event. 
 
COVID-19 Protocol Feedback: At the end of treatment (~8 weeks after TQD) participants will 
be asked to complete a brief questionnaire designed by our team to assess the perceived impact 
of COVID-19 related study procedures (e.g., mandatory COVID-19 testing, masks / PPE, virtual 
meetings) on key elements of their study experience (e.g., psilocybin session, relationship with 
study team, quit attempt, sense of safety). 
 
Functional Neuroimaging (fMRI; for MRI participating volunteers only):  
Smoking cessation and withdrawal have been well documented to affect brain function, 
including resting state functional connectivity, and smoking related cue-reactivity (McLernon et 
al., 2007; Sutherland et al., 2012). In order to examine the underlying neurobiological 
mechanisms associated with psilocybin-facilitated smoking cessation, and identify potential 
brain based mediating factors predictive of treatment outcomes, up to 60 participants will 
undergo two to three brain scans collecting fMRI data while performing the tasks detailed below. 
The first scanning session will take place in week 2 of treatment, after a 24-hour period of 
smoking abstinence. The second will occur in approximately week 5 of treatment (i.e., one day 
after the psilocybin session, or immediately before initiating NRT), after another 24-hour period 
of smoking abstinence. Participants who provide biologically verified (i.e., breath CO), and self-
report seven-day point prevalence abstinence at 3 months post-TQD will receive a final follow-
up MRI scan at that time. Functional neuroimaging will be conducted at NIDA IRP by trained 
MRI operators under the supervision of Dr. Amy C. Janes. In addition to these scanning sessions, 
MRI participating volunteers will also be given the option to participate in a preliminary MRI 
scan through a NIDA-approved sub-study protocol. Either the primary study scans or the 
preliminary study scan will include a clinical scan to be examined for incidental findings. 
 
State of the art, multimodal imaging will be performed on a Siemens 3T Trio scanner, 
located at the NIDA-IRP (intramural research program). Participants’ heads will be placed inside 
the RF coil and held in place by a head restraint that generally consists of soft foam padding. For 
most scanning experiments, a blipped, gradient-echo, echo-planar image (EPI) pulse sequence 
(e.g. TE = 27ms) is used with a TR of about 2 seconds. Specific imaging parameters (e.g. 
number of slices, slice angle, TR, TE, flip angle etc.) may be changed in order to maximize 
signal integrity. A “watchdog” program runs continuously on the MRI computer during all pulse 
sequences and ensures that no scanning parameter ever exceeds FDA guidelines. 
 
Resting Scan. An EPI scan to assess resting-state fluctuations (RSF) will be conducted. These 
scans will provide us with information relating to trait and perhaps state connectivity between 
different prefrontal and limbic brain regions. Completion time: ~10 min. 
 
Multisource Interference Task (MSIT): The MSIT is a cognitive control task that reliably and 
robustly activates the anterior cingulate cortex and fronto-parietal executive control and attention 
network (Bush & Shin, 2006). During each trial participants view three numbers (e.g., 2 1 1) and 
are required to identify the “oddball” number which differs from the other two (i.e., 2) as quickly 
as possible by pressing the corresponding number on a 3 button response box (1, 2, 3). On some 
trials the location of the oddball is the same as the location on the response box (e.g., 2 2 3) and 
sometimes it is different (e.g., 2 1 1). This latter trial type produces a slowing in response time 
that reflects conflict produced by flanker stimuli and the need to respond to stimulus identity 
(i.e., press 2) and suppress the response to stimulus order (i.e., press 1). Completion time 15min.     
 


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Cue-elicited Craving: Participants are presented two kinds of stimuli, smoking-related picture 
cues and neutral pictures (see Fig. 1). The smoking-related pictures are selected from Mucha’s 
study (Mucha et al., 1999) and the International Smoking Image Series (Gilbert and Rabinovich, 
1999) and similar smoking and neutral images from open source internet sites. The content of 
neutral cues are paired to smoking-related cues, but eliminate any smoking-related information.  
 
Fig. 1: Sample stimuli. One representative pair is showed above.  
Structural Images: A set of high resolution structural MR images will be collected. The images 
will be acquired using a T1-weighed three-dimensional MPRAGE sequence and will be used for 
the display of functional data. Completion time: ~5 min. 
 
Amygdala Reactivity Task: Participants will complete a simple perceptual task previously shown 
to produce robust bilateral amygdala activity (Pezawas et al., 2005; Hariri et al., 2002; Foland-
Ross et al., 2010), as well as top-down prefrontal regulation of amygdala reactivity (Hariri et al., 
2002; Foland-Ross et al., 2010). This blocked fMRI paradigm consists of two experimental 
conditions: a face matching condition, and a sensorimotor control condition. During the emotion 
matching condition, participants view an array of 3 faces and their task is to select (via button 
press) one of the two faces that matches the identity of the target face. During the sensorimotor 
control task, participants view an array of 3 geometric shapes (circles, vertical and horizontal 
ellipses) and select one of the two shapes (bottom) that matches the target shape (top). Each 
block begins with a brief instruction screen (“match face” or “match shape”). During each 
emotion block different images selected from a standard set of pictures of facial affect (Lang et 
al., 2001), are presented. During the control blocks, different geometric shapes are presented in a 
pseudo-random order. Completion time: ~7min 
 
Central executive function of attentional switching within verbal working memory task: Our 
previous work (Garavan et al, 2000) revealed widespread activation associated with attention 
switching within working memory (WM). Subjects will perform a verbal WM counting task.  In 
each trial, subjects will be presented with a series of large and small squares and, using a 
response device, must report final counts at the end of each trial. The order in which the squares 
are presented dictates whether an update of the same count is required (e.g., two large squares in 
succession requires two updates of the “large square” count) or whether subjects must switch 
attentional focus to update the “other” count (e.g., a large square followed by a small square 
requires an update of the “large square” count followed by a switch to the “small square” count 
and an update of it). A parametric manipulation will produce trials with different numbers of 
switches, thus, for each particular trial length there will be a LOW, MEDIUM, and HIGH 
switching density trials ~ 10 min. 
 


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N-back task: The n-back visual working memory task (Kane et al., 2007) will be administered to 
assess working-memory performance. During the n-back task participants are presented with a 
series of single letters in a pseudorandom order and are required to decide whether the current 
stimulus matches that which appeared n items previously (Kane et al., 2007). ~20min 
 
Dot Probe Task: A dot-probe task will be administered outside of the MRI scanner to assess for 
attentional bias to smoking-related stimuli (Ehrman et al., 2002). Each trial of the task begins 
with a fixation cross followed by a brief (~500ms) presentation of two images, one smoking-
related and one neutral image either side of the fixation cross. Immediately after the offset of 
these images a target (dot probe) appears either in the position where the smoking-related image 
was, or where the neutral image was. Participants are required to respond as quickly as possible 
to the dot probe and the latency to respond provides a behavioral measure of how much attention 
was directed to either the preceding smoking-related or neutral image. For example, if relatively 
greater attention is directed to smoking-related images, responding will be faster on trials where 
the probe appears behind the smoking-related image and slower on trials where the probe 
appears behind the neutral image. Completion time: ~5min 
 
Measures taken the morning of psilocybin session prior to drug administration (for 
psilocybin condition only): 
 
Pre-Session Questionnaire: To assess the psychological “set” of the volunteer before the 
session, subjects will complete a brief questionnaire before psilocybin administration on which 
they will rate various dimensions of psychological set (e.g., the extent of pre-session 
apprehension, preoccupation with thoughts and problems not related to the session, positive 
expectation). 
 
Staff Rating of Likely Experience: Study staff will complete a questionnaire before the session 
rating their expectations about the likely nature of the drug experience for that subject (e.g. 
likelihood that the experience will be interpreted as being spiritually significant or personally 
meaningful, or will involve a period of significant fear). This form was used in our previous 
psilocybin study (Griffiths et al., 2006). 
 
Measures taken throughout psilocybin session (10 min. before capsule, and 30, 60, 90, 120, 
180, 240, 300 min. after capsule; psilocybin condition only): 
 
Within-session Monitor rating form: At the same timepoints at which the heart rate and blood 
pressure will be taken, the two study staff will independently complete the Monitor Rating Form, 
which we used in our first psilocybin study. The form involves rating or scoring 26 dimensions 
of the subject’s behavior and mood (e.g., yawning, minutes sleeping, minutes speaking, 
nausea/vomiting, motor activity, sedation, anxiety/fear, paranoia, crying, sorrow/sadness, 
joy/intense happiness, peace/harmony, overall drug effect). 
 
Heart rate and blood pressure: At 10 minutes before and 30, 60, 90, 120, 180, 240, and 300 
minutes after psilocybin administration, heart rate and blood pressure will be monitored for 
safety and because psilocybin is known to produce modest but reliable elevations in blood 
pressure (Griffiths et al., 2006; Gouzoulis-Mayfrank et al., 1999b; Hasler et al., 2004). 
 


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Video and audio recordings: Video and audio recordings, which will be taken throughout the 
psilocybin session, will be reviewed by investigators. Video and audio recordings will permit an 
objective assessment of session activity and will provide a rich source of additional data about 
subject comments and behavior during the session that may be useful in characterizing the 
effects of psilocybin. Video and audio recordings will be treated as confidential research 
materials and will be stored in locked offices. 
 
Measures taken about 7 hours after psilocybin administration: 
 
Mystical Experience Questionnaire (MEQ; MacLean et al., 2012): This 30 item scale is an 
abbreviated version of the 100 item States of Consciousness Questionnaire (Pahnke, 1969; 
Richards, 1975; Richards et al., 1977). The MEQ was derived via exploratory factor analysis, 
and is intended to characterize the impact of single hallucinogen-occasioned drug sessions for 
common elements of mystical experience (e.g., unity, sacredness, transcendence of time/space, 
ineffability). 
 
Hallucinogen Rating Scale (Strassman et al. 1994; Riba et al. 2001): This questionnaire, 
which was designed to show sensitivity to the hallucinogen N,N-dimethyltryptamine, consists of 
six subscales assessing various aspects of hallucinogen effects (intensity, somaesthesia,, affect, 
perception, cognition, and volition). This scale was shown sensitive to the effects of psilocybin 
in our previous study (Griffiths et al., 2006). 
 
Post-session Monitor Rating Form: On this form, which was used in our previous study of 
psilocybin (Griffiths et al., 2006), monitors will rate the qualitative nature of the session at the 
conclusion of each session. 
 
Measure taken the day after psilocybin session (psilocybin condition only): 
 
Next-day Monitor Rating Form: On this form, which was used in our previous study of 
psilocybin (Griffiths et al., 2006), study staff will rate the qualitative nature of the session the 
day after each session after meeting with the volunteer. 
 
Headache Interview Form: This 14-item interview assesses incidence, duration, and severity of 
headache during or immediately after psilocybin sessions, as headaches have been found to occur 
in some individuals post-psilocybin (Johnson et al., 2012). 
 
c. Statistical plan including sample size justification and interim data analysis. 
 
This is a pilot comparative efficacy study with a randomized control condition. Demographics 
and smoking history at baseline will be examined for between group differences using Fisher’s 
exact tests and independent-samples t-tests. The primary outcome variable will be a between 
group comparison of the percent of volunteers who show biologically verified (via carbon 
monoxide and cotinine measures) and self-reported smoking abstinence post-TQD, allowing for 
a grace period for initiation of prolonged abstinence within 14 days after the target-quit date in 
line with current recommendations for best practices in smoking cessation clinical trials (Piper et 
al., 2020). For this primary analysis, positive cotinine samples will be counted as smoking 
abstinent if the person indicates on the TLFB that they have used non-smoking forms of nicotine. 
This comparison will be performed using a logistic regression analysis, with treatment condition 


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as the predictor variable and prolonged abstinence as the examined outcome. Although the study 
sample will be small, these results will provide useful preliminary data indicating whether follow 
up investigation in this area is warranted. Between groups comparisons of secondary measures 
will examine differences across treatment conditions on variables such as smoking urges and 
withdrawal using independent-samples t-tests. We will apply a 2-step approach when assessing 
between-group differences in these variables. First, we will compare values between all 
participants still enrolled in the study at 6-months post-TQD, then only among those still 
smoking at 6 months post-TQD according to 7-day point prevalence criteria. In order to rule out 
the role of alternative sources of nicotine in achieving smoking abstinence, we will perform a 
secondary analysis where participants who stopped smoking tobacco cigarettes and initiated 
alternative forms of nicotine use (e.g., e-cigarettes, smokeless tobacco) will be coded as non-
abstinent. 
 
Neuroimaging data will be analyzed to account for differences in BOLD signal and 
functional connectivity related to task parameters between groups. Resting state MRI will be 
assessed between groups and within-subjects as a function of relapse status to examine whether 
characteristics of resting state functional connectivity (rsFC) are associated with treatment 
success (vs. failure). Additionally, behavioral performance on each of the fMRI tasks assessing 
working memory, attention, processing speed, inhibitory control processes, cognitive control, 
reward responsiveness, amygdala, striatal, and impulsive decision making (e.g., reaction time, 
error rate, hit rate, reward bias) will provide task-related parameters necessary for analysis of 
BOLD and resting state data. Self-reported craving, withdrawal symptoms and mood/affect will 
also be employed as regressors in the analysis of task and resting BOLD data. No interim data 
analyses are planned. 
 
d. Early stopping rules. 
 
The investigators will monitor safety data and relevant literature and report information to the 
IRB that might increase the risk assessment of the study. 
 
7. Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected 
frequency. 
 
Smoking Withdrawal: Participants who quit smoking will likely experience nicotine 
withdrawal symptoms, which are expected to last approximately 2-4 weeks and peak within the 
first week after quitting. Symptoms might include craving cigarettes, restlessness, irritability, 
increased appetite, increased eating, dizziness, difficulty concentrating, nausea, anxiety, sleep 
disturbance, and depressed mood (Hughes, 2007). Long-term smoking is associated with 
increased health risks such as cancer and cardiovascular disease. Therefore the risk of discomfort 
resulting from nicotine withdrawal is outweighed by the long-term health benefits likely with 
sustained abstinence. 
 
MRI Scan Risks (for MRI participating volunteers only): Participants may find the tasks that 
they are asked to perform during, before and after MRI scanning sessions boring, difficult, 
and/or frustrating. In order to reduce discomforts associated with performing the emotional and 
cognitive tasks, scanning sessions and task sessions outside of the scanner are organized in such 
a way that participants will not perform tasks for extended periods of time and will be given a 
chance to rest between tasks. In addition, the tasks are designed to make performance neither too 


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difficult nor too easy. Ideally, individual adjustments of task difficulty enable participants to 
remain actively engaged in the task. Participants receive extensive training before the actual 
experimental task begins.  
 
When used on appropriately qualified individuals, MRI presents minimal risk as long as 
technical scan parameters remain within FDA guidelines. There is no exposure to x-rays or 
radioactivity. The radio waves used have produced burns (most of these minor) in about one in a 
million exams. The magnet may move metal implants in the body, the motion of which could be 
painful and harmful. Metal implants may also cause burns from the radio frequency energy used. 
While inside the magnet, subjects may experience an acute panic attack due to claustrophobia. 
Subjects may also experience mild, remittable discomfort from lying in the scanner. To ensure 
adherence to FDA guidelines for MRI, a trained MRI operator who has been instructed in these 
guidelines performs all machine manipulations. Other preventative measures include assuring 
that all equipment to be used during imaging sessions is MR compatible, that participants are 
familiar with the MRI environment (using the mock scanner), and that participants are aware of 
how to signal the MR operator if they need to do so during the session. Furthermore, participants 
are screened prior to each MRI session for any MR contraindications, including metal implants, 
pregnancy, fear of small, enclosed spaces, and inability to lie still for prolonged periods of time.  
 
Some subjects may experience temporary, reversible shifts in hearing threshold after 
MRI. The sound generated by an MR system usually consists of a series of repetitive pulses. 
Acoustic noise is a result of the mechanical vibration produced by the gradient coils when the 
large currents are applied to them to create time varying imaging gradient fields. The relevant 
safety parameters required to characterize such a noise are the peak impulse sound pressure level 
(L-peak) and the time integral of the A-weighted sound pressure level (Leq). In MR applications, 
the peak impulse sound pressure level is dependent upon the peak amplitude of the individual 
pulses, while the time integral of the A-weighted sound pressure level is dependent upon the 
continuous exposure to a series of such pulses. Based on Occupational Safety and Health 
Administration (OSHA, Occupational Noise Exposure – 1910.95, www.osha.gov) regulations: 1) 
exposure to impulsive or impact noise should not exceed 140 dB peak sound pressure level, and 
2) exposure to continuous noise for 2 hours per day should not exceed 100 dB. Note that these 
regulations are based on employees’ daily exposure to a noisy environment over their entire 
working career, whereas we use them here as a comparison for participants’ occasional exposure 
to MRI scanner noise, thus making these values extremely conservative measures. Measurements 
within our MRI scanner (provided by Siemens, the manufacturer) indicate that the maximum 
noise level produced by our standard fMRI pulse sequence is 116.5 dB. Based upon our typical 
echo spacing, this sound is in the 3-4 kHz range. According to the Occupational Safety and 
Health Administration regulations (OSHA, occupational noise exposure 1910.95, 
www.osha.gov): 1) Exposure to impulsive or impact noise should not exceed 140 dB peak sound 
pressure level, and 2) Exposure to continuous noise for 2 hours per day should not exceed 100 
dB. These guidelines are based on employees' daily exposure to a noisy environment over their 
entire working career, whereas we use them here as a comparison for participants' occasional 
exposure to MRI scanner noise. This study consists of a series of scans ranging in length from a 
few seconds to about ten minutes. Rest periods of up to a few (1-5) minutes occur regularly 
between scans while the next scan is being set up.  
 
During fMRI experiments, MRI compatible headphones with tubes for audio input and/or 
earplugs with or without tubes for audio input are routinely used for hearing protection. In 
addition, a vacuum pillow or other padding used for head stabilization may also attenuate noise. 
Based on the manufactures specifications, the earplugs with and without audio tubes have noise 
reduction ratings of approximately 25dB and 33 dB. The headphones have a noise reduction 


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rating of 29 dB. The vacuum pillow / padding foam provides additional noise reduction (values 
not available, but estimated at 5-15 dB). The noise reduction rating is a conservative measure 
that averages over frequencies and attempts to account for improper protection use. The mean 
noise attenuations at 3150 Hz, a frequency near that of our scanner, are actually 35dB, 47dB for 
the 2 types of earplugs and 40dB for the headphones used. Thus, the use of any two of these 
devices in combination reduces the noise level to levels much lower than that required by OSHA 
for lifetime exposure, and provides effective hearing protection for the participants. 
Nevertheless, some subjects may experience temporary, reversible shifts in hearing threshold 
after MRI. 
 
Incidental Findings (for MRI participating volunteers only): Sometimes there are unexpected 
findings on an MRI scan. Some findings are of unknown significance or importance to 
participants’ health, which may make them anxious and lead to further tests that may be 
unnecessary. We will inform participants about any finding that may require further evaluation 
or care. If needed, we will refer participants to a health care provider. If something unexpected is 
found, it may make it harder or more expensive for participants to buy life insurance or disability 
insurance. The costs for any care that will be needed to diagnose or treat an incidental finding 
would not be paid for by this research study. These costs would be the participants’ 
responsibility. 
 
NRT Adverse Effects: The most commonly reported adverse effects of nicotine transdermal 
patch use include skin irritations, gastrointestinal complaints, heart palpitations, chest pains, and 
insomnia (Mills et al., 2010). Discontinuation rates due to adverse effects for nicotine patch are 
generally lower than those of other smoking cessation treatments in clinical trials (Aubin et al., 
2008; Moore et al., 2009). Current data indicates that NRT can be safely administered over the 
counter, and that it does not pose a known risk in terms of human abuse liability (West et al., 
2000). A complete list of adverse effects will be provided to all participants (FDA label, 
PDR.net).  
 
Psilocybin Adverse Effects: Preclinical and clinical data show psilocybin to have a safe profile 
of physiological toxicity, as described below (in the section Psilocybin Pharmacology and 
Toxicology). Psilocybin and related hallucinogenic compounds were investigated in humans in 
numerous clinical research studies in the 1950s and 1960s. The incidence of adverse effects in 
these studies was very low, especially when participants were carefully screened, prepared, 
supervised, and followed up (Cohen 1960; Bergman, 1971; Strassman 1984). In previously 
described reviews of relative dependence potential and lethality for 20 commonly used 
psychoactive drugs, Gable (1993, 2004) concluded that heroin was associated with the greatest 
relative toxicity while psilocybin was associated with the least. 
 
Acute Psychological Effects of Psilocybin: The most likely potential adverse effect of 
psilocybin is anxiety, or possibly panic, during the period of acute drug action. The preparation 
and close supportive supervision provided to participants will minimize both the probability of 
such transient effects and, should they occur, the risk of any harmful consequences. Some 
individuals have been reported to develop paranoid and psychotic states while under the 
influence of hallucinogens, including psilocybin (Strassman 1992; IND 39,258, Strassman 
personal communication; Nielen et al., 2004). It is generally believed that individuals with 
previous psychiatric conditions, particularly psychosis or mania, are at an increased risk for 
hallucinogen-induced psychosis (Abraham et al., 1996). Furthermore, the risk that psilocybin 


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could precipitate in vulnerable individuals enduring psychiatric illness such as schizophrenia is 
very low, but cannot be excluded completely (Abraham et al., 1996). For this reason, all potential 
participants with personal or family histories of schizophrenia, psychotic disorders, or bipolar I 
or II disorder will be excluded from participation. Nevertheless, while we believe the risk to be 
minimal, it is possible that some participants may develop a brief psychotic reaction while under 
the influence of psilocybin. Such a reaction will be handled as described below under medical 
emergency procedures. To our knowledge, there have been no reports of persistent psychotic 
states associated with psilocybin (in contrast to LSD, which has a different pharmacological 
profile) (Abraham et al. 1996).  
 
In a previous human trial (Strassman 1992; IND 39,258, Strassman personal 
communication), one adverse psychological episode, involving transient anxiety and paranoia, 
was reported to FDA. The participant recovered quickly, and showed no long-term deleterious 
consequences of the episode. Our research team has been in personal communication with Dr. 
Strassman about this participant’s experience, and consistent with his recommendations we have 
designed our protocol to minimize the likelihood of a similar event. In other recent studies of 
psilocybin in humans (Hasler et al. 1997, 2004) including our studies, no adverse reactions other 
than the expected occasional episodes of fear or anxiety during the time of drug effect have been 
reported. Such transient episodes of fear or anxiety respond well to reassurance and have not 
required pharmacological or physician intervention. 
 
Psilocybin Pharmacology and Toxicology: Psilocybin and its analogues (psilocin, CEY-19, 
and CZ-74) are all psychoactive indoles with side-chains that place them within the general class 
of tryptamines. These compounds are analogues of hydroxytryptamine (5-HT, serotonin, a 
naturally-occurring neurotransmitter). The psychopharmacological mechanism of psilocybin and 
its analogues is similar to LSD and mescaline in that all these compounds seem to act as post-
synaptic agonists at 5HT2A and 5HT2C receptors (Sanders-Bush & Mayer 1996). In healthy 
human participants psilocybin increased thyroid stimulating hormone, adrenocorticotropic 
hormone, and cortisol, and moderately elevated blood pressure (Hasler et al. 2004). Psilocybin 
subjective effects in healthy participants were blocked by the 5HT2A antagonist ketanserin as 
well as by the mixed 5HT2/D2 antagonist risperidone (Vollenweider et al. 1998). Studies using 
positron emission tomography (PET) showed that psilocybin increased frontal glucose 
metabolism in healthy participants, suggesting that the behavioral effects of psilocybin involve 
the frontal cortex (Vollenweider et al. 1997; Gouzoulis-Mayfrank et al. 1999a). In a recent 
review of the pharmacology of psilocybin, Passie et al. (2002) concluded that psilocybin exhibits 
low toxicity and is physiologically well-tolerated. 
 
Animal studies suggest very low levels of general medical toxicity. The LD50 in rodents 
is approximately 2,000 to 3,000 times the usual human dose on a mg/kg basis (Usdin & Efron 
1972; Smith et al., 1996), comparing favorably with drugs such as aspirin and caffeine. 
Psilocybin and related hallucinogenic compounds were investigated in humans in numerous 
clinical research studies in the 1950s and 1960s. The incidence of adverse effects in these studies 
was low, especially when participants were carefully screened, prepared, supervised, and 
followed up (Cohen 1960; Strassman 1984). Gable (1993) reviewed over 350 research reports on 
the non-medical use of 20 psychoactive drugs (including alcohol and nicotine) in humans to 
compare these drugs in terms of their dependence potential and acute toxicity as rated by 24 
toxicologists who had published significant research in the area of abusable drugs. Results 
showed that the extremes were occupied by heroin (having the highest levels of acute toxicity 
and dependence potential) on the one hand and by psilocybin (having the lowest levels of both) 
on the other. In a recent follow up review and analysis of 3000 citations, Gable (2004) calculated 


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safety ratios for 20 psychoactive compounds, comparing lethal doses to commonly used doses, 
and found heroin was associated with the greatest toxicity and psilocybin the least.  
 
Physiological Safety Data in our Previous Studies of Psilocybin in Healthy Participants: 
Physiological effects of psilocybin consisted of moderately increased heart rate and blood 
pressure. The mean increase in heart rate was 19.8 beats per minute, the mean increase in 
systolic blood pressure was 31.4 mm Hg, and the mean increase in diastolic blood pressure was 
17.9 mm Hg. In terms of psychological adverse effects, 4 of the 36 volunteers reported the 
psilocybin session to be dominated by anxiety and dysphoria. An additional 4 participants 
reported that a significant portion of her/his psilocybin session was characterized by anxiety or 
dysphoria. These effects were easily managed with reassurance, and did not persist beyond the 
acute effects of the drug during the session. No volunteer reported the psilocybin session to have 
decreased her/his sense of well-being or life satisfaction. Minor adverse effects that may be 
associated with psilocybin administration are dizziness, nausea, vomiting, incontinence, and 
muscle twitching. During the period of drug action, there may be an increased risk of fall or 
other injury due to incoordination, misjudgment, or other effects of psilocybin. To mitigate this 
risk we have implemented new safeguards for session monitors as described in “steps taken to 
minimize risks.” Self-report data from online case reports after using psilocybin mushrooms 
recreationally (www.erowid.org; www.bluelight.ru; www.drugs-forum.com) and a summary 
report of psilocybin side-effects from previously published psilocybin studies (Studerus et al., 
2011) suggest that next-day leg or muscle pain is a possible effect. There may be an association 
between psilocybin administration and transient headache starting about 7 hours after 
administration (Johnson et al., 2012; Studerus et al., 2011).  
 
Non-Medical Use of Psilocybin: Varieties of mushrooms containing psilocybin as their primary 
active chemical are currently in use in religious rituals of native Americans (mainly in Mexico 
and Central and South America); this use is documented as early as the sixteenth century and 
probably reaches back into pre-Columbian times (Hofmann 1983). As reported in books, articles, 
and Internet reports, contemporary Western individuals and groups make use of psilocybin 
mushrooms with “spiritual” intent in settings and rituals inspired by indigenous use and in 
settings of contemporary design. However, along with other hallucinogens popular in 
contemporary American culture, psilocybin also continues to be a drug used for casual, 
unsupervised experimentation. 
 
In the United States, although psilocybin (in the form of psilocybin-containing 
mushrooms) is the second most commonly used of the classic hallucinogens, which include 
LSD, psilocybin, and mescaline (SAMHSA 2004b), psilocybin has not resulted in significant 
public health problems and medical emergencies resulting from its use are very rare (psilocybin 
is mentioned in only 0.1% of drug-related emergency department visits) (SAMHSA 2004a). The 
incidence of prolonged adverse psychological reactions to LSD, which is both a more potent and 
a longer-acting hallucinogen than psilocybin, was found to be very low in a follow-up survey of 
1,250 non-patient participants who received LSD under supervised research or therapeutic 
conditions (Cohen 1960). The single adverse event occurred with a participant who was an 
identical twin of a schizophrenic, and thus who would have been screened out of our present 
study. The adverse event, involving anxiety and depersonalization, resolved within five days. 
 
Concern that Psilocybin Administration Will Increase Drug Abuse: A potential concern 
about the proposed trial is the utilization of a drug with a known history of abuse (psilocybin) in 
the treatment of dependence on another drug of abuse (tobacco). Like many classes of 


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psychoactive drugs, classical hallucinogens such as psilocybin are sometimes used in a manner 
that jeopardizes the safety or well-being of the individual or others (e.g., driving while impaired; 
a pattern of use that interferes with work, school, or relationships). Under such circumstances 
hallucinogens are said to be abused. However, hallucinogens are not typically considered drugs 
of dependence in that they do not engender compulsive drug seeking (National Institute on Drug 
Abuse, 2001, 2006; O’Brien, 2006), consistent with the observation that they are not reliably 
self-administered in nonhuman animals (Poling and Bryceland, 1979; Griffiths et al., 1980; 
Fantegrossi et al., 2004). Further, they are not associated with a known withdrawal syndrome 
(O’Brien, 2006). Therefore, there is little risk that exposing human volunteers to hallucinogens 
will leave participants physically or psychologically dependent on these compounds. In our 
previous (Griffiths et al., 2006) and ongoing studies with psilocybin, exposing individuals with 
either no history of hallucinogen use or a history of minimal use (e.g. 1 - 3 times total and not 
within the last 5 years) in the context of a supervised and controlled research setting has not 
resulted in reported instances of subsequent illicit hallucinogen abuse.  
 
Perceptual Effects: Another type of potential adverse effect that has been associated with LSD 
use is a phenomenon of long-lasting perceptual disturbances (i.e. flashbacks). Such effects are 
extremely rare and associated primarily with LSD use (Strassman 1984; Halpern and Pope 1999; 
Abraham et al., 2002; Espiard et al., 2005). However, participants will be monitored for 
persisting visual effects as potential adverse effects of psilocybin. 
 
COVID-19 related risks: COVID-19 is a respiratory virus spread by respiratory droplets, 
mainly from person-to-person. This can happen between people who are in close contact with 
one another (less than 6 feet). It is also possible that a person can get COVID-19 by touching a 
surface or object (such as a doorknob or counter surface) that has the virus on it, then touching 
their mouth, nose or eyes. For most people, the new coronavirus causes only mild or moderate 
symptoms, such as fever and cough. For some, especially older adults and people with existing 
health problems, it can cause more severe illness, including pneumonia. While we are still 
learning about this virus, the information we have right now suggests that about 3 of 100 people 
who are infected might die from the virus. Individuals over 60 and with chronic conditions such 
as cancer, diabetes and lung disease have the highest rates of severe disease from the infection. 
 
b. Steps taken to minimize the risks. 
 
This study proposes a combination of careful screening, preparation, supervision, and follow-up 
designed to minimize any risks of psilocybin and NRT administration and their aftereffects. 
Many of these procedures have been used successfully in our previous and ongoing trials with 
psilocybin. Existing safety data indicate that research using psilocybin in a controlled setting 
with appropriate screening and preparation will expose participants to minimal risk. Likewise, 
administration of NRT to carefully screened and prepared individuals under medical supervision 
will minimize the risk of adverse events. In this study, volunteers will be carefully screened 
medically and psychologically, and will be carefully monitored throughout the course of 
treatment. We expect the risk of psychiatric adverse events during psilocybin sessions to be 
reduced further by the provisions made to help participants feel psychologically at ease and 
physically safe. The session room will be furnished to be inviting and comfortable. The presence 
throughout the session of the one or more monitors, with whom the participant will have engaged 
in a period of trust-building, will provide further reassurance. As a safety measure, after 


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psilocybin has been administered and throughout the period of drug action, physical support or 
guidance may be provided if we judge participants to be at risk for falls or dangerous behavior. 
 
Study Staff Overseeing Conduct of Psilocybin Sessions: Study staff will have significant 
human relation skills and have had self-described experience with altered states of consciousness 
induced by means such as meditation, yoga, or relaxation techniques. Each participant will be 
introduced to study staff team members before the psilocybin administration in a preparation 
session to develop rapport. One or more study staff members will be present in the session room 
with the participant during the psilocybin session. Each study staff member will be specially 
trained and knowledgeable about the medical and psychological markers of potential adverse 
reactions to the drug session. Study staff members will also be interviewed by the principal 
investigator before each drug session. If the study staff, participant, or investigator believes that 
the session is contraindicated for any reason, the session will be cancelled or postponed. 
 
Medical Emergency Procedures: The physician will be on the Bayview campus and 
immediately available via pager to come to the research site or for telephone consultation for at 
least 3 hours or until the peak effects of psilocybin have subsided, whichever is longer. We are 
confident that this duration of medical coverage is sufficient based on the known time-course of 
psilocybin, and based on our previous studies of psilocybin (Griffiths et al., 2006, 2011). Acute 
anxiety, agitation or panic will be handled with reassurance. In the unlikely event that these 
symptoms do not respond to reassurance, or in the unlikely event that the volunteer experiences 
psychosis, clinical judgment will determine the most appropriate medical treatment. Oral 
benzodiazepine will be available for on-site treatment of acute anxiety if needed (e.g., oral 
diazepam, 5 - 10 mg). An oral anti-psychotic will be available for on-site treatment of psychosis 
(e.g., oral tablets or orally disintegrating tablets of risperidone, 0.5 - 1 mg). (Note: The use of 
emergency medications for acute anxiety or psychosis will be at the judgment of the treating 
physician; use of specific medications is not protocolized). In research with psilocybin (our 
ongoing studies; Strassman 1992; IND 39,258; Strassman personal communication), similar 
precautions were taken; however, there were no reactions requiring pharmacological or physician 
intervention. In the unlikely event of a medical or psychiatric emergency that takes place after 
drug administration and that cannot be safely managed by staff with reassurance or 
pharmacological intervention, the study team will contact the adjacent Bayview Medical Center 
Emergency facility. If appropriate, participants will be transferred to the Emergency Department 
for continued care when symptoms have been sufficiently stabilized.  
 
Cardiovascular Monitoring During Psilocybin Session: During a psilocybin session, if 
systolic pressure is >170, diastolic >100, or heart rate >110, vital signs will be checked every 5 
minutes until systolic pressure is <170, and diastolic <100 and heart rate <110. If blood pressure 
is >170 to 200 systolic or >100 to 110 diastolic for more than 30 minutes (i.e. after 7 consecutive 
elevated readings at 5 minute intervals), session monitors will contact the study physician. If 
there is no evidence that blood pressure is trending upwards, the study physician can authorize 
changing the frequency of blood pressure assessments to 15 minute intervals. When blood 
pressure has decreased to (or below) 170 systolic and 100 diastolic, blood pressure assessments 
will resume at originally scheduled timepoints (e.g. at post-administration minutes 30, 60, etc.).  
During a drug session, if blood pressure is >200 systolic or >110 diastolic for three 
consecutive readings (i.e., 15 minutes), the participant will be treated with sublingual 
nitroglycerin 0.4mg. If blood pressure readings do not decrease below these thresholds after 5 
minutes, the same dose of nitroglycerin will be administered. A third dose of nitroglycerin will 


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be given after another 5 minutes, if readings remain elevated above these levels (maximum dose 
is 0.4mg x 3). If the need to administer nitroglycerin arises due to sustained elevated blood 
pressure the physician will administer the drug unless a nurse or nurse practitioner is available at 
BPRU to administer the drug by order of the physician. If blood pressure remains >200 systolic 
or >110 diastolic, at the judgment of the treating physician, the participant will be transported to 
the Emergency Department. 
 
Aversive Reactions to Sublingual Nitroglycerin: The following effects have occurred in 
clinical trials: headache, hypotension, cutaneous vasodilation with flushing, dizziness and 
weakness, as well as other signs of cerebral ischemia associated with postural hypotension. Also 
possible are nausea, vomiting, restlessness, pallor, perspiration and collapse, drug rash and/or 
exfoliative dermatitis, paresthesia, rhinitis, peripheral edema, asthenia, and abdominal pain. 
 
Continuation of Data Collection: To the extent possible without interfering with appropriate 
medical response to any adverse effects, we will continue collecting data from volunteers even if 
adverse effects occur that warrant stopping study participation. Thus, "stopping study 
participation," means stopping or delaying any study procedures that would interfere with 
appropriate medical response and care. The study data collection procedures entail minimal risk -
- interviews and questions and ratings. They represent the scientific and societal benefit aspects 
of this study and we believe they should be continued to the extent possible.  
 
Exiting the Drug Session: Participants will remain under observation at least 7 hours and until 
subjective and objective drug effects have subsided. Participants will be released into the custody 
of a close friend or family member who has agreed to take charge of the study participant as a 
condition of leaving the testing facility. In the unlikely circumstance that the friend or family 
member is unable to pick up the volunteer from the laboratory as scheduled, a staff member will 
escort the participant home by taxi. Both the study staff and medical personnel will be on call for 
24 hours following the drug session in order to assist with any post-session adverse reactions. 
Although we expect that all drug effects will have subsided and that participants will be ready to 
leave BPRU 7 to 10 hours after drug administration, participants will be kept overnight and 
under observation the next day if we judge it to be indicated. 
 
Post-session Headache: Because preliminary observations suggest there may be an association 
between psilocybin administration and transient headache starting about 7 hours after 
administration, on the first meeting after each session, study staff will conduct a formal interview 
with the volunteer about post-session headache onset, duration and severity. 
 
Persisting visual perceptual effects: To assess for possible persisting visual perceptual effects 
after psilocybin administration, a questionnaire is included to document the occurrence of 
various visual phenomena such as changes in color intensity, after-images, and apparent 
movement of stationary objects. This questionnaire is completed at screening, approximately 1 
week after the psilocybin session and at approximately 3, 6, and 12 months after the psilocybin 
session. 
 
COVID-19 related risks: Participants will complete a pre-visit COVID-19 symptom 
questionnaire within 24 hours of their visit, and/or be screened with a symptom questionnaire 
upon arrival at the Behavioral Pharmacology Unit (BPRU), with other relevant procedures for 
dosing and MRI visits as described above. The measures outlined above will be adhered to until 


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both JH SOM leadership and the study team agree that risk of SARS-CoV-2 transmission is low 
enough to warrant resumption of routine in-person practices. 
c. Plan for reporting unanticipated problems or study deviations. 
 
The investigators will report adverse events to the IRB according to the Johns Hopkins and 
federal guidelines. 
 
d. Legal risks such as the risks that would be associated with breach of confidentiality. 
 
While breach of confidentiality could be embarrassing and disturbing, study records involve no 
documentation of specific illegal acts. 
 
e. Financial risks to the participants. 
 
There will be no financial risks to participants. 
 
8. Benefits 
a. Description of the probable benefits for the participant and for society. 
 
The probable benefits from the study for participants is a possible cessation or reduction in 
cigarette smoking and nicotine dependence. Furthermore, for participants in the psilocybin 
condition, some mental health and religious professionals have reported that hallucinogens, 
under specific circumstances of administration, can provide unusual opportunities for deep 
reflection. However, no such benefit from the drug session can be promised to volunteers in this 
study. All volunteers may benefit from the general review of life values and direction that will 
occur in meetings with the study staff over a period of several months. Society will benefit from 
gaining a more detailed understanding of the effects of psilocybin on smoking cessation or for 
other forms of substance dependence. Additionally, the proposed neuroimaging portion of the 
study will produce novel findings with regards to the intermediate (i.e., next-day) effects of 
psilocybin, and how these may contribute to longer-lasting behavioral and psychological 
changes, including smoking cessation. 
 
9. Payment and Remuneration 
a. Detail compensation for participants including possible total compensation, proposed 
bonus, and any proposed reductions or penalties for not completing the protocol. 
 
Volunteers will not receive monetary compensation for the treatment portion of the study (i.e, 
treatment meetings, follow-ups). However, MRI participating volunteers (n=60) will receive an 
hourly compensation of $20/hr. for all MRI scanning days, including participation in the 
preliminary NIDA sub-study protocol (possible total compensation=$480). Funding for this 
compensation will be provided by NIDA IRP. In order to match potential earnings between all 
MRI participating volunteers, those who do not undergo a paid 3-month follow-up MRI scan 
(i.e., who are smoking at that time) will be compensated at a $20/hr. rate for their time during the 
3-month follow-up. Funding for this compensation will be provided by the research study 
budget. No penalties will be assessed for not completing the protocol. Volunteers will receive 
free parking vouchers for all scheduled study visits. 
 


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10. 
Costs 
a. Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify 
who will pay for them. 
 
Other than travel to and from the study site, there are no costs to participants. All treatment 
counseling and pharmacotherapy will be provided at no cost to the participant. Furthermore, 
participants and family or friends who pick up participants after psilocybin sessions will be 
provided with free parking vouchers for all in-person meetings. 


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