Response from Rick Doblin, Ph.D. and Dr. Sue Sisley

June 5, 2017

We appreciate having worked with Ryan Vandrey, Ph.D, and Johns Hopkins University (JHU) in an effort to study four different varieties of marijuana in the treatment of 76 veterans with chronic, treatment-resistant posttraumatic stress disorder (PTSD).  We have learned much from our collaboration. We’re disappointed that our working relationship has ended before Ryan/JHU enrolled a single subject.

We’re writing now to respond to some of Ryan’s statements in his emails to Sean that we see quite differently. We hope our reply will  help clarify some factual matters and illuminate  the differing perspectives that led to Ryan/JHU withdrawing from the protocol.

Ryan wrote,  “They [MAPS/Rick and Sue] like to complain about how the feds wouldn’t approve their study because they don’t want to approve a study on the health benefits of cannabis.  The real truth is that MAPS couldn’t get approval because they had a horrible protocol that wouldn’t pass review at the federal level because it was bad science, and because none of the people involved had any credible research experience.”

On April 28, 2011, MAPS’ marijuana/PTSD protocol was accepted by the FDA.

On August 16, 2011, NIDA/PHS reviewers unanimously rejected the protocol.

On October 25, 2012, the University of Arizona Institutional Review Board (IRB) approved the study protocol.

On March 12, 2014,  NIDA/PHS reviewers,  after previously rejecting the protocol,  reevaluated their decision and went ahead and approved the original protocol design and agreed to sell MAPS the marijuana required for the study.

On June 27, 2014, Dr. Sue Sisley was fired by the University of Arizona for political reasons.

MAPS had obtained FDA, IRB and NIDA/PHS approval for the original  marijuana/PTSD protocol before Sue was fired by the University of Arizona.  Marcel Bonn-Miller contacted MAPS after Sue was fired to inquire about him and Ryan Vandrey collaborating with MAPS as we sought a new location for the study other than the University of Arizona. Ryan and Marcel played no role in obtaining approval for the original protocol.

Ryan wrote,  “Marcel and I completely redesigned their original protocol…”

The revised protocol currently being implemented by MAPS and Dr. Sisley  was amended with several changes to the original protocol, nothing close to a complete redesign.

Three consequential changes were, 1) we eliminated half the subjects using vaporizers and had all the subjects smoke,  2) we reduced the two periods of  daily marijuana administration from four weeks each to three weeks each, and  3) we introduced a standardized dosing procedure for the first but not the second of the two introductory exposures to marijuana in the treatment facility and standardized the presentation of calming exercises in case of challenging emotions.

The four different kinds of marijuana stayed the same (THC, CBD, THC/CBD combination, Placebo),  the two four-hour introductory sessions remained in the protocol, the amount of marijuana given to subjects per day (1.8 grams) stayed the same, the freedom for the subjects to smoke as much or as little of their daily amount at whatever times of day or night they wanted stayed the same (even though Marcel and Ryan wanted to standardize this), the number of subjects stayed the same, the primary outcome measures stayed the same,  the statistical analysis plan stayed the same, and most other elements of the protocol remained identical.

The elimination of the vaporization group is  not something MAPS considers an improvement but was a compromise MAPS made with Ryan and Marcel who wanted fewer experimental conditions than we wanted for our drug development purposes.  We made that compromise since MAPS has shared its marijuana/PTSD protocol with a Canadian medical marijuana company, Tilray, that is using the protocol to conduct their own marijuana/PTSD study with  their own marijuana using only vaporization. As a result, there will still be data gathered about vaporization of marijuana in PTSD patients.

The reduction of  the period of dosing from four weeks to three was made for a variety of reasons,  primarily economic and practical because three weeks would still be enough to gather useful information on marijuana’s effects on PTSD. This change was mutual but I don’t recall who first suggested it.

The standardization of the amount of marijuana used in the first but not the second introductory session was also a compromise MAPS made with Marcel and Ryan. The first subject enrolled used the standardized dosing procedure, had major anxiety, vomited and almost withdrew from the study.  However, he decided to come for the second introductory session where he could use whatever amount he wanted. He used much less and enrolled in the study. We then changed this standardized dosing procedure.

Ryan wrote that he and Marcel, “…wrote the grant to the state of CO.”

Dr. Sisley had already initiated contact and engaged in discussions  with the State of CO regarding funding our study well before MAPS was contacted by Marcel and Ryan.  Our view is that MAPS staff wrote substantially more than half the grant application.

Ryan wrote, “Neither Rick or Sue are trained in the conduct of clinical research, they misunderstand a lot of important nuances to doing good clinical research, and I would have to argue on every phone call to get them to agree to very fundamental protocol decisions.”

Our disagreements were about  differences between drug development research and academic research, we understand important nuances. MAPS staff collectively, including Rick and Sue, have substantial experience and training in clinical drug development research both from prior work in for-profit Pharma and/or academic training.  Since 2000, MAPS has sponsored a series of Phase 2 studies of MDMA-assisted psychotherapy for people with posttraumatic stress disorder (PTSD). MAPS has been approved by  FDA to move into Phase 3 studies,  and is coming to agreement with FDA on Phase 3 protocol designs in an extensive Special Protocol Assessment (SPA) process.

Marcel and Ryan’s efforts to  change the protocol to standardize dosing and eliminate the vaporization arms were about differing priorities between  MAPS’ drug development/regulatory research seeking approval for prescription use at least cost in time and money, and their academic research approach seeking knowledge.  MAPS’ original protocol was a drug development exploratory Phase 2 protocol seeking just enough information  to design further Phase 2 pilot studies or perhaps even a Phase 3 study which FDA requires to prove safety and efficacy prior to approval for prescription use.  Ryan and Marcel were interested in reducing variables to provide greater certainty in interpretation.  MAPS and Sue were interested in gathering more information in an exploratory manner.

We all made some compromises to agree on a revised protocol sponsored by MAPS. That protocol is now being conducted at a single site in Phoenix, AZ,  with Sue as Site-PI and  Marcel as Coordinating PI. We believe we will be able to enroll all 76 veterans with PTSD in our Phoenix site but would have preferred to continue to work with Ryan/JHU.

Ryan wrote, ” I have major problems with them compromising the integrity of the protocol by using it as a basis for leveraging their own political and personal agendas…”

The integrity of the protocol depends on the research methodology and the conduct of the study, not on whether MAPS and Sue remain silent or speak about the quality of NIDA marijuana and the need to end the NIDA monopoly. Neither would the integrity of the study have been compromised because  Ryan has received major funding from NIDA over his career, nor is it compromised because Marcel is now working for the for-profit  Zynerba Pharmaceuticals that is trying to develop “innovative transdermal synthetic cannabinoid treatments” that could directly compete with smoked marijuana for some indications, that Paula Riggs, MD, who is also overseeing the conduct of the study, is on the Science Advisory Board of Smart Approaches to Marijuana (SAM) that is opposed to the legalization of marijuana, or that MAPS’ donors  and staff mostly already believe marijuana can be helpful for PTSD.  When it comes to the integrity of research findings, scientific methodology is king.

Sue and Rick considered it important to let the public know  about the quality of marijuana available from NIDA  (not optimal) and about the results of our independent analysis of NIDA marijuana. We also felt it was important that we discuss the DEA-protected NIDA monopoly  which should be ended.  NIDA itself agrees  its monopoly on federally-legal marijuana for use in FDA-regulated studies should be ended. NIDA marijuana can only be used in research and cannot be sold as a prescription medicine. FDA requires Phase 3 studies to be conducted with the exact same drug that would be marketed should FDA approve the drug. As a result, NIDA marijuana will not be accepted by FDA for use in Phase 3 studies. MAPS considers it important for patient welfare for there to be new DEA-licensed suppliers and disagrees that  trying to end the NIDA monopoly, or criticizing the quality of NIDA marijuana,  compromises the integrity of the protocol or inappropriately introduces politics into scientific research.

We appreciate that Ryan wrote, “To reiterate, I am not aware that MAPS has done anything that is in violation of any regulatory rules or against the study protocol…”

We wish Ryan/JHU well as they move forward with other research.

Rick Doblin, Ph.D.
Executive Director
MAPS
3 Francis Street
Belmont, MA 02478 USA
c. 617-276-7806
maps.org | mdmaptsd.org