Psychedelic Drugs: 
Considerations for 
Clinical Investigations 
Guidance for Industry 
 
 
 
DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact (CDER) Kofi Ansah at 301-796-4158.  
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
June 2023 
Clinical/Medical 
 
52950908dft 
06/09/23 
   
Psychedelic Drugs: 
Considerations for 
Clinical Investigations  
Guidance for Industry 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
June 2023 
Clinical/Medical 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  DISCUSSION .................................................................................................................... 2 
A.  Chemistry, Manufacturing, and Controls ................................................................................... 2 
B.  Nonclinical ...................................................................................................................................... 3 
C.  Clinical Pharmacology................................................................................................................... 5 
D.  Abuse Potential Assessment .......................................................................................................... 6 
E.  Clinical ............................................................................................................................................ 8 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Psychedelic Drugs: Considerations for Clinical Investigations 
2  Guidance for Industry1 
3   
4   
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page.   
12   
13   
14   
15   
16  I.  INTRODUCTION 
17   
18  The U.S. Food and Drug Administration (FDA or Agency) is issuing this guidance to provide 
19  general considerations to sponsors developing psychedelic drugs for treatment of medical 
20  conditions (e.g., psychiatric disorders, substance use disorders). For the purposes of this 
21  guidance, the term psychedelic is used as shorthand to include classic psychedelics, typically 
22  understood to be 5-HT2 agonists such as psilocybin and lysergic acid diethylamide (LSD), as 
23  well as entactogens or empathogens such as methylenedioxymethamphetamine (MDMA).  
24   
25  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
26  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
27  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
28  the word should in Agency guidances means that something is suggested or recommended, but 
29  not required.  
30   
31   
32  II.  BACKGROUND 
33   
34  In recent years, interest in the therapeutic potential of psychedelic drugs has been increasing. 
35  Psychedelic drug development programs are subject to the same regulations and same 
36  evidentiary standards for approval as other drug development programs. However, designing 
37  clinical studies to evaluate the safety and effectiveness of these compounds presents a number of 
38  unique challenges. Psychedelic drugs can cause intense perceptual disturbances and alterations in 
39  consciousness that can last for several hours. Some drug development programs incorporate a 
40  psychological or behavioral intervention. Investigators hypothesize that psychedelic drugs have 
41  both rapid-onset and long-term benefits after only one or a few doses. These and other unusual 
42  characteristics should be considered when designing clinical studies so that the results of those 
43  studies can be interpretable.  
 
1 This guidance has been prepared by the Division of Psychiatry in the Center for Drug Evaluation and Research at 
the Food and Drug Administration.  
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
44   
45  Because this is an emerging area of drug development, there is limited experience as to the 
46  configuration of programs that may support approval of a psychedelic drug. Rather than 
47  providing specific recommendations on study design, this guidance will present foundational 
48  constructs that all sponsors, including academic sponsor-investigators, studying the therapeutic 
49  potential of psychedelic drugs should consider. Sponsors may also request meetings with FDA 
50  for advice on a specific drug development program.2 
51   
52  This guidance applies to clinical trials that will be conducted under an investigational new drug 
53  application (IND), including such clinical trials (e.g., research or academic studies) that are not 
54  intended to support marketing applications. The principles in this guidance are intended to 
55  support the ethical conduct of clinical trials as well as to ensure the integrity of the trial and the 
56  reliability of the results.  
57   
58   
59  III.  DISCUSSION 
60   
61  Below, we outline general considerations, by discipline, for drug development programs 
62  evaluating the therapeutic potential of psychedelic drugs. The Agency is open to discussing 
63  various approaches to address these considerations; sponsors should engage divisions early in the 
64  drug development process.  
65   
66  A.  Chemistry, Manufacturing, and Controls 
67   
68  Sponsors must provide sufficient chemistry, manufacturing, and controls information to ensure 
69  proper identification, quality, purity, and strength of the investigational drug substance and drug 
70  product.3 This is true for all phases of clinical trials.  
71   
72    Chemistry data submitted by a sponsor to FDA may be proprietary. In general, sponsors 
73  interested in conducting a clinical investigation with a psychedelic drug under an IND 
74  must either submit their own information or incorporate information previously submitted 
75  by a person other than the sponsor when the sponsor has a right of reference for such 
76  information.4 
77   
 
2 See the draft guidance for industry Formal Meetings Between the FDA and Sponsor or Applicants of PDUFA 
Products (December 2017). When final, this guidance will represent the FDAs current thinking on this topic. For 
the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents. 
 
3 See 21 CFR 312.23(a)(7). 
 
4 See 21 CFR 312.23(b). 
 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
78    If using plant material, algae, macroscopic fungi, or a combination of these, the 
79  investigational product may be considered a botanical, as that term is defined in the 
80  guidance for industry Botanical Drug Development (December 2016).5  
81   
82    Although some psychedelic compounds are derived from plants or fungi, drug products 
83  that are genetically modified; produced by fermentation of yeast, bacteria, or plant cells; 
84  or highly purified substances from naturally occurring sources are not considered 
85  botanicals for purposes of this document and the guidance for industry Botanical Drug 
86  Development.  
87   
88    Drugs must be manufactured in compliance with current good manufacturing practice 
89  (CGMP) under section 501(a)(2)(b) of the Federal Food, Drug, and Cosmetic Act. For 
90  most drug products manufactured in support of phase 1 studies, manufacturers should 
91  follow the recommendations in the guidance for industry, CGMP for Phase 1 
92  Investigational Drugs (July 2008). Certain drug products manufactured in support of 
93  phase 1 studies and drug products manufactured in support of phase 2 studies and beyond 
94  must comply with applicable CGMP regulations in 21 CFR part 211.6,7 Studies in which 
95  subjects are enrolled to measure the effectiveness of a drug for a particular indication or 
96  indications are generally considered phase 2 studies;8 therefore, the drug product used in 
97  those phase 2 studies must be manufactured in accordance with CGMP requirements.9 
98  Each phase of the investigation requires sufficient information to ensure identification, 
99  purity, and strength of the investigational drug substance and drug product.10 
100  Investigators and sponsors are encouraged to refer to the guidance for industry INDs for 
101  Phase 2 and 3 Studies; Chemistry, Manufacturing, and Controls Information (May 2003) 
102  and the guidance for industry Content and Format of INDs for Phase 1 Studies of Drugs, 
103  Including Well-Characterized, Therapeutic, Biotechnology-Derived Products (October 
104  2000).11  
105   
106  B.  Nonclinical 
107   
108  The nonclinical program for psychedelic drugs should follow recommendations outlined in the 
109  ICH guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical 
 
5 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at  
https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
6 See 21 CFR 210.2(c). 
 
7 See 21 CFR part 211. 
 
8 See 21 CFR 312.21(b). 
 
9 See 21 CFR 210.2(c). 
 
10 See 21 CFR 312.23(a)(7)(i). 
 
11 For more general information about the IND process, see https://www.fda.gov/drugs/types-
applications/investigational-new-drug-ind-application. 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
110  Trials and Marketing Authorization for Pharmaceuticals (January 2010).12 However, the 
111  following considerations may be unique to psychedelic drugs. 
112   
113    It may be reasonable for clinical studies with certain psychedelic drugs to be initiated 
114  under an IND in the absence of the typical animal toxicology testing when extensive 
115  human exposure and information are available from previously conducted clinical studies 
116  and no serious safety concerns were identified. Sponsors should plan to conduct 
117  nonclinical studies to support further drug development after initiation of the IND unless 
118  there are adequate data in the published scientific and medical literature.13,14  
119   
120    An IND must include adequate information about pharmacological and toxicological 
121  studies of the drug on the basis of which the sponsor has concluded it is reasonably safe 
122  to conduct the proposed clinical investigations.15 Therefore, psychedelic drugs without a 
123  history of adequate clinical exposure should not be tested in humans until safety has been 
124  established in nonclinical studies.16    
125   
126    Although current psychedelic drug development programs are exploring single-dose or 
127  intermittent-dose treatment paradigms, most of the conditions being studied to date in 
128  these programs are chronic. Nonclinical studies to support chronic or chronic-intermittent 
129  dosing should be provided if the treatment effect is not durable and repeat dosing is 
130  expected.17 Sponsors should determine the most appropriate dosing paradigm (e.g., 
131  dosing intervals) for each animal species in the repeat-dose toxicity studies to support 
132  their intended clinical studies. The number and types of nonclinical studies to support 
133  approval of a marketing application will largely depend on treatment paradigm.  
134   
135    Because psychedelic drugs have serotonin (5-HT) activity, a thorough evaluation of 
136  binding to 5-HT receptor subtypes should be conducted. Binding to the 5-HT2B receptor 
137  subtype has been linked to heart valvulopathy in humans; therefore, sponsors should 
138  assess functional activity at the 5-HT2B receptor subtype. If a psychedelic drug is shown 
139  to be an agonist at 5-HT2B receptors, a thorough microscopic evaluation of the heart 
 
12 We support the principles of the 3Rs, to reduce, refine, and replace animal use in testing when feasible. We 
encourage sponsors to consult with us if it they wish to use a non-animal testing method they believe is suitable, 
adequate, validated, and feasible. We will consider if such an alternative method could be assessed for equivalency 
to an animal test method.  
  
13 See 21 CFR 312, 314, and 601 (for information about the requirements for an IND, a new drug application, or a 
biologics license application). 
 
14 See the ICH guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials 
and Marketing Authorization for Pharmaceuticals (January 2010). 
 
15 21 CFR 312.23(a)(8). 
 
16 See the guidance for industry Safety Testing of Drug Metabolites (March 2020) and ICH M3(R2).  
 
17 See 21 CFR 312.23(a)(8) (providing information on requirements in INDs. The regulation specifies that [t]he 
kind, duration, and scope of animal and other tests required [to conduct the proposed clinical investigation] varies 
with the duration and nature of the proposed clinical investigations). 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
140  should be conducted to assess for potential heart valve thickening in both rodent and 
141  nonrodent repeat-dose toxicity studies, including sectioning of all heart valves. 
142   
143  C.  Clinical Pharmacology 
144   
145  Pharmacokinetics and/or pharmacodynamics of psychedelic drugs should be adequately 
146  characterized both in vitro and in vivo. Sponsors should also consider the following clinical 
147  pharmacology aspects when developing psychedelic drugs. 
148   
149    Sponsors should evaluate the effect of a high-fat meal on the pharmacokinetics of an oral 
150  psychedelic drug early in development to inform clinical study design and potential 
151  labeling. 
152   
153    Sponsors should evaluate potential drug-drug and drug-disease interactions to inform 
154  inclusion and exclusion criteria and prohibited concomitant medications for clinical 
155  studies and to inform potential labeling.18,19,20 
156   
157    Long-term exposure to 5-HT2B agonists may induce cardiac valve stiffening. Currently, 
158  FDA recommends that sponsors exclude subjects with preexisting valvulopathy or 
159  pulmonary hypertension from multiple-dose studies of drugs with this mechanism until 
160  this risk can be better characterized. 
161   
162    Known pharmacodynamic interactions to consider include the following: 
163   
164    Chronic use of selective serotonin reuptake inhibitors or monoamine oxidase 
165  inhibitors may reduce the effect of psychedelic drugs. 
166   
167    Chronic use of tricyclic antidepressants or lithium and acute use of selective 
168  serotonin reuptake inhibitors or monoamine oxidase inhibitors use may potentiate 
169  psychedelic effects. 
170   
171    The dose-response relationship for most psychedelic drugs is poorly understood. 
172  Sponsors should take appropriate steps to characterize the dose-response relationship, 
173  both for efficacy and for safety.  
174   
 
18 See the guidance for industry In Vitro Drug Interaction Studies  Cytochrome P450 Enzyme- and Transporter-
Mediated Drug Interactions (January 2020). 
 
19 See the guidance for industry Clinical Drug Interaction Studies  Cytochrome P450 Enzyme- and Transporter-
Mediated Drug Interactions (January 2020). 
 
20 See the guidance for industry Evaluation of Gastric pH-Dependent Drug Interactions With Acid-Reducing Agents: 
Study Design, Data Analysis, and Clinical Implications (March 2023).  
 
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
175  D.  Abuse Potential Assessment 
176   
177  The assessment of the abuse potential of a drug product under development is generally 
178  conducted as a component of its safety evaluation. Drug products that are assessed for abuse 
179  potential include new molecular entities that are active on the central nervous system, as well as 
180  those products that contain drugs that are already controlled under the Controlled Substances 
181  Act.  
182   
183    Psychedelic drugs act on the central nervous system, produce psychoactive effects (e.g., 
184  mood or cognitive changes, hallucinations), and need to be evaluated for abuse potential 
185  during drug development.21 Data from the abuse potential assessment and a proposal for 
186  drug scheduling under the Controlled Substances Act is required to be included in a new 
187  drug application submission.22 Many psychedelic drugs are Schedule I substances under 
188  the Controlled Substances Act23 because they have high abuse potential and do not have a 
189  currently accepted medical use in the United States. Should a psychedelic drug that is a 
190  Schedule I controlled substance receive FDA approval as a drug product, the abuse 
191  potential assessment would assist in determining an appropriate rescheduling action 
192  under the Controlled Substances Act. For general information on how to conduct the 
193  abuse potential evaluation, including recommended methodologies, and what studies 
194  should be included as part of the new drug application submission, see the guidance for 
195  industry Assessment of Abuse Potential of Drugs (2017).  
196   
197    For psychedelic drugs that are Schedule I controlled substances, activities associated with 
198  investigations under an IND must comply with the applicable Drug Enforcement 
199  Administration (DEA) regulations for research, manufacturing, importation/exportation, 
200  handling, and storage requirements for a Schedule I drug.24 This requirement includes 
201  DEA registration of the investigator who intends to conduct research, per 21 U.S.C. 
202  823(g) and the implementing regulation 21 CFR 1301.18. A Schedule I registration 
203  issued by DEA is required before the initiation of nonclinical and clinical studies. 
204  Authorization to conduct the research is required for each specific protocol and may need 
205  to be supplemented for amendments made to a protocol.25 Sponsors should contact DEA 
206  to discuss and ensure compliance with all applicable DEA requirements.   
207   
208    For some psychedelic drugs that are Schedule I controlled substances, there have been 
209  numerous investigations of these drugs, as documented in the published scientific 
210  literature. When appropriate, sponsors should propose the use of scientifically valid, 
211  published investigations to support the abuse potential assessment. For those psychedelic 
212  drugs that have not been well-characterized previously in preclinical and clinical studies, 
 
21 See 21 CFR 314.50(d)(5)(vii). 
 
22 Ibid. 
 
23 See 21 CFR 1308.11. 
 
24 See 21 CFR part 1301. 
 
25 21 CFR 1301.18.  
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
213  sponsors should conduct a full abuse potential assessment, as described in the guidance 
214  for industry Assessment of Abuse Potential of Drugs, before submission of a new drug 
215  application.  
216   
217    A human abuse potential study should generally be conducted when a drug has shown 
218  abuse-related signals in animal and/or human studies. However, a human abuse potential 
219  study may not be scientifically necessary for certain psychedelic drugs to support the 
220  abuse potential assessment in a new drug application when the subjective effects 
221  predictive of abuse are well characterized from extensive clinical studies and robust 
222  epidemiological data exist to demonstrate that individuals are using the psychedelic drug 
223  for abuse purposes.    
224   
225    An adverse event (AE) for purposes of IND safety reporting means any untoward 
226  medical occurrence associated with the use of a drug in humans, whether or not 
227  considered drug related.26 An evaluation of psychedelic responses that occur during 
228  clinical studies should be obtained through the inclusion of validated subjective scales 
229  and through monitoring abuse-related AEs, such as euphoria, hallucinations, stimulation, 
230  and emotional lability. Abuse-related AEs are monitored and reported as a safety concern 
231  even if they are hypothesized to be associated with the therapeutic response.27 Thus, for 
232  psychedelic drugs, investigators and session monitors should be trained to record all 
233  abuse-related AEs, including psychedelic ones. The incidence of these abuse-related AEs 
234  in comparison to placebo or active control in studies should be reported by study, 
235  population, and dose and should be displayed in tabular format. Narratives describing 
236  these events should also be provided. Sponsors are encouraged to discuss their abuse-
237  related AE monitoring plan early in development with the Controlled Substance Staff 
238  (through the primary review division). For more information about procedures for 
239  monitoring and assessing abuse-related AEs, refer to section V.B. of the guidance for 
240  industry Assessment of Abuse Potential of Drugs.  
241   
242    An assessment of the potential for physical dependence with a psychedelic drug may be 
243  appropriate as part of the abuse potential assessment depending on the proposed 
244  conditions of use for which the drug is being studied (e.g., acute intermittent use versus 
245  prolonged continuous use).   
246   
247    For all animal and human abuse potential and dependence-related studies that will 
248  contribute to the abuse potential assessment, it is generally recommended that these 
249  studies be conducted only after the therapeutic dose range is determined, which typically 
250  occurs when phase 2 clinical studies are completed. FDA recommends submitting 
251  proposed protocols to the Agency for review and comment before conducting these 
252  abuse-related studies. 
253   
 
26 21 CFR 312.32(a). 
 
27 21 CFR 312.32(c). 
 
  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
254    Sponsors are encouraged to discuss their plans for an abuse potential assessment with 
255  FDA early in the IND stage of drug development and request (through the primary 
256  review division) review and comment on these plans from the Controlled Substance Staff 
257  in the Center for Drug Evaluation and Research.   
258   
259  E.  Clinical  
260   
261  The substantial evidence standard for establishing effectiveness of psychedelic drugs is the same 
262  as it is for all other drugs.28 However, the following considerations may be unique to psychedelic 
263  drugs. 
264   
265    Adequate and well-controlled (AWC) clinical studies are generally required to meet the 
266  substantial evidence standard to establish effectiveness in a marketing application.29 
267  However, the characteristics of psychedelic drugs present challenges for sponsors in 
268  designing AWC clinical studies.  
269   
270    An AWC study uses a design that permits a valid comparison with a control to 
271  provide a quantitative assessment of a drugs effect.30 In the context of psychedelic 
272  drug development, the use of a traditional placebo as a control can be problematic for 
273  assessing efficacy. Subjects receiving an active drug experience functional unblinding 
274  because of the intense perceptual disturbances that can develop; those who receive a 
275  placebo in the context of high expectancy may experience a nocebo effect (i.e., 
276  worsening symptoms as a result of knowing they did not get active treatment). 
277  However, an inactive control allows for better contextualization of any safety 
278  findings. Alternatives to an inert placebo (e.g., subperceptual doses of a psychedelic 
279  drug, other psychoactive drugs that mimic some aspects of the psychedelic 
280  experience) may be considered as well.  
281   
282    In an AWC study, adequate measures are taken to minimize bias on the part of the 
283  subjects, observers, and analysts of the data.31 Sponsors should consider the use of 
284  video or central raters blinded to treatment allocation and visit number. The use of a 
285  blinding questionnaire for both subjects and investigators/raters can be helpful to 
286  evaluate the impact of functional unblinding.  
287   
288    Complementary trial designs across phases 2 and 3 could address different challenges 
289  in psychedelic drug development. For example, a trial using a low, middle, and high 
290  dose without a placebo could be paired with a placebo-controlled trial. The trial 
291  without a placebo could provide information about dose-response without the risk of 
 
28 See section 505(d) of the FD&C Act; see also the draft guidance for industry Demonstrating Substantial Evidence 
of Effectiveness for Human Drug and Biological Products (December 2019). When final, this guidance will 
represent the FDAs current thinking on this topic. 
 
29 See section 505(d) of the FD&C Act; 21 CFR 314.126. 
 
30 See 21 CFR 314.126(b)(2).  
 
31 See 21 CFR 314.126(b)(5) 
  8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
292  a nocebo effect. The placebo-controlled trial may raise concerns about functional 
293  unblinding but will allow for better characterization of safety signals.  
294   
295    Many of the psychedelic drug development programs involve administering the 
296  investigational drug and then engaging in psychological support or psychotherapy either 
297  while the subject is experiencing the acute effects of the drug or in a subsequent session. 
298  This additional variable both complicates the assessment of effectiveness and presents a 
299  challenge for any future product labeling. 
300   
301    As of the publication date of this guidance, the contribution of the psychotherapy 
302  component to any efficacy observed with psychedelic treatment has not been 
303  characterized. 
304   
305    Psychotherapeutic interventions have the potential to increase expectancy and 
306  performance biases. Sponsors should plan to justify the inclusion of a psychotherapy 
307  component and describe any trial design elements intended to reduce potential bias or 
308  to quantify the contribution of psychotherapy to the overall treatment effect. A 
309  factorial design may be useful for characterizing the separate contributions of drug 
310  and psychotherapy to any observed treatment response.  
311   
312    The therapist monitoring the session can usually deduce the treatment assignment by 
313  observing the subjects behavior. Therefore, it is preferable that the in-session 
314  monitor is not involved in post-session psychotherapy because their knowledge of the 
315  treatment could bias the delivery of subsequent therapy. 
316   
317    FDA may place a study under an IND under clinical hold if it finds, among other reasons, 
318  that human subjects are or would be exposed to an unreasonable and significant risk of 
319  illness or injury.32 Subjects receiving active treatment with psychedelic drugs remain in a 
320  vulnerable state for as long as 12 hours. Given this concern, so that subjects are not 
321  placed at an unreasonable and significant risk of illness or injury, safety-monitoring 
322  should include the following: 
323   
324    Observation by two monitors for the duration of the treatment session  
325   
326    A healthcare provider with graduate-level professional training and clinical 
327  experience in psychotherapy, licensed to practice independently, serving as the 
328  lead monitor. Examples of such professional credentials include the following: 
329   
330    Clinical or counseling psychologist (PhD or PsyD) 
331    Psychiatrist or other physician (MD or DO) 
332    Master of Social Work (MSW) 
333    Licensed Clinical Professional Counselor (LCPC) 
334    Licensed Marriage and Family Therapist (LMFT)  
335    Psychiatric Nurse Practitioner (Psychiatric NP). 
 
32 21 CFR 312.42.  
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336   
337    An assistant monitor with a bachelors degree and at least 1 year of clinical 
338  experience in a licensed mental healthcare setting.   
339   
340    If the lead monitor is not a physician, availability of a licensed on-call physician able 
341  to reach the clinical site within 15 minutes in the event of a medical emergency. 
342   
343    The informed consent should clearly describe that subjects may experience changes in 
344  perception, cognition, and judgment that persist for many hours, as well as increased 
345  vulnerability and suggestibility during the treatment session. 
346   
347    Sponsors should plan to characterize the dose-response relationship for both safety and 
348  efficacy early in the drug development program.  
349   
350    Sponsors should plan to characterize the durability of response for their drug product, the 
351  recommended interdose interval for maintenance of effect, and the safety and efficacy of 
352  repeat dosing. At a minimum, for the treatment of a chronic illness such as post-traumatic 
353  stress disorder or major depressive disorder, sponsors should evaluate the effect of 
354  treatment at 12 weeks. However, sponsors should continue to follow subjects in an open-
355  label extension period for a year beyond the Week 12 endpoint to monitor for symptom 
356  recurrence or, potentially, the need for repeat dosing.  
357   
358    For drugs that have been shown to have functional activity at the 5-HT2B receptor, it is 
359  likely that baseline and follow-up echocardiograms to assess valve structure and function 
360  and pulmonary artery pressures should be included in the study for drugs that are to be 
361  chronically administered. In general, patients with preexisting valvulopathy or pulmonary 
362  hypertension should be excluded until the cardiac risk has been characterized. 
363  Recommendations for when and how to assess QT interval and blood pressure can be 
364  found in the guidance for industry E14 Clinical Evaluation of QT/QTc Interval 
365  Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs (October 
366  2005) and the draft guidance for industry Assessment of Pressor Effects of Drugs 
367  (February 2022).33 
368   
369    Sponsors should address how adverse events or serious risks are mitigated during the 
370  clinical studies and if similar strategies can be implemented post marketing. Sponsors 
371  should consider where the drug would be dispensed and administered if approved and 
372  whether the healthcare system would be able to prevent nonmedical use, accidental 
373  exposure, and overdose for both patients and nonpatients. Sponsors should also consider 
374  if gaps exist in the health care system regarding safe use. For the majority of drugs, 
375  routine risk mitigation measures, such as providing health care providers with risk 
376  information through FDA-approved prescribing information, are sufficient to preserve 
377  benefits while minimizing risks. In some cases, however, FDA may consider whether a 
 
33 When final, this guidance will represent the FDAs current thinking on this topic. 
 
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378  risk evaluation and mitigation strategy may be necessary to ensure that the benefits of the 
379  drug outweigh its risks.34  
380   
381    FDA may consider the public health effects of the drug as part of the overall benefit-risk 
382  assessment. Public health effects of the drug include its potential effect on risks that are 
383  related to nonmedical use, substance use disorder, accidental exposure, and overdose for 
384  patients and nonpatients. 
 
34 See 505-1(a) of the FD&C Act. 
  11