Challenging Psychedelic Drug Research Restrictions
By Christopher Gunlock
Psilocybin, the primary psychoactive component in the psilocybe-genus of mushrooms, also one of the most common psychedelics, was recently granted breakthrough therapy status by the Food and Drug Administration (FDA) for the treatment of depression –. Despite this recognition and demonstration of safety by several clinical trials, psilocybin and all other classical psychedelics have remained schedule-I substances since 1970 . The initial fears that led to prohibition have not been affirmed by current research and cultures around the world are known to use psychedelic plants and mushrooms in a variety of beneficial ways. Recent studies on a large variety of mental disorders and rising trends in mental dysfunction indicate these foreign cultures were probably on to something modern society has yet to understand. Therefore, the potential for quality, accessible and affordable treatments to some of the world’s worst epidemics should not be overshadowed by conflicting and inaccurate prohibition laws.
All classical psychedelics are held behind the world’s strictest administrative and legislative barriers. Beginning in 1970, Richard Nixon made history when he signed the Controlled Substances Act (CSA) and created the Drug Enforcement Administration (DEA), which classified all known psychedelics as schedule-I substances . These substances are considered to not have any medical use and they require special licenses/protocols for researchers to gain access to them . Most psychedelics had only early-phase clinical trials to investigate their efficacy and safety before hasty prohibition, which begs the question of why they were placed in such a highly restrictive category in the first place.
It is difficult to determine the scientific reasoning for the drugs under schedule-I designation. The DEA distinguishes these drugs in terms of their high potential for abuse, lack of accepted medical use, and lack of safety under medical supervision. The first criteria evokes a definition of the vague term, “abuse.” The DEA officially states that “abuse” is determined by the way people take the drug under undefined circumstances. They state that if people take too much of the drug, take it outside legitimate drug channels, or without medical advice then it is a drug of abuse. One problem with this logic is that if a drug is unscheduled, then it is likely there won’t be any regulated and standardized ways of taking it yet, and would therefore be considered a drug of abuse before it even had a chance. Another problem is that under this definition, both alcohol and tobacco would be notorious drugs of abuse except the DEA doesn’t even consider them at all , despite high rates of nicotine addiction and alcoholism . Secondly, “accepted medical use” is a common phrase we see in the DEA literature and they have stated it requires large-scale clinical studies to qualify, which is reasonable except for how difficult it is to do so when a substance is already schedule-I. The third criteria for abuse challenges safety in controlled settings, which psychedelics happen to do an especially good job with according to a large number of the published clinical studies since 1994 , , , –.
For the U.S., a gauntlet of prohibitive barriers between psychedelics and legal medicine involves multiple stages. If taking the route of federal legalization, a single psychedelic compound would have to pass enough phase 1 and 2 trials (safety and efficacy) to be approved for a large-scale, phase 3 efficacy study. Methylenedioxymethamphetamine (MDMA) has achieved this, but no classical psychedelic ever has . Psilocybin for depression is now acquiring funds for phase-3 trials, which would make it the first official psychedelic to do so . Other psychedelics like Lysergic acid diethylamide (LSD), N,N-Dimethyltryptamine (DMT), Ayahuasca, and Ibogaine (Iboga root) have shown promise in multiple small-scale early-phase studies in recent years. LSD and mescaline were also studied internationally in small-scale studies prior to prohibition, but that’s as far as any other psychedelic has gotten . Once the Food and Drug Administration (FDA) has accepted an application containing successful phase-3 studies of a psychedelic, the FDA will make a recommendation to the DEA to investigate. The DEA works with the Department of Health and Human Services (HHS) to evaluate evidence, which the DEA administrator then has the final decision to approve or not . Being that an enormous amount of scientific resources are required to make it that far, it is prudent to point out the possibility of human bias having veto power in the final decision.
Because the weight of the legalization decision relies so much on individual human interpretation, political strategies may also be leveraged in this process. In the research phases, authorities in charge of federal research grants have administrative power as mentioned. An argument for bias at this level could be made due to the fact that all psychedelic research grant proposals have been rejected by all government research institutions. This is especially strange now that the FDA recognizes psilocybin and MDMA as breakthrough therapies, but still questionable in light of the hundreds of early phase studies showing high amounts of safety and efficacy . In government institutions like the DEA, there is a clear political role. The DEA administrator, in particular, is subject to policies of the two-party system. This is because the DEA administrator is appointed by the attorney general who is nominated by the president and appointed by congress . On one hand, this is daunting if the president has a conservative stance on illegal drugs, but one could also see it as an opportunity for grassroots efforts to sway public opinion enough to elect a more psychedelic-friendly president.
If taking the state-legislative route, a state only needs to get something on an electoral ballot. What language is used on the ballot would determine the type of legalization for the psychedelic. Oregon and Denver are on their way to doing this for the 2020 election. Oregon is proposing a license to grow psilocybe mushrooms for therapeutic uses , whereas Denver is proposing decriminalization legislation . What other states decide will vary, but if at least one state is successful, it could be more likely other states will follow. However, this still leaves the looming federal prohibition, but also the Convention on Psychotropic Substances of 1971, an international treaty holding psychedelics under the highest level of restriction . Therefore, state-legalization would eventually need to be augmented by the expensive and bias-ridden federal-legalization route, also subject to international scrutiny.
Around the world and throughout history, psychedelics like psilocybe mushrooms, peyote, ayahuasca and amanita muscaria mushrooms have been used for various purposes. Records up to 5700 years ago indicate the use of peyote in Mexico, and the use of a potent brew containing dimethyltryptamine (DMT), Ayahuasca, in cultures throughout the Amazon . This begs the question of why these substances are so widely unaccepted in modern medicine. There was even a psychedelic born from modern medicine, lysergic-acid diethylamide (LSD). In the United States, psychedelic use became more well-known after the inadvertent discovery of it in 1938. After its discovery, LSD researchers postulated it had some unique effects that may be useful in psychiatry during a time where there were few sophisticated pharmaceutical treatments available. Notable effects such as repressed memory recall, ego dissolution and vivid depictions of the subconscious led many researchers to encourage further investigation into their psychotherapeutic potential , , . Additionally, much of the early work on the serotonergic system was done through animal research with LSD , .
The negative effects of drugs like LSD were studied as well, but the majority of evidence shows the list is short when drug experiences are conducted in safe, controlled settings . These controlled tests showed an absence of physiological toxicity (overdose)  and only a minor increase in blood pressure, heart rate and fluctuations in body temperature . The worst effects were reported to be the possibility of lasting psychosis, lasting perceptual distortions, and physical harm related to extreme decision-making. However, recently and even in the 1960’s, researchers concluded instances of these negative effects are far more likely in an uncontrolled and, unfacilitated settings , , –.
Since near-global prohibition took hold in 1971 shortly after the U.S. signed the CSA , research on all psychedelics was severely diminished, that is, until recently. Beginning in 1994, a new wave of psychedelic research consisting of more rigorously controlled studies has demonstrated that they hold the potential to be a quality treatment in multiple areas . The drastic changes in perception to positive, health-affirming lifestyles have been correlated with positive outcomes in psychiatric illnesses , . Psychedelics have also performed as good or better than Methadone treatment for opioid withdrawal , don’t require long-term or daily doses to be effective, and under controlled conditions have an extremely low side-effect profile. To date, psilocybin alone has had 146 recorded patients in published studies, and no serious adverse events have been reported . Technology has also made some advances, and experts in neuroimaging have brought even more insights and validation as to the nature of the psychedelic experience , , , . To summarize this short history of psychedelic research, there is a public agreement among published clinical data, research with healthy volunteers, pre-prohibition studies, modern surveys of large population data, and toxicology that psychedelics are safe in controlled settings , –.
Assuming one is convinced of psychedelics as medicine, the next question one might ask is what exactly would psychedelics be used for? Both pre-prohibition and modern research have looked at a variety of psychiatric illnesses such as depression, anxiety, obsessive-compulsive disorder, addiction, and schizophrenia. Non-psychotic illnesses seem to respond well to psychedelic therapy, but the one that has the most heads turning is treatment-resistant depression . Not only is there an increasing prevalence of depression across the modern world, but socioeconomic burden is highly correlated with this debilitating illness. This and other factors indicate that the options for successful care of depression are disproportionate to its disease burden . It is important to understand that the psychedelic experience is usually an adjunct to psychotherapy. This is especially true in the more refined protocols that modern clinical studies follow, so the safety and efficacy of psychedelics does seem to demand care beyond the session itself. Nonetheless, it should be noted this evidence is also in direct conflict with the laws and political views surrounding them.
Many of today’s researchers are aware of the data presented here, culminating in recent calls for reform to drug policies. Along with the recent breakthrough therapy status of psilocybin, researchers at prestigious institutions are suggesting that psilocybin be the first psychedelic to be rescheduled from I to IV due to substantial evidence that it could perform better than conventional antidepressants and cognitive-behavioral therapy , . This could be a major start to the re-evaluation of psychedelics as medicine.
 M. W. Johnson, R. R. Griffiths, P. S. Hendricks, and J. E. Henningfield, “The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act,” Neuropharmacology, Jun. 2018.
 COMPASS, “COMPASS Pathways Receives FDA Breakthrough Therapy Designation for Psilocybin Therapy for Treatment-resistant Depression,” COMPASS, 2018. [Online]. Available: https://compasspathways.com/compass-pathways-receives-fda-breakthrough-therapy-designation-for-psilocybin-therapy-for-treatment-resistant-depression/. [Accessed: 22-Jan-2019].
 C. for D. E. and Research, “Food and Drug Administration Safety and Innovation Act (FDASIA) - Frequently Asked Questions: Breakthrough Therapies.”
 J. J. H. Rucker, J. Iliff, and D. J. Nutt, “Psychiatry & the psychedelic drugs. Past, present & future,” Neuropharmacology, 2018.
 G. Bertrand, “The DEA Years,” vol. 54, no. 5, pp. 1244–1252, 2004.
 L. Shen, H. Farid, and M. A. Mcpeek, “Drugs of Abuse,” U.S. Dep. Justice Drug Enforc. Adm., pp. 72–73, 2017.
 D. J. Drobes, “Concurrent Alcohol and Tobacco Dependence,” National Institute on Alcohol Abuse and Alcoholism, 2002. [Online]. Available: https://pubs.niaaa.nih.gov/publications/arh26-2/136-142.htm. [Accessed: 23-Jan-2019].
 R. G. dos Santos, F. L. Osório, J. A. S. Crippa, and J. E. C. Hallak, “Antidepressive and anxiolytic effects of ayahuasca: a systematic literature review of animal and human studies,” Rev. Bras. Psiquiatr., vol. 38, no. 1, pp. 65–72, Mar. 2016.
 L. Roseman, L. Demetriou, M. B. Wall, D. J. Nutt, and R. L. Carhart-Harris, “Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression,” Neuropharmacology, 2018.
 P. Gasser, K. Kirchner, and T. Passie, “LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: A qualitative study of acute and sustained subjective effects,” J. Psychopharmacol., vol. 29, no. 1, pp. 57–68, Jan. 2015.
 G. E. Noller, C. M. Frampton, and B. Yazar-Klosinski, “Ibogaine treatment outcomes for opioid dependence from a twelve-month follow-up observational study,” Am. J. Drug Alcohol Abuse, vol. 44, no. 1, pp. 37–46, Jan. 2018.
 S. Ross et al., “Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial,” J. Psychopharmacol., vol. 30, no. 12, pp. 1165–1180, 2016.
 T. S. Krebs and P. Ør. Johansen, “Lysergic acid diethylamide (LSD) for alcoholism: Meta-analysis of randomized controlled trials,” J. Psychopharmacol., vol. 26, no. 7, pp. 994–1002, 2012.
 T. C. Malone et al., “Individual Experiences in Four Cancer Patients Following Psilocybin-Assisted Psychotherapy.,” Front. Pharmacol., vol. 9, p. 256, 2018.
 M. Andersson, M. Persson, and A. Kjellgren, “Psychoactive substances as a last resort-a qualitative study of self-treatment of migraine and cluster headaches.,” Harm Reduct. J., vol. 14, no. 1, p. 60, Dec. 2017.
 R. J. Strassman, “Human psychopharmacology of N,N-dimethyltryptamine.,” Behav. Brain Res., vol. 73, no. 1–2, pp. 121–4, 1996.
 E. Tagliazucchi et al., “Increased Global Functional Connectivity Correlates with LSD-Induced Ego Dissolution,” Curr. Biol., vol. 26, no. 8, pp. 1043–1050, 2016.
 A. C. de M. Galvão et al., “Cortisol Modulation by Ayahuasca in Patients With Treatment Resistant Depression and Healthy Controls,” Front. Psychiatry, vol. 9, p. 185, May 2018.
 MAPS, “MDMA-Assisted Psychotherapy,” Multidisciplinary Association for Psychedelic Studies, 2019. [Online]. Available: https://maps.org/research/mdma. [Accessed: 22-Jan-2019].
 E. J. Kyzar, C. D. Nichols, R. R. Gainetdinov, D. E. Nichols, and A. V Kalueff, “Psychedelic Drugs in Biomedicine.,” Trends Pharmacol. Sci., vol. 38, no. 11, pp. 992–1005, Nov. 2017.
 Z. Leary, “Episode 35: Rick Doblin, MAPS 2018 Year in Review,” 2018.
 L. Dancyger, “Psychedelic Mushrooms: Oregon Considering Legalizing Psilocybin,” Rolling Stone, 2018. [Online]. Available: https://www.rollingstone.com/culture/culture-news/psychedelic-psilocybin-legalizing-mushrooms-oregon-763032/. [Accessed: 22-Jan-2019].
 “Decriminalize Denver.” [Online]. Available: https://decriminalizedenver.org/. [Accessed: 23-Jan-2019].
 UNODC, “Convention on Psychotropic Substances,” Final Act United Conf. Adopt. a Protoc. Psychotr. Subst., pp. 1–28, 1971.
 S. J. Belouin and J. E. Henningfield, “Psychedelics: Where we are now, why we got here, what we must do,” Neuropharmacology, 2018.
 R. J. Boakes, P. B. Bradley, I. Briggs, and A. Dray, “Antagonism by LSD to effects of 5-HT on single neurones,” Brain Res., vol. 15, no. 2, pp. 529–531, Oct. 1969.
 E. C. Savini, “The antagonism between 5-hydroxytryptamine and certain derivatives of lysergic acid.,” Br. J. Pharmacol. Chemother., vol. 11, no. 3, pp. 313–7, Sep. 1956.
 S. Cohen, “Lysergic Acid Diethylamide: Side Effects And Complications,” J. Nerv. Ment. Dis., vol. 130, no. 1, pp. 30–40, Jan. 1960.
 J. H. Halpern and H. G. Pope, “Hallucinogen persisting perception disorder: what do we know after 50 years?,” Drug Alcohol Depend., vol. 69, no. 2, pp. 109–119, Mar. 2003.
 S. Cohen and K. S. Ditman, “Prolonged Adverse Reactions to Lysergic Acid Diethylamide,” Arch. Gen. Psychiatry, vol. 8, no. 5, p. 475, May 1963.
 R. J. Strassman, “Adverse reactions to psychedelic drugs. A review of the literature.,” J. Nerv. Ment. Dis., vol. 172, no. 10, pp. 577–95, Oct. 1984.
 R. R. Griffiths et al., “Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial,” J. Psychopharmacol., vol. 30, no. 12, pp. 1181–1197, 2016.
 International Narcotics Control Board (INCB), “List of Psychotropic Substances under International Control,” vol. 53991, no. May, p. 35, 2016.
 R. L. Carhart-Harris et al., “Implications for psychedelic-assisted psychotherapy: functional magnetic resonance imaging study with psilocybin,” Br. J. Psychiatry, vol. 200, no. 03, pp. 238–244, Mar. 2012.
 F. Palhano-Fontes et al., “Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial,” Psychol. Med., pp. 1–9, Jun. 2018.
 T. K. Brown and K. Alper, “Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes,” Am. J. Drug Alcohol Abuse, vol. 44, no. 1, pp. 24–36, Jan. 2018.
 S. Atasoy, L. Roseman, M. Kaelen, M. L. Kringelbach, G. Deco, and R. L. Carhart-Harris, “Connectome-harmonic decomposition of human brain activity reveals dynamical repertoire re-organization under LSD,” Sci. Rep., vol. 7, no. 1, pp. 1–18, 2017.
 M. Kaelen et al., “LSD modulates music-induced imagery via changes in parahippocampal connectivity,” Eur. Neuropsychopharmacol., vol. 26, no. 7, pp. 1099–1109, 2016.
 B. G. Eisner and S. Cohen, “Psychotherapy with lysergic acid diethylamide.,” J. Nerv. Ment. Dis., vol. 127, no. 6, pp. 528–39, Dec. 1958.
 J. B. Grindspoon, L. Bakalar, “The psychedelic drug therapies,” Curr. Psychiatr. Ther., vol. 20, pp. 275–283, 1981.
 R. L. Carhart-Harris et al., “Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study,” The Lancet Psychiatry, vol. 3, no. 7, pp. 619–627, 2016.
 M. W. Johnson and R. R. Griffiths, “Potential Therapeutic Effects of Psilocybin,” Neurotherapeutics, vol. 14, no. 3, pp. 734–740, Jul. 2017.
 S. Moussavi, S. Chatterji, E. Verdes, A. Tandon, V. Patel, and B. Ustun, “Depression, chronic diseases, and decrements in health: results from the World Health Surveys.,” Lancet (London, England), vol. 370, no. 9590, pp. 851–8, Sep. 2007.
 Johns Hopkins, “Reclassification Recommendations for Drug in ‘Magic Mushrooms,’” Johns Hopkins Medicine, 2018. [Online]. Available: https://www.hopkinsmedicine.org/news/newsroom/news-releases/reclassification-recommendations-for-drug-in-magic-mushrooms. [Accessed: 11-Nov-2018].