After a fifty-year hiatus, psychedelic compounds have returned to clinical research with unprecedented rigor. This analysis examines the evidence base—from Phase 3 MDMA trials to psilocybin depression studies—evaluating what the data actually show, where the science remains uncertain, and what sophisticated readers should understand about this emerging therapeutic frontier.

The resurgence of clinical psychedelic research represents one of the most significant developments in psychiatry this century. Compounds once dismissed as dangerous relics of the counterculture are now the subject of rigorous clinical trials at institutions including Johns Hopkins, Imperial College London, and NYU. The FDA has granted "Breakthrough Therapy" designation to both MDMA for post-traumatic stress disorder and psilocybin for treatment-resistant depression—an acknowledgment that these substances may offer substantial improvements over existing treatments.

Yet the path from promising research to approved medicine has proven more complex than early enthusiasts anticipated. The FDA's 2024 rejection of MDMA-assisted therapy for PTSD—despite compelling efficacy data—underscores that scientific promise alone does not guarantee regulatory approval. Understanding this landscape requires examining both the impressive clinical evidence and the legitimate methodological concerns that remain.

I. Historical Context: The First Wave and the Fifty-Year Pause

The current research renaissance is actually a resumption of work that began decades ago. Between 1950 and 1965, psychedelic research flourished within mainstream psychiatry. During this fifteen-year period, LSD alone generated over 1,000 scientific papers, several dozen books, and six international conferences. More than 40,000 patients received LSD as part of clinical treatment, primarily for alcoholism and mood disorders.

Sandoz Pharmaceuticals, which first synthesized LSD in 1938 and discovered its psychoactive properties in 1943, distributed the compound to researchers under the trade name Delysid. Early results appeared promising: a 1959 Canadian study reported that a single high-dose LSD session helped nearly 50% of alcoholic patients maintain sobriety at one-year follow-up—outcomes far exceeding conventional treatments. The British psychiatrist Humphry Osmond, who coined the term "psychedelic" (meaning "mind-manifesting"), used LSD extensively in treating alcoholism and reported similarly encouraging results.

However, the research of this era suffered from methodological limitations that would prove significant. Most studies lacked placebo controls, randomization, or standardized outcome measures. Researchers often conducted sessions themselves, introducing potential bias. Patient populations were poorly defined. While the clinical impressions were compelling, the evidence base fell short of modern standards.

The countercultural explosion of the 1960s transformed public and political perception of psychedelics. As recreational use spread—often encouraged by figures like Timothy Leary—psychedelics became associated with anti-establishment values and perceived threats to social order. Reports of adverse reactions, though often exaggerated, generated legitimate safety concerns. The U.S. government responded by restricting research access beginning in 1966, and the Controlled Substances Act of 1970 placed LSD, psilocybin, and other psychedelics in Schedule I—defined as substances with high abuse potential and no accepted medical use.

This classification effectively ended legitimate research for nearly half a century. The few studies that continued faced extraordinary regulatory hurdles. The first FDA-approved human study of a classic psychedelic (DMT) since the 1970s wasn't conducted until 1990, by Dr. Rick Strassman at the University of New Mexico. The research renaissance that followed emerged gradually, driven by a small group of scientists who navigated the regulatory obstacles with persistence.

II. MDMA-Assisted Therapy for PTSD: The Most Advanced Program

The most clinically advanced psychedelic research program to date involves MDMA (3,4-methylenedioxymethamphetamine) as an adjunct to psychotherapy for post-traumatic stress disorder. Unlike classic psychedelics such as psilocybin and LSD, MDMA is classified as an "entactogen"—a compound that enhances feelings of emotional closeness and reduces fear responses without producing the perceptual distortions characteristic of traditional psychedelics.

The Multidisciplinary Association for Psychedelic Studies (MAPS), founded in 1986 by Rick Doblin, has sponsored MDMA research since the 1990s. Their systematic clinical development program culminated in two Phase 3 trials: MAPP1 (NCT03537014) and MAPP2 (NCT04077437), conducted from 2018 to 2022.

The results were striking. In MAPP1, participants receiving MDMA-assisted therapy showed a mean CAPS-5 score reduction of -24.4 points compared to -13.9 for placebo (p<0.0001). MAPP2 replicated these findings: -23.7 for MDMA versus -14.8 for placebo. The between-group effect size (Cohen's d) was 0.91 in MAPP1 and 0.74 in MAPP2—large effects by conventional standards.

Perhaps more clinically meaningful: at study completion, 71% of participants in the MDMA groups no longer met diagnostic criteria for PTSD, compared to 48% in placebo groups. In MAPP2, 87% of MDMA recipients achieved at least a 10-point reduction in CAPS-5 scores (considered clinically meaningful), versus 69% of placebo recipients.

The FDA Rejection and Its Implications

Despite these results, the FDA declined to approve MDMA-assisted therapy in August 2024. The agency's concerns centered not on efficacy but on methodological issues and safety signals. In June 2024, an FDA advisory committee voted 9-2 against approving the treatment, citing several concerns that merit examination.

Functional unblinding: Because MDMA produces distinctive subjective effects (euphoria, empathy, physical sensations), participants could often identify whether they received active drug or placebo. Post-hoc analyses confirmed this: most participants correctly guessed their assignment. This functional unblinding potentially inflates treatment effects in subjective outcome measures like CAPS-5, which relies on patient self-report.

Expectancy effects: Many participants sought out the trials specifically hoping for MDMA treatment, introducing potential expectancy bias. The therapeutic context—eight-hour sessions with two trained therapists—differs dramatically from standard PTSD care and may contribute independent effects difficult to separate from pharmacology.

Cardiovascular concerns: MDMA increases heart rate and blood pressure, raising concerns about cardiovascular safety in broader populations. While serious adverse events in trials were rare, the FDA requested additional long-term safety data.

Abuse potential: MDMA is a Schedule I substance with known recreational use. The FDA sought more data on abuse liability in therapeutic contexts and risk mitigation strategies.

The rejection does not necessarily mean MDMA therapy will never be approved. Lykos Therapeutics (formerly MAPS PBC) is working to address FDA concerns, potentially through additional trials with modified designs. The Australian Therapeutic Goods Administration (TGA) approved MDMA-assisted therapy for PTSD in 2023, demonstrating that regulatory pathways remain open.

III. Psilocybin for Depression: Multiple Programs, Convergent Evidence

Research on psilocybin—the psychoactive compound in "magic mushrooms"—for depression has proceeded along multiple parallel tracks, generating substantial evidence from several independent research groups.

Johns Hopkins University

The Johns Hopkins Center for Psychedelic and Consciousness Research has conducted some of the most influential modern psychedelic studies. Their 2016 study of psilocybin for cancer-related psychological distress (published in the Journal of Psychopharmacology) showed that a single high-dose session produced rapid and sustained reductions in depression and anxiety, with effects persisting at six-month follow-up.

In 2020, Johns Hopkins published the first randomized controlled trial of psilocybin for major depressive disorder (NCT03181529). Twenty-four participants with moderate-to-severe MDD received two psilocybin sessions (20mg/70kg and 30mg/70kg) alongside supportive psychotherapy. At one week post-treatment, 67% achieved a ≥50% reduction in depression scores; at four weeks, 71% responded to treatment. Remarkably, 54% achieved remission (GRID-HAMD score ≤7) at four-week follow-up.

Imperial College London

The Centre for Psychedelic Research at Imperial College, led initially by Dr. Robin Carhart-Harris, has produced foundational work on psilocybin's therapeutic mechanisms and clinical applications. Their 2016 open-label feasibility study treated 12 patients with treatment-resistant depression (defined as failure of two or more antidepressant trials). All patients showed some reduction in depression scores at one week; five achieved remission, and effects persisted at three-month follow-up for most participants.

Most significant was their 2021 head-to-head comparison of psilocybin versus escitalopram for major depressive disorder, published in the New England Journal of Medicine. Fifty-nine participants were randomized to receive either two doses of 25mg psilocybin (plus daily placebo pills) or daily escitalopram (plus two doses of 1mg psilocybin as an active placebo). At six weeks, both groups showed similar reductions on the primary outcome (QIDS-SR-16 scores), with psilocybin showing numerical advantages on secondary measures including anxiety, anhedonia, and wellbeing.

A 2024 six-month follow-up of this trial found that improvements were sustained in both groups, though the psilocybin group maintained an advantage on several secondary measures. Importantly, the psilocybin group achieved these outcomes with just two doses versus 43 daily doses of escitalopram.

COMPASS Pathways Phase 2b

The largest psilocybin trial to date was conducted by COMPASS Pathways, testing their proprietary formulation COMP360 for treatment-resistant depression (NCT03775200). This Phase 2b study randomized 233 participants across 22 sites to receive single doses of 25mg, 10mg, or 1mg (control) psilocybin with psychological support.

At three weeks post-dose, 37% of participants in the 25mg group showed response (≥50% reduction in MADRS scores) compared to 18% in the 1mg control group. The 25mg group also showed significantly greater remission rates. However, response rates declined over time, and by 12 weeks the difference between groups had attenuated.

The study revealed important safety signals: 9 participants (12%) in the 25mg group reported suicidal ideation (compared to 2 in the 1mg group), and 3 participants made suicide attempts during the study period. While suicide ideation is common in treatment-resistant depression, these findings prompted ongoing discussion about patient selection and monitoring protocols.

COMPASS Pathways has initiated Phase 3 trials (COMP360-PSY-3001, 3002, 3003) with modified designs including enhanced psychological support and closer safety monitoring. Results are anticipated in 2026.

IV. Ketamine and Esketamine: The Approved Psychedelic

While often overlooked in discussions of the "psychedelic renaissance," ketamine represents the only psychedelic-adjacent compound with regulatory approval for psychiatric use. In March 2019, the FDA approved esketamine (Spravato), the S-enantiomer of ketamine, as a nasal spray for treatment-resistant depression. In 2020, it received an additional indication for major depressive disorder with acute suicidal ideation or behavior.

Ketamine and esketamine differ mechanistically from classic psychedelics: rather than acting primarily on serotonin 5-HT2A receptors, they antagonize NMDA glutamate receptors. However, they share several features with other psychedelic-assisted therapies: dissociative subjective effects during administration, rapid antidepressant action, and proposed mechanisms involving neuroplasticity.

The regulatory path for esketamine illustrates both the possibilities and limitations of psychedelic medicine. The FDA approved esketamine despite mixed efficacy data—only two of five Phase 3 short-term trials achieved statistical significance on primary endpoints. A relapse prevention trial showed more robust benefits. The approval reflected the urgent unmet need in treatment-resistant depression and the compound's novel mechanism.

Real-world implementation has highlighted challenges. Spravato must be administered in certified healthcare settings with post-dose monitoring due to dissociative effects and abuse potential. The wholesale cost exceeds $5,000 per month for maintenance dosing. Insurance coverage varies widely. These factors have limited access despite FDA approval.

Meanwhile, off-label use of racemic ketamine (containing both S- and R-enantiomers) through IV infusions has expanded rapidly, operating in a regulatory gray zone. Ketamine clinics have proliferated across the United States, offering treatment at prices ranging from $300 to $800 per infusion. Quality and safety standards vary considerably across providers.

V. DMT and Ayahuasca: Emerging Research

N,N-Dimethyltryptamine (DMT), whether in pure form or as the active component of the traditional Amazonian brew ayahuasca, represents the newest frontier in psychedelic clinical research. DMT produces intense but brief psychedelic experiences when smoked or injected (lasting 15-30 minutes) or longer effects when combined with monoamine oxidase inhibitors as in ayahuasca (4-6 hours).

The short duration of pure DMT has attracted commercial interest as a potentially more practical therapeutic option. A single DMT-assisted therapy session could theoretically be completed within a standard clinical appointment, rather than requiring the 6-8 hour sessions needed for psilocybin or MDMA.

Small Pharma (now part of Cybin) conducted the first placebo-controlled trial of DMT for major depressive disorder. Their Phase 2a study of SPL026 (intravenous DMT plus psychological support) reported positive results in January 2023, meeting its primary endpoint of statistically significant reduction in MADRS depression scores at two weeks compared to placebo. Additional data showed improvements in self-reported anxiety scores and quality of life measures.

A Phase 2 trial by Algernon Pharmaceuticals (NCT04673383) is evaluating DMT for major depressive disorder. Early results suggest potential efficacy, though published peer-reviewed data remains limited.

Ayahuasca research has proceeded primarily through observational studies and small trials, many conducted in South America where ceremonial use has traditional acceptance. A 2019 randomized controlled trial in Brazil treated 29 patients with treatment-resistant depression with a single dose of ayahuasca versus placebo. At day seven, the ayahuasca group showed significantly greater reductions in depression and anxiety scores, with effect sizes comparable to those seen in psilocybin trials.

This same research group published the first evidence that ayahuasca modulates brain-derived neurotrophic factor (BDNF) in depressed patients—a finding supporting proposed neuroplasticity mechanisms.

VI. Mechanisms: How Might Psychedelics Work?

Understanding how psychedelics produce therapeutic effects remains an active area of research. Multiple mechanisms likely contribute, and the relative importance of pharmacological versus psychological factors remains debated.

5-HT2A Receptor Agonism

Classic psychedelics (psilocybin, LSD, DMT) share the property of agonizing serotonin 5-HT2A receptors, particularly those located on layer V pyramidal neurons in the prefrontal cortex. When the 5-HT2A antagonist ketanserin is administered before psilocybin, both the subjective psychedelic effects and the antidepressant effects are blocked—demonstrating that 5-HT2A activation is necessary for psilocybin's therapeutic action.

Activation of 5-HT2A receptors triggers a cascade of intracellular signaling involving increased glutamate release, activation of AMPA receptors, and downstream effects on gene expression. This pathway converges with the mechanism of ketamine, suggesting a final common pathway involving glutamatergic neurotransmission.

Neuroplasticity and Neurotrophic Factors

Psychedelics rapidly induce structural and functional neuroplasticity. Rodent studies demonstrate that a single dose of psilocybin, LSD, or DMT increases dendritic spine density and synaptic connectivity, particularly in the prefrontal cortex. These effects emerge within hours and persist for weeks—far outlasting the acute drug effects.

Brain-derived neurotrophic factor (BDNF) appears central to this process. Psychedelics upregulate BDNF expression, and BDNF signaling through TrkB receptors mediates both the structural plasticity and antidepressant effects. Recent research suggests psychedelics may directly bind TrkB receptors independently of 5-HT2A—a potential mechanism for novel "non-psychedelic psychedelic" compounds under development.

The mammalian target of rapamycin (mTOR) pathway, activated downstream of BDNF-TrkB signaling, orchestrates protein synthesis required for new synapse formation. Ketamine's antidepressant effects depend on mTOR activation, and similar mechanisms likely apply to classic psychedelics.

Default Mode Network Disruption

Functional neuroimaging has revealed that psychedelics consistently reduce activity and connectivity within the default mode network (DMN)—a set of brain regions including the medial prefrontal cortex, posterior cingulate cortex, and angular gyrus that are active during self-referential thought, rumination, and "mind-wandering."

The DMN is overactive in depression, where it contributes to excessive rumination and rigid, negative self-referential thinking. By temporarily "resetting" DMN function, psychedelics may interrupt maladaptive thought patterns and permit new perspectives to emerge. Neuroimaging studies show that greater acute DMN disruption during psilocybin administration predicts better therapeutic outcomes.

A landmark 2024 study published in Nature used high-resolution neuroimaging to demonstrate that psilocybin produces unprecedented "desynchronization" of brain activity—a temporary dissolution of the hierarchical organization that normally constrains neural dynamics. The researchers proposed this engages "homeostatic plasticity" mechanisms, triggering adaptive reorganization as the brain returns to baseline.

The Mystical Experience Correlation

One of the most intriguing and controversial findings in psychedelic research is the correlation between the quality of the acute psychedelic experience and therapeutic outcomes. Specifically, experiences meeting criteria for "mystical" or "peak" experiences—characterized by feelings of unity, transcendence of time and space, ineffability, and sacredness—predict better clinical outcomes across multiple studies and indications.

The Mystical Experience Questionnaire (MEQ) has been validated for use in psilocybin research. Higher MEQ scores predict greater reductions in depression and anxiety at follow-up, sustained changes in personality traits (increased openness), and enduring changes in attitudes and behavior.

This correlation raises profound questions. Is the mystical experience merely an epiphenomenon of sufficient pharmacological intensity? Or does the psychological content of the experience—the subjective meaning participants derive—contribute causally to therapeutic outcomes? The answer has implications for drug development: if the experience matters, efforts to create "non-hallucinogenic psychedelics" that preserve neuroplasticity without subjective effects may prove therapeutically inferior.

VII. The Therapeutic Model: Preparation, Session, Integration

Contemporary psychedelic-assisted therapy employs a structured three-phase model that distinguishes it fundamentally from conventional pharmacotherapy. Understanding this model is essential for evaluating both the potential and the implementation challenges of psychedelic medicine.

Preparation

Before the psychedelic session, participants undergo multiple preparation sessions (typically 3-8 hours total) with trained therapists. These sessions serve multiple functions: establishing therapeutic rapport, reviewing the participant's history and intentions, providing psychoeducation about expected effects, developing coping strategies for challenging experiences, and creating a framework for interpreting whatever emerges.

The concept of "set and setting"—originally articulated by Timothy Leary—refers to the importance of psychological mindset (set) and physical/social environment (setting) in shaping psychedelic experiences. Contemporary clinical protocols operationalize this concept through careful preparation and controlled administration environments.

The Session

Dosing sessions typically occur in comfortable, living room-like environments rather than clinical settings. Participants recline on a couch, wear eyeshades, and listen to carefully curated music playlists. Two trained therapists remain present throughout, offering support but minimal intervention, encouraging participants to direct attention inward.

For psilocybin sessions, which last 4-6 hours, and MDMA sessions, which last 6-8 hours, this represents a significant commitment of therapeutic resources. The therapist-to-patient ratio (2:1) and session duration create scalability challenges for widespread implementation.

The therapeutic approach is generally "non-directive"—therapists provide safety and support while allowing the psychedelic experience to unfold without structured interpretation or intervention. When difficult material arises (fear, grief, traumatic memories), therapists encourage participants to "approach rather than avoid"—to explore rather than resist challenging content.

Integration

Following the psychedelic session, participants engage in multiple integration sessions where they process their experience with therapists, identify insights or realizations, and work to translate these into concrete changes in attitudes, behaviors, or relationships. Integration may employ techniques from cognitive-behavioral therapy, acceptance and commitment therapy, or other modalities.

The importance of integration has become increasingly recognized. Psychedelic experiences can produce powerful insights, emotions, and even apparent revelations—but without subsequent psychological work to contextualize and apply these experiences, therapeutic gains may not endure. The phenomenon of "psychedelic afterglow," a period of enhanced mood and psychological flexibility following dosing sessions, may represent a window of enhanced neuroplasticity when new patterns can be more easily established.

VIII. Remaining Questions and Legitimate Concerns

Despite impressive early results, substantial questions remain about the clinical viability and safety of psychedelic-assisted therapies.

Durability of Effects

While many studies report sustained benefits at 6-12 month follow-up, the optimal dosing frequency for maintenance remains unknown. The COMPASS Pathways Phase 2b data showing attenuation of response over 12 weeks raises questions about whether single or widely spaced sessions provide durable benefits, or whether periodic "booster" sessions will be needed. This has implications for both efficacy and cost-effectiveness.

Scalability

The current therapeutic model—requiring two trained therapists for sessions lasting 6-8 hours, plus extensive preparation and integration—creates significant implementation challenges. There are not enough trained therapists to meet potential demand, and training programs are only beginning to scale. The cost per treatment episode may exceed $10,000-15,000 in real-world implementation. Whether abbreviated protocols or group treatment models can maintain efficacy while improving access remains to be demonstrated.

The Blinding Problem

Functional unblinding—participants' ability to identify whether they received active drug or placebo based on subjective effects—challenges the interpretability of all psychedelic clinical trials. This is not unique to psychedelics (antidepressant trials face similar issues due to side effects), but the magnitude of subjective psychedelic effects makes the problem more severe.

Various approaches have been proposed: using active placebos (niacin, which causes flushing), low-dose psychedelics as comparators (as in the COMPASS trials), or treating all participants with active drug at different timepoints. None fully resolves the fundamental challenge of studying treatments that produce unmistakable subjective states.

Patient Selection and Safety

Clinical trials typically exclude patients with personal or family history of psychotic disorders, active substance use disorders, significant cardiovascular disease, and other conditions. How well results generalize beyond these carefully selected populations remains uncertain. Post-marketing surveillance, once approvals occur, will be essential.

The emergence of suicidal ideation in some psilocybin trial participants, while potentially attributable to the treatment-resistant population studied, requires continued monitoring. Reports of prolonged psychological difficulties following psychedelic experiences—sometimes termed "spiritual emergencies" or, more clinically, prolonged perception disorders—exist, though systematic data on incidence in therapeutic contexts are limited.

Therapist Effects and Boundaries

The intimate, emotionally intense nature of psychedelic therapy sessions creates potential for boundary violations and therapeutic misconduct. Reports of inappropriate behavior by underground practitioners have emerged, and even in clinical trials, the regulatory environment has flagged concerns about therapist-patient dynamics. Developing robust training, supervision, and accountability structures will be essential for ethical implementation.

Mechanism Uncertainty

Despite extensive neuroimaging and preclinical work, we do not definitively understand how psychedelics produce therapeutic effects. The relative contributions of pharmacology (neuroplasticity induction), psychology (insight, meaning-making, processing of emotional material), and context (therapeutic relationship, preparation, setting) remain unclear. This uncertainty complicates optimization of treatment protocols.

IX. Legal Landscape and Investment Implications

The legal status of psychedelics is evolving rapidly, creating a complex patchwork of federal, state, and international regulations.

United States

At the federal level, psilocybin, MDMA, DMT, and LSD remain Schedule I controlled substances. This classification creates significant barriers to research (requiring DEA registration and approval), prohibits prescribing, and exposes users to criminal penalties.

However, several states have moved to create legal access outside the federal framework. Oregon became the first state to legalize regulated psilocybin services on January 1, 2023, through the Oregon Psilocybin Services (OPS) program created by Measure 109. The program licenses "service centers" where adults can receive psilocybin under the supervision of trained "facilitators." As of early 2026, the program has served over 10,000 clients.

Colorado followed in 2022 with Proposition 122, creating a framework for regulated access to psilocybin and other natural psychedelics (DMT, mescaline, ibogaine). Implementation is ongoing, with the first licensed healing centers expected in 2025-2026.

Numerous cities have enacted decriminalization measures that make enforcement of psychedelic possession laws a low priority, including Denver, Oakland, Seattle, and Washington D.C. These do not create legal access but reduce criminal risk for personal use.

International

Australia's Therapeutic Goods Administration (TGA) took the unprecedented step in February 2023 of rescheduling both psilocybin and MDMA to Schedule 8 (controlled drugs), permitting their prescription by authorized psychiatrists for treatment-resistant depression and PTSD respectively. Implementation began July 2023, making Australia the first country to formally legalize psychedelic-assisted therapy.

Canada permits psilocybin therapy through special access provisions for patients with serious conditions who have exhausted other options. Several practitioners have received exemptions to provide treatment.

The Netherlands maintains a legal loophole permitting sale of psilocybin-containing "magic truffles," which has supported a legal retreat industry and some informal therapeutic use.

Investment Landscape

The psychedelic sector attracted significant investment between 2019 and 2022, with several companies going public. COMPASS Pathways (CMPS) and Atai Life Sciences (ATAI) listed on NASDAQ; Field Trip Health, Numinus, and others traded on Canadian exchanges. Total capital raised exceeded $1 billion during this period.

However, the sector has since faced headwinds. The FDA's MDMA rejection dampened enthusiasm, and several companies have reduced operations or shut down (Small Pharma was acquired by Cybin; Field Trip ceased clinic operations). Stock prices for publicly traded psychedelic companies have declined 70-90% from peaks.

For sophisticated investors, several factors merit consideration:

Regulatory uncertainty: The path from promising trial results to approved medicine remains unclear, as the MDMA rejection demonstrated. FDA concerns about blinding, expectancy effects, and the indivisibility of drug and psychotherapy create novel regulatory challenges without established precedent.

Intellectual property questions: Psilocybin, MDMA, and DMT are public-domain compounds. Companies are pursuing patent protection through novel formulations, delivery methods, and therapeutic protocols, but the defensibility of these strategies remains untested.

Market size uncertainty: If approved, psychedelic therapies would target large patient populations (depression, PTSD, addiction). But scalability constraints and high per-treatment costs may limit actual market penetration. The ketamine clinic industry, which demonstrates the market for psychedelic-adjacent treatments, has grown but remains a niche service.

Reimbursement challenges: Insurers are accustomed to pharmaceutical pricing, not the combination of drug plus extended therapy sessions that psychedelic treatment requires. Establishing reimbursement pathways will be essential for broad access but remains an open challenge.