Hallucinogens for the Treatment of Depression

Hallucinogens for the Treatment of Depression: A Literature Review

Roland Matthews

(Spring 2017)  

Abstract

          This literature review examined the reported efficacy of hallucinogenic substances as a potential treatment for depression, particularly major depressive disorder (MDD).  The project critically reviewed the efficacy of current medication treatment models such as prescribed medications for MDD.  Many studies have shown that, although pharmacological agents are the standard of care for depression, this treatment approach has many drawbacks including medication tolerance, side effects, and less than optimal effectiveness.  Research, though limited, suggests that hallucinogenic substances are potentially helpful in the treatment of depression.  Research on substances such as ayahuasca, psilocybin, and ketamine indicate that these substances may reduce symptoms of depression fairly quickly, and, when used properly, with well-trained support, may have manageable side effects.  After examining the research literature on the use of hallucinogenic substances for treating depression, especially MDD, the conclusion of this review is that treatment with some of these substances shows promise and additional research with more diverse and larger sample groups is warranted.

          Keywords: Hallucinogens, Depression, Major Depressive Disorder, Psychedelics, and Antidepressants.

Introduction

Depression, particularly major depressive disorder (MDD) is classified as a mood disorder with profound effects on individuals’ behavior and quality of life (Palhano-Fontes, Alchieri, Oliveira, Soares, Hallak, Galvao-Coelho, & deAraujo, 2014).  According to the World Health Organization (WHO), MDD is currently the fourth leading cause of morbidity worldwide (Fava & Kendler, 2000).  The WHO anticipates that within 20 years, depression will be the chronic disease with the most significant social and economic impacts and will be the second leading cause of morbidity worldwide (Fava & Kendler 2000).  Globally, MDD has a 17% prevalence, is twice as common in women, and usually begins in the third decade of life (Palhano-Fontes et al, 2014).  In addition, up to 25% of patients diagnosed with MDD also have a comorbid chronic illness, such as Panic Disorder and Anxiety, which may be a contributing source of the depression (Palhano-Fontes et al, 2014). 

While psychotherapy is a helpful treatment for many people with MDD, current treatment approaches for MDD often focuses on pharmacological therapy (Montagne, 2007).  According to Kantor, Rehm, Haas, Chan, and Giovannucci (2015) antidepressant medications are prescribed to 13% of individuals with MDD.  The most common form of pharmacological treatment of MDD is intervention based on medications such as selective serotonin reuptake inhibitors (SSRIs) (Palhano-Fontes et al, 2014). While these medications help many people, they have several adverse side-effects (Montagne, 2007).  For example, many SSRIs take several weeks to achieve desired effects and have less than optimal effectiveness in up to 50% of patients (Palhano-Fontes et al, 2014).  In addition, tolerance to these medications can develop after daily dosing and higher doses may be required to maintain therapeutic effects (Montagne, 2007).  Though less common, other medications used to treat depression such as tricyclics (TCAs) and monoamine oxidase inhibitors (MAOIs) may also have adverse side effects (Palhano-Fontes et al, 2014).  These antidepressant side effects may include urinary retention, constipation, orthostatic hypotension, and weight gain (Palhano-Fontes et al, 2014).  MAOIs also increase the risk for hypertension (Grady & Stahl, 2012).  Despite progress in the development of new antidepressant drugs such as SSRIs, TCAs, and MAOIs, less than 50% of patients taking these medications achieve remission (Warden, Rush, Trivedi, Fava, & Wisniewski, 2007). 

Because of the adverse side effects of SSRIs, TCAs, and MAOIs, different types of substances are being explored to treat MDD (Montagne, 2007).  One alternative method that is being explored for the potential treatment of MDD is the use of hallucinogenic substances.  As early as the 1950s, hallucinogenic substances were recognized for their effectiveness in the clinical treatment of depression before they became prohibited from medical research (Montagne, 2007).  The hallucinogenic substances that have been considered and studied in depression treatment include lysergic acid diethylamide (LSD), psilocybin, 3,4-methylenedioxy-methamphetamine (MDMA), N N-dimethyltryptamine (DMT), mescaline, ketamine, ibogaine, and ayahuasca (Montagne, 2007).  Some of the early recreational hallucinogenic drug users discovered that the drugs had an impact on the symptoms of their depression allowing them to recognize and explore the traumatic basis of their symptoms and condition (Riedlinger & Montagne, 2001).  Grof (2009) indicates that hallucinogenic substances have the potential to enable individuals to both identify a problem and its solution, guided by the power of the unconscious. 

For example, ayahuasca tea is traditionally prepared by decoction of the bark of the Banisteriopsis caapi vine with leaves of the Psychotria viridis bush (Palhano-Fontes et al, 2014).  Osorio (2011) found that harmine, a substance found in the ayahuasca vine, has antidepressant effects similar to MAOIs.  According to Palhano-Fontes and colleagues (2014), results of their studies showed that depressive symptoms were reduced after a single ayahuasca dose and that the effects last about two weeks. 

According to Montagne (2007), depression in the spiritual sense can be considered a sickness of the soul and represents an individual that is disconnected from society, family, and friends.  Because of this, Montagne (2007) indicates that hallucinogenic substances can help individuals gain spiritual insights and thus diminish depression.  After using hallucinogenic substances, some patients report improved mood, relaxation, self-esteem, and more adaptive interpersonal relationships with others (Montagne, 2007).  

Though there is some evidence indicating that hallucinogenic substances may be helpful for treating depression, Winkleman and Roberts (2007) indicate that many cautions must be observed when considering these drugs as medications.  For example, hallucinogens can activate parts of the unconscious including traumatic experiences or childhood fears and should only be used as part of treatment with a therapist (Winkleman & Roberts, 2007).  Individual reactions to hallucinogenic substances vary widely and pregnant women using them can trigger miscarriages (Winkleman & Roberts, 2007).  Another potential caution is that hallucinogenic substances are time-consuming to use, even in low dosages, pronounced psychoactive and behavioral effects can last more than five hours, and patients need to be supervised throughout this period and several hours afterwards to minimize adverse effects (Montagne, 2007).  However, despite these cautions, hallucinogenic substances used within psychotherapy have the potential to be part of a healing process that can facilitate a long-lasting resolution to depression (Montagne, 2007) and the literature in this area should be thoroughly reviewed.  

Hypothesis:

The hypothesis of this project was that the research literature would show that the use of hallucinogenic substances reduces symptoms of depression in individuals diagnosed with major depressive disorder.

Operational Definitions:

          The specific operational definitions of hallucinogenic substances were based on each individual study reviewed.  In general, the concept of an hallucinogenic substance is one which acts on the body as a 2A receptor (5-HT2AR) serotonin agonist (Garcia-Romeu, Kergaard, & Addy, 2016).  Examples of hallucinogenic substances include: lysergic acid diethylamide (LSD), psilocybin, mescaline, ketamine, ibogaine, ayahuasca, 3,4-methylenedioxy-methamphetamine (MDMA), and N N-dimethyltryptamine (DMT) (Garcia-Romeu, et al, 2016).  According to Baumeister, Barnes, Giaroli, & Tracy (2014), the subjective effects of these substances do not include true hallucinations, but rather perceptual alterations of real stimuli.  Consistent with the United States Drug Enforcement Agency classification system, hallucinogenic substances are categorized as ‘schedule I’ illicit substances indicating that they have a high potential for abuse, no accepted medical usage, and a lack of safety even when used under medical supervision (Baumeister et al, 2014, & www.dea.gov). 

          The conceptual definition for major depressive disorder (MDD) is based on the levels of frequency and severity of symptoms of depression which meet diagnostic criteria (Garcia-Romeu et al, 2016).  The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) lists the diagnostic features of major depressive disorder as a clinical course characterized by one or more major depressive episodes lasting a period of at least 2 weeks during which there is either depressed mood or the loss of interest or pleasure in nearly all activities, without a history of manic, mixed, or hypomanic episodes (American Psychological Association, 2000).  Because symptoms can vary considerably, researchers have used many different assessment techniques to operationally define the symptoms of depression.  For example, symptoms have been assessed using scores on the Beck Depression Inventory (Garcia-Romeu, et al, 2016).  The Beck Depression Inventory (BDI: Beck, Ward, Mendelson, Mock, & Erbaugh, 1961) is a 21-item, self-report rating inventory that measures characteristic attitudes and symptoms of depression.  The Hamilton Rating Scale for Depression (HAM-D: Hamilton, 1960), the Montgomery-Åsberg Depression Scale (MADRS: Montgomery & Åsberg, 1979), and the Anxious-Depression subscale of the Brief Psychiatric Rating Scale (BPRS: Overall & Gorham, 1962) have also been used to assess symptoms of major depressive disorder (Osorio, Sanches, Macedo, Santos, Maia-de-Oliveira, Wichert-Ana, … & Hallak, 2015). 

Methods

          The design of this project was a comprehensive review of the published literature on the effectiveness of hallucinogenic substances for reducing symptoms of major depressive disorder.  This type of design was chosen because it allowed for an extensive examination of the published research on the topic.  In addition, due to the legal restrictions surrounding the use of schedule I substances, such as hallucinogenic substances, in research, it was beyond the scope of an undergraduate project to conduct an empirical study on the effects of these substances.  The bulk of the sources for the research studies that were critically reviewed were peer-reviewed journal articles available through the Bastyr University online databases including PsychInfo, ProQuest, PubMed, and Psych & Behavior.  Available texts and visual media were also be included.  The specific Boolean search terms, also utilizing any available database thesaurus, included, but were not limited to: Hallucinogens, Psychedelics, Depression, and Treatment.  Some of the potential difficulties that were faced involved methodological inconsistencies in reported results, potential limitations with the size and demographics of research participants in the reviewed studies, the limitations of the databases, and the potential for personal bias.  I was as objective as possible in searching and reviewing the material and endeavored to seek out articles that both supported and failed to support the hypothesis.

Results

Major Depressive Disorder (MDD) is a mood disorder which, according to the World Health Organization, is the fourth leading cause of morbidity in the world affecting up to 17% of all populations (Fava & Kendler, 2000).  Treatment can become complicated because up to 25% of those diagnosed with MDD have a comorbid chronic illness such as panic disorder or anxiety (Palhano-Fontes et al, 2014).  The typical treatments being used to assist those with MDD are psychotherapy alone or psychotherapy paired with medications (Montagne, 2007).  According to Kantor, Rehm, Haas, Chan, and Giovannucci (2015), about 13% of individuals in the U.S. with MDD are treated with antidepressant medications such as selective serotonin reuptake inhibitors (SSRIs).  While these medicines may help many people, they also take several weeks to achieve full potency (Palhano-Fontes et al, 2014).  In addition, tolerance to these medications can develop after daily dosing and higher doses may be required to maintain therapeutic effects (Montagne, 2007). Adverse side effects of SSRIs may include sexual dysfunction, sleepiness, and weight gain (Cascade, Kalali, & Kennedy, 2009).  Though less common, other medications used to treat depression such as tricyclics (TCA) and monoamine oxidase inhibitors (MAOIs) may also have adverse side effects such as urinary retention, constipation, orthostatic hypotension, weight gain, and an increased risk of hypertension (Palhano-Fontes et al, 2014).  In a survey of 700 patients using antidepressant medications, up to 38% experienced at least one of these negative side effects, while 26% reported a high level of side effects (Cascade, et al, 2009).

Because of the adverse side effects of SSRIs, TCAs, and MAOIs, different types of substances are being explored to treat MDD (Montagne, 2007).  One alternative method that is being explored for the potential treatment of MDD is the use of hallucinogenic substances.  The hallucinogenic substances that have been considered and studied for use in depression treatment include lysergic acid diethylamide (LSD), psilocybin, 3,4-methylenedioxy-methamphetamine (MDMA), N N-dimethyltryptamine (DMT), mescaline, ketamine, ibogaine, and ayahuasca (Montagne, 2007).

Research exploring the utility of these substances and their effectiveness for treating the symptoms of MDD in conjunction with psychotherapy has generated some interesting results.  Osorio and colleagues (2015) conducted a trial of the effectiveness of a single dose of ayahuasca in an inpatient psychiatric unit with 6 volunteers having current depressive episodes.  Results indicated statistically significant reductions in symptoms of depression at days 1, 7, and 21 in up to 82% of individuals.  Symptoms of depression were measured with several scales including the Hamilton Rating Scale for Depression (HAM-D: Hamilton, 1960), the Montgomery-Åsberg Depression Scale (MADRS: Montgomery & Åsberg, 1979), and the Anxious-Depression subscale of the Brief Psychiatric Rating Scale (BPRS: Overall & Gorham, 1962).  Scores on the Young Mania Rating Scale (YMRS: Young, Biggs, Ziegler, & Meyer 1978) and the thinking disorder subscale of the BPRS did not change, suggesting that ayahuasca does not induce episodes of mania and / or hypomania in patients with depression (Osorio, Sanches, Macedo, et al, 2015).

Dos Santos, Osorio, Crippa, Riba, Zuardi, and Hallak (2016) conducted a review of peer-reviewed clinical trials on the effectiveness of hallucinogenic substances for treating mental illness 1990-2015.  Out of 150 identified articles, only 6 (4 on psilocybin, 1 on LSD, and 1 on ayahuasca) met the author’s criteria which included only clinical trials published in peer-reviewed journals, involving patients diagnosed with either anxiety, depression, or dependency disorders based on structured diagnostic interviews, including comparisons for placebo and active placebos, and reductions of the diagnoses measured with validated scales (Dos Santos, et al, 2016).  Results of each of the 6 studies showed that these substances have anxiolytic, antidepressant, and antiaddictive properties useful for the treatment of drug dependence, anxiety and mood disorders.  The results appeared to be particularly strong for individuals who had experienced treatment-resistance to other medications (Dos Santos, et al, 2016).  However, they also acknowledged that all the studies that were reviewed had small sample sizes. 

Another review by Garcia-Romeu and colleagues (2016) compared the clinical applications of hallucinogens.  This review presented data on several types of hallucinogens for which clinical utility had been documented. Information on each type was emphasized, presenting the most current information on clinical research with these substances, including important ramifications for their potential therapeutic value.  Of the studies they reviewed, several appeared to focus primarily on efficacy for reducing symptoms of MDD, while others addressed a wider set of symptoms.

In one highlighted feasibility study on psilocybin with 12 patients (6 men and 6 women) diagnosed with moderate to severe MDD, subjects were given 2 doses of psilocybin, 10 mg and 25 mg, 7 days apart in a supportive setting with no control group (Carhart-Harris, Bostridge, Rucker, Day, Erritzoe, Kaelen, Bloomfield,… & Nutt, 2016). Psychological support was provided before, during, and after each session.  Patients were monitored for adverse reactions during the dosing sessions and at subsequent clinic and remote follow-up.  Depressive symptoms were assessed from 1 week to 3 months after treatment, with the 16-item Quick Inventory of Depressive Symptomatology (QIDS: Rush, Trivedi, Ibrahim, Carmody, Arnow, Klein, Markowitz,… & Keller, 2003).  Scores on the BDI also revealed complete remission in 8 patients (67%) at 1 week and 4 patients (42%) at 3 months after high dose, suggesting psilocybin may function as a rapid acting antidepressant (Carhart-Harris, et al, 2016).  Another study on psilocybin assessed effects using Functional Magnetic Resonance Imaging (fMRI) in 15 healthy volunteers (Drevets, Price, & Furey, 2008).  A small dose of 2 mg in 10 mL saline was found to decrease activity in the medial prefrontal cortex (mPFC) area of the brain, which is known to exhibit increased activation in individuals experiencing depression (Drevets, et al, 2008).

Garcia-Romeu and colleagues (2016) also identified several promising studies on the effects of mescaline, however, there is limited research possibly due to its tendency to induce nausea, or its longer duration of action with lesser potency than LSD.

According to Callaway (1994) and McKenna (2004) ayahuasca may reduce symptoms of MDD because it appears to influence serotonin neurotransmission and hypothalamic-pituitary-adrenal axis function.  According to Soler and colleagues (2016), ayahuasca also appeared to increase mindfulness related capacities 24 hours after use in 25 healthy volunteers.  In addition, according to Shahar and colleagues (2010), ayahuasca could be used to enhance mindfulness-based treatments for depression. 

Several studies have investigated the effects of ketamine on symptoms of depression (Berman, et al 2000; Diazgranados, et al, 2010; Abdallah, et al, 2015; Sos, et al, 2013; and Luckenbaugh, et al, 2014).  In one such study, the effects last from 3 to 7 days after, but is eliminated from the body within 3 hours (Diazgranados et al, 2010).  Clinical response rates of 40% - 60% were reported at 24 hours post infusion in treatment-resistant populations experiencing MDD (Abdallah et al, 2015).  In a double-blind, crossover, placebo-controlled clinical trial with 27 subjects, Sos and colleagues (2013) found a significant correlation between acute psychomimetic effects during ketamine infusion and decreased depression scores at 7 days post infusion.  Luckenbaugh and colleagues (2014) found that the acute dissociative effects of ketamine significantly associated with decreased depression scores at 230 minutes and 7 days post infusion in a sample of 108 treatment-resistant inpatients with MDD.

According to Garcia-Romeu and colleagues (2016), identified research on LSD, mescaline, MDMA, ibogaine, and cannabis as a useful treatment for MDD was either very limited or showed results that were not promising.

Lastly, while the serotonin system has long been implicated in depressive disorders, research has shown that hallucinogenic substances are able to alter the functioning of this system, but not in the same way as currently prescribed medications (Baumeister, Barnes, Giaroli, & Tracy, 2014).  Despite the commonly shared mechanisms, individual agents differ in their exact pharmacodynamic actions regarding both receptor affinity as well as the degree of functional selectivity, also known as the subsequent activation of intracellular signaling pathways (Wacker, Wang, Katritch, Han, Huang, Vardy, … & Stevens, 2013). However, the study of hallucinogens may offer a potential for a better understanding of the neurobiology of depression and of providing novel therapeutic agents (Baumeister, et al 2014)

Discussion

          The evidence presented by previous research studies suggests that the use of certain hallucinogenic substances under clinically supervised conditions may be an effective treatment for symptoms of MDD.  Some of the benefits of using hallucinogens appear to be the low risk for negative side effects, long term positive results without the need for repeat treatment, the need for low dosage levels, and the minimal risk for tolerance (Montagne, 2007).  For example, research conducted by Carhart-Harris and colleagues (2016) has shown that psilocybin has a remission rate of 42% in comparison to SSRIs, which has a 20% remission rate.  Research generally supports the hypothesis  that the use of hallucinogenic substances can reduce the symptoms of depression in individuals diagnosed with major depressive disorder.

 In traditional medicine, whole plants or mixtures of plants are used rather than isolated compounds (Rosoanaivo, Wright, Willcox, & Gilbert, 2011).  Crude plant extracts often have greater in vitro and / or in vivo activity than isolated constituents at an equivalent dose (Rosoanaivo, et al, 2011).  There is also evidence for several types of positive interactions between different components of medicinal plants resulting in pharmacodynamic synergy between various plant extracts when traditionally combined (Rosoanaivo, et al, 2011).  Another difference is that pharmacokinetic interactions can occur, between constituents so that they can be more rapidly absorbed than the pure drug (Rosoanaivo, et al, 2011). 

Hallucinogenic drug users of the 1960s discovered that the hallucinogens had an impact on the symptoms of their depression allowing them to explore the traumatic basis of their symptoms (Riedlinger & Montagne 2001).  When guided by the power of their own unconscious, individuals may have the potential to both identify a problem and its solution while using hallucinogenic substances (Grof, 2009).  One example, harmine, a substance found in the ayahuasca vine, has antidepressant effects similar to MAOIs, and studies have shown that after a single ayahuasca dose depressive symptoms were reduced and that the effects last about two weeks (Palhano-Fontes, et al, 2014).  For some people, depression may be considered a spiritual illness created by a disconnection from society, family, and friends (Montagne, 2007).  Hallucinogenic substances may be able to help individuals gain spiritual insights and thus diminish depression due to social disconnection (Montagne, 2007).  This could be partly because, according to Mabey (2016), plants appear to have consciousness, spirit, and intentions of their own.  

However, many cautions must be observed when considering these drugs as medications because hallucinogens can activate parts of the unconscious including traumatic experiences or childhood fears (Winkleman & Roberts, 2007).  According to Winkleman and Roberts (2007), this is why people should not experiment with these substances alone without supervision and the substances should only be used as part of treatment with a therapist.  Another potential caution is that even in low dosages, hallucinogenic drugs may produce pronounced psychoactive and behavioral effects that can last more than five hours (Montagne, 2007).  Patients need to be supervised throughout the active period of the drug and for several hours afterwards in order to minimize adverse effects (Montagne, 2007).  Another potential hazard is hallucinogen persisting perception disorder (HPPD), also known as flashbacks, which are associated with illegally purchased substances taken in uncontrolled settings without supervision (Tupper, Wood, Yensen, & Johnson, 2015).  Even under clinical supervision, anxiety, fear, delayed onset headaches, increased heart rate and blood pressure can occur with dangerous behavior such as fleeing the research facility (Tupper, et al, 2015).  However, despite these cautions, hallucinogenic substances used within psychotherapy have the potential to be part of a healing process that can facilitate a long-lasting resolution to depression because they can potentially help to address not only the symptoms, but also the source of the disorder (Montagne, 2007).   

One substance that is often listed alongside others in the hallucinogenic category is cannabis (DEA, 2016). Research on the use of cannabis for MDD has yielded contradictory results and its use in treatment should be approached with caution (Allen & Holder, 2013).  Although an effective treatment for nausea, seizures, and potentially for other problems such as PTSD, research on cannabis for treating depression is inconclusive (Garcia-Romeu, et al, 2016).  For example, Durdle and colleagues (2008) reported that cannabis use and dependence increased the risk for MDD, but a longitudinal study by Pedersen (2008) did not find a link between use and subsequent depression, although it was associated with later suicidal ideation and attempts.  In a six year study, the depressive symptoms of young girls between the ages of 5 and 8 years old who were predisposed to depression, were worsened by cannabis, but did not appear to directly cause depression (Marmorstein et al, 2010).  Degenhardt and colleagues (2001) found that, after controlling for neuroticism, demographics, and poly-drug use, cannabis was no longer associated with anxiety, and its abstinence was associated with higher levels of depression.

Future research on the efficacy of hallucinogenic substances for treating MDD would be facilitated by the legalization of these substances, for use in research and clinical practice.  The loosening of restrictions would enable the use of larger sample sizes and investigation of the potential therapeutic effects in a wider variety of individuals.  This could potentially result in treatment centers specializing in hallucinogenic therapies with safe and comfortable settings and more accurate analysis of their effectiveness.  Mescaline and Psilocybin in particular could have potential for treatment of MDD, but further studies are required to be certain. 

Some of the drawbacks to this project were the difficulties in finding clinical research with large sample sizes, the difficulties in finding research information not based on political bias, and overcoming my own personal bias of wanting to find information that supported the hypothesis.  Due to the illicit nature of these substances, most sample sizes were small (less than 30 participants) with the exception of a study conducted by Krebs and Johansen (2013) of psychedelics and mental health.  Krebs and Johansen used the 2001-2004 data from the National Survey on Drug Use and Health which included 130,152 randomly selected adult respondents.  Each participant completed a set of standardized screening measures to assess mental health over the past year.  The results indicated that 13.4% of respondents reported lifetime hallucinogenic drug use was not associated with an increase in mental health difficulties (Krebs & Johansen, 2013).  In fact, in several cases, hallucinogenic drug use was associated with a lower rate of mental health problems (Krebs & Johansen, 2013).   Finally, the current research review was conducted with an open mind and willingness to learn new information, which was helpful in overcoming my own biases of support for the hypothesis.  In addition, literature searches were specifically focused on finding studies that supported and failed to support the hypothesis. 

In conclusion, this project explored the hypothesis that hallucinogenic substances, such as LSD, psilocybin, MDMA, DMT, mescaline, ketamine, ibogaine, and ayahuasca could potentially treat symptoms of MDD.  While not numerous, research studies did indicate that some hallucinogenic substances, but not all, have the potential to be effective in the treatment of MDD symptoms and could present a novel approach to boost and support psychotherapeutic success.     

References:

Abdallah, C., Averill, L., & Krystal, J. (2015). Ketamine as a promising prototype for a new generation of rapid-acting antidepressants. Translational Neuroscience in Psychiatry, 1344, 66-77. doi: 10.1111/nyas.12718

Allen, J., & Holder, M. (February 2013). Marijuana use and well-being in university students. Journal of Happiness Studies, 15(2), 301-321. doi:10.1007/s10902-013-9423-1

American Psychiatric Association (2000). American Psychiatric Association practice guidelines for the treatment of psychiatric disorders: Compendium 2000. Washington, DC: Author.

American Psychiatric Association. First, M. (Ed.). (2000). DSM-IV-TR: Text revision (4th ed.). Washington, DC: American Psychology Association.

Baumeister, D., Barnes, G., Giaroli, G., & Tracy, D. (2014). Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles. Therapeutic Advances in Psychopharmacology, 4(4), 156-169. doi:10.1177/ 2045125314527985

Beck, A., Ward, C., Mendelson, M., Mock, J., & Erbaugh, J. (1961) An inventory for measuring depression. Archives of General Psychiatry, 4, 561-571.

Berman, R., Cappiello, A., Anand, A., Oren, D., Heninger, G., Charney, D., & Krystal, J. (2000).  Antidepressant effects of ketamine in depressed patients. Biological Psychiatry 47, 351-354.

Callaway, J., Airaksinen, M., McKenna, D., Brito, G., & Grob, C. (1994). Platelet serotonin uptake sites increased in drinkers of ayahuasca. Psychopharmacology, 116(3), 385-387.

Callaway, J., McKenna, D., Grob, C., Brito, G., Raymon, L., Poland, R., … Mash, D. (1999).  Pharmakinetics of hoasca alkaloids in healthy humans. Journal of Ethnopharmacology, 65(3), 243-256.

Carhart-Harris, R., Bostridge, M., Rucker, J., Day, C., Erritzoe, D., Kaelen, M., Bloomfield, M.,    … & Nutt, D. (2016). Psilocybin with psychological support for treatment-resistant depression: An open-label feasibility study. Lancet Psychiatry, 3(7), 619-627.

Cascade, E., Kalali, A., & Kennedy, S. (2009). Real world data on SSRI antidepressant side effects. Psychiatry, 6(2), 16-18.

Cipriani, A., Furukawa, T., Salanti, G., Geddes, J., Higgins, J., Churchill, R., … Barbui, C. (2009). Comparative efficacy and acceptability of 12 new-generation antidepressants: A multi-treatments meta-analysis. Lancet, 373(9665), 746-758.

Davey, C., Allen, N., Harrison, B., & Yucel, M. (2011). Increased amygdala response to positive social feedback in young people with major depressive disorder. Biological Psychiatry, 69(8), 734-741.

DEA (2016). Drug Scheduling. Free offerings from DEA sites. Retrieved from  www.dea.gov/druginfo/ds.shtml

Degenhardt, L., Hall, W., & Lynskey, M. (2001). The relationship between cannabis use and     other substance use in the general population. Drug and Alcohol Dependence, 64(3),    319-327. Retrieved from  http://dx.doi.org/10.1016/S0376-8716(01)00130-2

Diazgranados, N., Ibrahim, L., Brutsche, N., Ameli, R., Henter, I., Luckenbaugh, D., Machado- Viera, R., & Zarate, C. Jr. (2010). Rapid resolution of suicidal ideation after a single   infusion of an NMDA antagonist in patients with treatment-resistant major depressive            disorder. Journal of Clinical Psychiatry, 71(12), 1605-1611. doi: 10.4088/JCP.09m05327blu

Dobbs, F., Christopherson, S., & Coplin, M. (Producers). (2010, June 9). Psychedelic medicines      and their current researched clinical applications [DVD of presentation]. Bastyr University Library. RM315.P79

Dos Santos, R., Osorio, F., Crippa, J., Riba, J., Zuardi, A., & Hallak, J. (2016). Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): A systematic review of clinical trials published in the last 25 years.             Therapeutic Advances in Psychopharmacology, 6(3), 193-213. doi:10.1177/ 2045125316638008

Drevets, W., Price, J., Furey, M. (2008). Brain structural and functional abnormalities in mood disorders: Implications for neurocircuitry models of depression. Brain Structure and Function 213(1-2), 93-118. doi: 10.1007/s00429-008-0189-x

Durdle, H., Lundahl, L., Johansen, C., & Tancer, M. (2008). Major depression: The relative contribution of gender, MDMA, and cannabis use. Depression and Anxiety, 25(3), 241-  247. doi: 10.1002/da.20297

Fava, M., & Kendler, K. (2000). Major depressive disorder. Neuron, 28(2), 335-341.

Garcia-Romeu, A., Kergaard, B., & Addy, P. (2016). Clinical applications of hallucinogens: A review. Experimental and Clinical Psychopharmacology, 24, 229-268. doi:10.1037/pha0000084

Grady, M., & Stahl, S. (2012). Practical guide for prescribing MAOIs: Debunking myths and removing barriers. CNS Spectrums, 17(1), 2-10.

Grof, S. (2001). LSD psychotherapy. Sarasota, FL: Multidisciplinary Association for Psychedelic Studies.

Grof, S. (2009). LSD: Doorway to the numinous. Rochester, VT: Inner Traditions.

 Hamilton, M. (1960). A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry, 23, 56-62. doi: 10.1136/jnnp.23.1.56

Kantor, E., Rehm, C., Haas, J., Chan, A., & Giovannucci, E. (2015). Trends in prescription drug  use among adults in the United States from 1999-2012. JAMA, 314 (17), 1818-1831. doi: 10.1001/jama.2015.13766

Krebs, T., & Johansen, P. (2013). Psychedelics and mental health: A population study. PLOS ONE, 8 (8). doi: 10.1371/journal.pone.0063972

Labate, B. & Cavnar, C. (Eds.). (2014). The therapeutic use of ayahuasca. San Francisco, CA: Springer.

Leonard, B. (2007). Inflammation, depression, and dementia: Are they connected? Neurochemical Research, 32(10), 1749-1756.

Luckenbaugh, D., Niciu, M., Ionescu, D., Nolan, N., Richards, E., Brutsche, N., Guevara, S., &  Zarate, C. (2014). Do the dissociative side effects of ketamine mediate its antidepressant effects? Journal of Affective Disorders, 159, 56-61.  doi: 10.1016/j.jad.2014.02.017

Lukoff, D., Zanger, R., & Lu, F. (1990). Transpersonal psychology research review: Psychoactive substances and transpersonal states. Journal of Transpersonal Psychology, 22, 107-147.

Mabey, R. (2016). The cabaret of plants: Forty thousand years of plant life and the human imagination. New York, NY: W.W. Norton & Company, Inc.

Marmorstein, N., White, H., Chung, T., Hipwell, A., Stouthamer-Loeber, M., & Loeber, R. (2010).  Associations between first use of substances and change in internalizing symptoms among girls: Differences by symptom trajectory and substance use type. Journal of Clinical Child Psychology, 39(4), 545-558. doi: 10.1080/15374416.2010.486325

McKenna, D. (2004). Clinical investigations of the therapeutic potential of ayahuasca: Rationale      and regulatory challenges. Pharmacology & Therapeutics, 102(2), 111-129.  doi: 10.1016/j.pharmthera.2004.03.002

Montagne, M. (2007). Psychedelic therapy for the treatment of depression. In M. Winkleman & T. Roberts (Eds.), Psychedelic medicine: New evidence for   hallucinogenic substances as treatments (pp. 177-184). Portsmouth, NH: Greenwood Publishing Group.

Montgomery, S., & Asberg, M. (1979). A new depression scale designed to be sensitive to change. British Journal of Psychiatry, 134 (4), 382–389. doi: 10.1192/bjp.134.4.382   

Nour, M., & Krzanowski, J. (2015). Therapeutic potential of psychedelic agents. British Journal of Psychiatry, 206, 433-436. doi:10.1192/bjp.206.5.433

Osorio, F., Sanches, R., Macedo, L., Santos, R., Maia-de-Oliveira, J., Wichert-Ana, L.   . . . Hallak, J. (2015). Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: A preliminary report. Revista Brasileira de Psiquiatria, 37, 13-20. doi:10.1590/1516-4446-2014-1496

Osorio, F. (2011). The therapeutic potential of harmine and ayahuasca in depression: Evidence from exploratory animal and human studies. In R.G. dos Santos (Ed.). The ethnopharmacology of ayahuasca, 75-85. Kerala, India: Transworld Research Network.

Overall, J., & Gorham, D. (1962). The brief psychiatric rating scale. Psychological Reports, 10, 799-812.

Palhano-Fontes, F., Alchieri, J., Oliveira, J., Soares, B., Hallak, J., Galvao-Coelho, N., & deAraujo, D. (2014). The therapeutic potentials of ayahuasca in the treatment of depression. In B. Labate & C. Cavnar (Eds.), The therapeutic use of ayahuasca (pp. 23-39). San Francisco, CA: Springer.

Pedersen, W. (2008). Does cannabis use lead to depression and suicidal behaviors? A population-based longitudinal study. Acta Psychiatrica Scandinavica, 118(5), 395-403. doi: 10.1111/j.1600-0447.2008.01259.x

Riba, J., Rodriguez-Fornells, A., Urbano, G., Morte, A., Antonijoan, R., Montero, M., Callaway, J., & Barbanoj,M. (2001). Subjective effects and tolerability of the South American psychoactive beverage ayahuasca in healthy volunteers. Psychopharmacology, 154(1), 85-95.

Riba, J., Valle, M., Urbano, G., Yritia, M., Morte, A., & Barbanoj, M. (2003). Human  pharmacology of ayahuasca: Subjective and cardiovascular effects, monoamine  metabolite excretion, and pharmakinetics. Journal of Pharmacology and Experimental therapeutics, 306(1), 73-83. doi: 10.1124/Jpet.103.049882

Riedlinger, J., & Montagne, M. (2001). Using MDMA in the treatment of depression. In Ecstasy: The complete guide, Holland, J. (Ed.), 261-272. Rochester, VT: Park Street Press.

Rosoanaivo, P., Wright, C., Willcox, M., & Gilbert, B. (2011). Whole plant extracts versus single compounds for the treatment of malaria: Synergy and positive interactions. Malaria Journal, 10(Sup. 1): S4. doi:10.1186/1475-2875-10-S1-S4

Rush, A., Trivedi, M., Ibrahim, H., Carmody, T., Arnow, B., Klein, D., … & Keller, M. (2003). The 16-item quick inventory of depressive symptomatology (QIDS) clinician rating (QIDS-C)  and self report (QIDS-R): A psychiatric evaluation in patients with chronic major            depression. Biological Psychiatry, 54, 573-583.

Sessa, B. (2005). Can psychedelics have a role in psychiatry once again? British Journal of  Psychiatry, 186, 457-458.

Shahar, B., Britton, W., Sbarra, D., Figueredo, A., & Bootzin, R. (2010). Mechanisms of change in mindfulness-based cognitive therapy for depression: Preliminary evidence from a randomized controlled trial. International Journal of Cognitive Therapy, 3(4), 402-418.

Sheline, Y., Barch, D., Donnelly, J., Ollinger, J., Snyder, A., & Mintun, M. (2001). Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: An fMRI study. Biological Psychiatry, 50(9), 651-658.

Sos, P., Klirova, M., Novak, T., Kohutova, B., Horack, J., & Palenicek, T. (2013). Relationship of  ketamine’s antidepressant and psychotomimetic effects in unipolar depression.  Neuroendocrinology Letters, 34(4), 287-293.

Tupper, K., Wood, E., Yensen, R., & Johnson, M. (2015).  Psychedelic medicine: A re-emerging therapeutic paradigm. CMAJ, 187(14), 1054-1059. doi:10.1503 /cmaj.141124 

Wacker, D., Wang, C., Katritch, V., Han, G., Huang, X., Vardy, E., … Stevens, R.     (2013). Structural features for functional selectivity at serotonin receptors.    Science, 340(6132),   615–619. doi:10/1126/science.1232808

Warden, D., Rush, A., Trivedi, M., Fava, M., & Wisniewski, S. (2007). The STAR*D Project results: A comprehensive review of findings.  Current Psychiatry Reports, 9(6), 449-459.

Winkleman, M., & Roberts, T. (Eds.). (2007). Psychedelic medicine: New evidence for hallucinogenic substances as treatments. Portsmouth, NH: Greenwood Publishing  Group.

Wong, M., & Licino, J. (2001). Research and treatment approaches to depression. Nature Reviews Neuroscience, 2(5), 343-351.

Young, S. (2013). Single treatments that have lasting effects: Some thoughts on the antidepressant effects of ketamine and botulinum toxin and the anxiolytic effect of psilocybin. Journal of Psychiatry Neuroscience, 38(2), 78-83. doi:10.1503/jpn.120128

Zunszain, P., Anacker, C., Cattaneo, A., Carvalho, L., & Pariante, C. (2011). Glucocorticoids, cytokines, and brain abnormalities in depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 35 (3), 722-729. doi:10.1016/j.pnpbp.2010.04.011