Motivation and emotion/Book/2021/Psychedelic treatment of depression

Overview


Depression is a prevalent psychiatric disorder that holds significant morbidity rates globally, (Muttoni et al., 2019). There are many factors, inclusive of biological, psychological, and social influences that may lead to the development of psychiatric disorders such as depression, (Bares et al.,2011). How individuals perceive and react to the world around them contributes significantly to the development of depression. The APA Dictionary of Psychology,(2014) defines Emotion as patterns of reactions that involve experiential, behavioral, and physiological components. An individual will then try to process this with a personally significant matter or event. The specific amount of emotion is determined by the significance of the event. Emotion usually involves feeling but this ideas do not mean it is the same as feeling or having an apparent or implicit involvement with the world,( APA Dictionary of Psychology,2014).

Traditional treatments of depression have provided multiple resources and outlets to aid in the coping and recovery of depression in individuals. However, over the last decade research on the potential therapeutic benefits of psychedelic drugs in treating depression has resurfaced, evident in the steady increase of published review articles and clinical trial reports,(Reiff et al., 2020). Psychedelic use has indeed been hindered by existing regulations such as the Controlled Substances Act, created to protect the public after President Richard Nixon declared the “War on Drugs,” (Reiff et al., 2020). Protests from the war on drugs are depicted in figure 1. Psychedelic experimentation for therapeutic use was halted in pharmacology because of this, sparking psychedelic use in counterculture movements, (Reiff et al., 2020). Research has shown promising outcomes for using psychedelic treatments as alternative methods for treating depression in contrast to and in conjunction with traditional practices, (Welcome · Mind Medicine Australia, n.d.).

Focus questions

 * What are Psychedelics?
 * What is Depression?



What are Psychedelics?
Psychedelic compounds are powerful substances that can elicit strong hallucinogenic effects when ingested. Psychedelics cause changes in cognitive functioning and connectivity in the brain, (Kyzar et al., 2017).

Although Psychedelics derived from plants have been used in multiple cultural and religious practices for centuries, it was not until 1938 that the Swiss chemist Albert Hofmann synthesized the first synthetic hallucinogen, lysergic acid diethylamide (LSD), while working with the pharmaceutical company Sandoz. Recreational use of psychedelics was met with heavy speculations due to concerns for abuse potentials and the lack of medical purpose, despite offering no dependency and a high degree of physiological safety. Psychedelics are still classed as an illegal substance in many counties, making research into their therapeutic benefits difficult. However, over the last decade, there has been an increase in the ethical studies of psychedelics treatments for various medical conditions.

Psychedelic Drug Types/ Affects
Psychedelics come in many forms and can be ingested in various ways to get the desired effects. Not all psychedelics work in the same way; according to‌ Reiff et al., (2020), Psychedelics can be divided into four classes based on their pharmacological profiles and chemical structures:

Classic Psychedelics

 * See figures 2,3,and 4


 * (serotonin 2A [5-HT2A] receptor agonists),


 * Psilocybin (Magic Mushrooms),


 * Lysergic Acid Diethylamide (LSD)


 * Ayahuasca N,N-Dimethyltryptamine (DMT)

Empathogens or Entactogens

 * (mixed serotonin and dopamine reuptake inhibitors and releasers)

==== Dissociative Anesthetic agents ====
 * 3,4-Methyl​enedioxy​methamphetamine (MDMA)


 * (N-methyl-D-aspartate [NMDA] antagonists)
 * Ketamine 5-MeO-DMT structure.svg

The Effects of Psychedelics
Classic Psychedelics ( LSD, Psilocybin, DMT) have been the most widely researched class of hallucinogen regarding the treatment of psychiatric disorders, biomedicines, and psychotherapy. Psychedelic therapy involves an acute amount of high-dose psychedelic dose administrations aimed to assist a profound and transformative psychological experience,(Roseman et al., 2018).

According to the Alcohol and Drug Federation Australia, (2019), the effects of Psychedelics are dependent on factors such as:


 * Height/ Weight
 * Physical and mental health status
 * Frequency of use
 * Other drugs are taken at the same time
 * Dosage/ strength of dose

Depending on the above factors, the effects of psychedelics can last several hours and vary considerably, depending on the specific type of psychedelic. Psychedelics may elicit various bodily and mental responses including:
 * Euphoria
 * sense of relaxation and wellbeing
 * Hallucinations
 * Cognitive impairments

Physiological reactivity or responses to stress are also critical determinants of mental and physical health,(Waugh et al., 2012). Individuals will vary in their responses to psychedelics depending on physiological factors. It is important to keep this in mind when investigating how psychedelics can be implemented in treating depression as not all individuals will have the same responses due to internal and external factors.
 * dizziness
 * blurred vision
 * clumsiness
 * Cardiovascular changes
 * Quick breathing
 * vomiting
 * sweating and chills
 * numbness

Theories upon the emotional effects of psychedelic drugs
Psychological theories of emotion can be divided into three categories:

Physiological theories suggest that responses within the body are responsible for emotions,( Lang,1994).

- James Lange Theory

Cognitive theories argue that thoughts and other mental activity play an essential role in forming emotions., (Dror, 2016) - Schachter-Singer Theory

Neurological theories propose that activity within the brain leads to emotional responses, (Brown et al., 2019)

- Biological responses

- Psychophysiology

- Mental states

These theories may be implemented to explain psychedelics' ability to elicit powerful emotional effects on the body and mind. It is important to understand theories of emotion when looking at the psychedelic treatment of depression as they serve as powerful enforcers over human behavior. Emotions have the potential to alter our feelings and behavior through their associations with a range of psychological factors such as mood, personality, temperament, and motivation. Different psychological theories provide a variety of perspectives of why and how emotions alter our mental states. Furthermore, psychedelics directly influence individuals' emotional states by creating physiological responses in the body that created altered emotions.

Definition
Depression is a psychiatric condition that is characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities,(Liverant et al., 2008). Those affected may also occasionally have delusions or hallucinations. According to the World Health Organization,(2019), depression affects over 350 million individuals and is the global leading cause of disability, (Muttoni et al., 2019). Figure 8 depicts how sufferers of depression may feel.

How is depression Treated?
According to the Department of Health | What are the treatments for depression?,( 2019) depression is treated using:

Antidepressants

 * Tricyclic Antidepressants (TCAs) (eg imipramine, nortriptyline, etc)
 * Selective Serotonin Reuptake Inhibitor (SSRI) antidepressant medication (eg fluvoxamine, fluoxetine, paroxetine, sertraline, citalopram etc)
 * Venlafaxine - this is a Serotonin and Noradrenaline Reuptake Inhibitor (SNRI) antidepressant

Psychological therapy

 * Cognitive behavioral therapy (CBT)
 * Interpersonal Therapy (IPT)
 * Problem Solving Therapy (PST)

Focus Questions:

 * How can Psychedelics be used to treat Depression?
 * What are the potential benefits of Psychedelic treatment?
 * What are the potential negative effects/ costs of Psychedelic treatment?

How can Psychedelics be used to treat Depression?
The use of psychedelic-assisted psychotherapy therapy using classic psychedelic's (ayahuasca, psilocybin or LSD) has recently been investigated as a potential medical alternative to traditional treatments in unresponsive patients, (Muttoni et al., 2019). Psychedelics have the ability to elicit profound psycho-spiritual experiences as well as enhance neurobiological mechanisms involved in mood and affective disorders, to reduce their symptoms, (Reiff et al., 2020). Psychedelic Therapy incorporates elements of pharmacotherapy but is better distinguished as a form of drug-assisted psychotherapy, (Roseman et al., 2018). Psychedelic therapy involves a series of psychedelic administration (dosage dependent on mg/kg body weight) usually twice a week over a few weeks to months, depending on the persistence of symptoms, (Carhart-Harris,. et al, 2017). clinical trials ensure that individuals are administered treatment in safe and controlled environments to maximize effectiveness and lower risk potentials such as bad reactions or overdose. These sessions are intended to create safe psychedelic experiences and potentially transformative psychological experiences, (Carhart-Harris,. et al, 2017).

Visual Processing
Psychedelics can potentially alter the processing of threat-related visual stimuli via feedback connections from the amygdala to the visual cortex,(Muttoni et al., 2019). This can be implemented as a therapeutic measure in treating depression as negative cognitive bias has been identified as a persistent symptom of the disorder. Enhanced attentional focus on negatively social and environmental stimuli is associated with increased reactivity of the amygdala,(Schmid et al., 2015). This has the potential to hinder the processing of positive information due to the limitations of the visual cortex to process multiple stimuli at a time,(Kyzar et al., 2017). Threat sensitivity can be decreased in the visual cortex with the administration of psychedelics, leading to top-down suppression of negative stimuli, as appose to Lange theory of bottom up processing of stimuli ,Lang,(1994). Thus acutely shifting emotional biases from negative to positive stimuli. This has the potential to create openness to psychotherapies where individuals are able to have faster acting relief from negative symptoms.

Serotonin / 5HT2A-receptor
Psychedelics affect the body's neurotransmitters, particularly Serotonin. Links can be made between individuals struggling with depression and low levels of serotonin. Classic psychedelics bind to serotonin receptors and subtypes to produce their effects. In particular, psychedelics share similarities with the 5-HT2A receptor (see figure 9), which is central in mood regulation and emotional face recognition, (Reiff et al., 2020). The stimulation of the 5-HT2A receptors causes a glutamate-dependent increase in activation of the pyramidal cells in the pre-frontal cortex (PFC),(Kyzar et al., 2017). Classic psychedelics have the ability to alter and control the activity of the PFC. Increasing cortical glutamate concentration by ingesting psychedelics indirectly stimulates the expression of brain-derived neurotrophic factor (BDNF), which is associated with increased neurogenesis and neuroplasticity, (Idell et al., 2017). As depression has been linked to deficient neurogenesis and neurotrophic activity, psychedelics administration can aid in the normalization of BDNF levels,(Idell et al., 2017). This has the potential to create a therapeutic effect for individuals suffering from depression as it alters neurological states to allow for the development of more positive mindsets,(Idell et al., 2017).

Default Mode Network
The Default Mode Network (DMN) is the name given to a network of brain regions,(Barrett et al., 2020). The DMN is active in the brain at rest and becomes deactivated when performing tasks,(Kyzar et al., 2017). The DMN being activated is the state in which an individual is awake and alert but not participating in any sort of attention-demanding or goal-directed task,(Kyzar et al., 2017). The default mode network is responsible for worries and ruminates when it becomes overly critical. This has the potential to lead to depression in individuals,(Muttoni et al., 2019). Psilocybin has been shown to assists in making the DMN hyperflexible by decreasing the functional connectivity of the DMN,(Barrett et al., 2020). Ayahuasca administration has also shown that it decreases activation of, and connectivity within, hubs of the default mode network after administration, (Kyzar et al., 2017). This hype flexibility has the potential to aid individuals in developing new habits to alleviate worry and rumination. By doing this, individuals may be able to break depressive cycles and form new habits for better mental health states.

Spiritual Experience
Psychedelics have the potential to elicit significant spiritual experiences in their users, (Griffiths et al., 2019). The duration and intensity of these experiences have shown evidence for being predictive of long-term therapeutic efficacy. This is due to the alteration of emotional states facilitated by psychedelics. These alterations provide psychotherapeutic potential as they can ease the augmentation of unhealthy thoughts, emotions, and behaviors, (Muttoni et al., 2019). This allows people to make progressive changes in their thoughts by inducing an increased state of consciousness,(Griffiths et al., 2019). Negative patterns of thoughts and compulsions associated with depression dissipate as they are inhibited by psychedelics. This has the potential to increase an individual's mental flexibility and leads to enduring positive changes in attitudes, moods, perspectives, values, and behavior.

SSRIS and Psychedelics
SSRIS are the most common medical intervention prescribed to people suffering from depression. Like SSRIs, classic psychedelics elicit their effect by working on the serotonin system. In contrast, psychedelics are direct agonists at the 5-HT2A receptor, (Reiff et al., 2020). SSRIs can take up to several weeks to have noticeable effects, whereas psychedelics can provide relief from depression symptoms within one day. Additionally, traditional anti-depressant treatments need to be administered daily as opposed to psychedelic medication, which only needs to be administered twice a week over a few months to make permeant changes. By providing individuals with an alternative medical treatment that provides rapid therapeutic interventions to symptoms, non-compliance with medical administration may decrease and contribute to decreased morbidity of depression.

Potential Benefits of Psychedelic Treatment
Psychedelic's treatment has yielded positive results across many studies. In the 1960s and 70's psychiatry viewed its effects as having the potential to be the net big step in mental health treatment. due to the Nixon campaign, this research has been significantly slowed down and only recently resurfaced in medical treatment. This limits the available information regarding the beneficial use of psychedelics treatments. With the implementation of adequate clinical support, psychedelic administration can be provided to individuals in a safe and supportive environment. short term benefits have been observed in a number of trials (see example for reference) and have produced remission results after only a short program. When used in safe medically controlled contexts, psychedelic compounds have shown to be non-addictive and fast-acting, providing sufferers with symptom relief faster with minimal side effects that may be observed in traditional medications. Psychedelics-assisted therapies have also produced promising results for other mental illnesses such as PTSD, anxiety, end-of-life distress, dementia, anorexia, and opioid, alcohol and smoking addictions. Although there have been many short-term benefits observed, the continuation of safe clinical trials is essential so that the long-term effects can be observed to conclude if psychedelic use is sustainable over time, (Welcome · Mind Medicine Australia, n.d.). The beneficial effects of psychedelics can be observed over several months with less administration is required compared to typical pharmacotherapy for depression. This provides cost-beneficial incentives as less frequent administration has the potential to ease financial expenditures such as consistent therapy and medication prescriptions associated with traditional treatments of depression.

Potential Negative Effects/ Costs of Psychedelic treatments
Although there is a number of compelling research conclusions in support of the implementation of psychedelic treatment of depression, there are still many limitations hindering its progression. Psychedelics drugs have faced high stigmatization throughout history, largely due to the implication of the "war on drugs" by US President Nixon in the 1960s. Law reforms resulted in psychedelics being classified as a schedule 1 drug on the US Controlled Substances Act of 1970. his is the highest classification meaning it is the most restricted and regulated substance. This sparked a chain reaction with similar laws being implemented internationally. These restrictions have had lasting hindrances to the research of psychedelic compounds being used to treat psychiatric conditions such as depression. Because of this, there is very limited research and resources. studies available conclude supportive results, however, due to the small sample size these findings cannot be generalized to the population. More research trials are needed to conclude the safe and effective use of psychedelics in treating depression.

Furthermore, due to the lack of understanding about the use of psychedelics in treating depression research has been approached with caution. The long-term effects of psychedelic use are unknown due to the limited studies. Psychedelics in clinical practice has been limited by concerns about the possible damage they may cause to the synaptic receptors in the short term, as well as implications for recovery in the long term. Therefore, psychedelic therapy should be implemented with caution. Roseman et al.,( 2018), outlined safety guidelines for psychedelic research as adequate subject preparation, environmental setting, and presence of clinician with sufficient knowledge and experience of administering psychedelics.

Example: Carhart-Harris et al., (2017), Psilocybin with psychological support for treatment-resistant depression: six-month follow-up
Twenty participants who suffered from unipolar, treatment-resistant depression were administered 10 and 25 mg, of psilocybin orally 7 days apart. Environments were created to be encouraging and relaxing to reduce the potentials of bad reactions. Depressive symptoms were assessed and recorded for 6 months with the self-rated QIDS-SR16,(Carhart-Harris et al., 2017). Throughout the 6 months, treatment was recorded as generally well tolerated Relative to baseline, marked reductions in depressive symptoms were observed. Within the first 5 weeks post-treatment (Cohen’s d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001) 13 participants met the criteria for response and remission at week 5, (Carhart-Harris et al., 2017). Positive results continued at 3 and 6 months(Cohen’s d = 1.5 and 1.4, respectively,both p < 0.001). None of the 20 participants sought conventional antidepressant treatment within 5 weeks of psilocybin, (Carhart-Harris et al., 2017)Although there are limitations in the conclusions that can be drawn from this study, positive correlations between tolerability and the sample size was positive where symptom improvement and reduction was observed after just two doses of psyboclin. Psychedelic treatment of depression offers a promising alternative for individuals who suffer from traditional treatment-resistant depression. further research in double-blind randomized control trials is needed to enhance knowledge of effects on a long-term basis.

Conclusion
Depression is a severe psychological disorder with one of the highest morbidity rates. Research into psychedelic therapy has produced promising results. Psychedelics are powerful substances that have the ability to elicit powerful emotional effects on individuals. Although psychedelics are still controlled substances in many countries, research and clinical trials have resurfaced over the last decade providing promising insights into their effectiveness with mental health treatment. Psychedelics are able to provide individuals with fast-acting relief from depressive symptoms specifically, classic psychedelics have shown that individuals treated with psychedelics have had positive and consistent results in the reduction of depressive symptoms. Psychedelics are able to provide individuals with fast-acting relief from depressive symptoms with less frequent doses than traditional antidepressants. Psychedelics' have also produced positive results for treating other mental health conditions such as anxiety, PTSD, and addiction issues. Although current research has produced promising results, there are still limitations in the knowledge of the long-term effects of psychedelic treatments of depression. Future research is needed to conclude the safety and consistency of long-term use of psychedelic treatments for mental health issues.