UPRA manifesto: what scientific evidence we rely on and what we strive for

UPRA began its activities in pre-digital times and formulated its mission and values before the full-scale invasion. Today, however, much of our attention is focused on overcoming the consequences of Russia's criminal military aggression against Ukraine.

In the first month alone, the full-scale war directly affected more than 23 million Ukrainians [1]. This impact carries the risk of severe mental health consequences, with the most common being post-traumatic stress disorder (PTSD), depression and anxiety disorders. It will only be possible to quantify these effects accurately over time. However, some idea of the scale of the problem can be gained from scientific research on the impact of wars on mental health.

According to a conservative WHO estimate, approximately 10% of people who have experienced traumatic events will have PTSD. Another 10% may have behavioural disorders that affect quality of life. In some large population-based studies, the number of people with clinical depression or anxiety disorders as a result of wars reaches 30%-40%. A much larger number of people may experience some symptoms of depression (up to 88.0%) and anxiety (up to 80.0%) [2], [3], [4].

Due to the high psychological stress associated with service, PTSD is 2-3 times more common among military personnel than among civilians [5]. In the presence of traumatic brain injuries, this percentage is even higher [6]. PTSD can last for 10 years or more [7], [8].

Of course, this does not mean that every Ukrainian will necessarily have some kind of disorder or that 20% of the military will definitely have PTSD. The Ukrainian reality is a little more complicated than the statistics from other countries. But, given the number of people affected by the war, such statistics allow us to at least roughly estimate the scale of the upcoming crisis [9], [10].

Therefore, the projected number of people who will need psychological support (about 15 million Ukrainians) and medical treatment (3-4 million Ukrainians) announced by the Ministry of Health looks quite realistic [11].

Psychotherapy, such as cognitive behavioural therapy (CBT), cognitive therapy (CT), cognitive processing therapy (CPT), and prolonged exposure (PE), is the first choice for treating PTSD. Among the alternatives, experts suggest narrative exposure techniques (NET) and eye movement desensitisation and reprocessing (EMDR). Medication is also suggested, mainly with the use of certain SSRI antidepressants [12]. Similar approaches are recommended by the Ministry of Health of Ukraine [13].

Clinical studies show that all of these methods can significantly improve PTSD symptoms, but only up to 40% of patients recover completely [14], [15], [16], [17], [18].

The situation is similar in the treatment of depression. Although it is difficult to quantify, researchers generally agree that psychotherapy and pharmacotherapy are effective in relieving the symptoms of depression in mild cases, but at least 30% of patients do not respond to treatment at all [19], [20], [21].

The most difficult and resistant to treatment are cases of simultaneous PTSD and depression. According to statistics, this combination occurs in more than half of PTSD cases. The risk of this combination among military personnel is higher than among patients in other categories [22].

Psychedelic-assisted therapy could be useful in treatment-resistant cases.

Psychedelic-assisted therapy (PAT) involves the use of artificially induced short-term changes in the functioning of various neural networks in the brain to facilitate psychotherapeutic effects. Certain psychotropic drugs are used for this purpose.

PAT with MDMA and psilocybin is already permitted and used in expanded access programmes in Israel, the United States, Canada and Australia. In 2017, the US FDA officially recognised MDMA-assisted treatment as a breakthrough treatment for PTSD, and in 2018, psilocybin-assisted treatment was recognised as a breakthrough treatment for depression [23], [24].

Since 2020, the website clinicaltrials.gov 107 new clinical trials of PAT for the treatment of various mental disorders were registered (including 55 in the USA, 21 in the EU, 12 in Canada, and 2 in Israel).

In the summer of 2022, the second clinical trial of a Phase 3 study of MDMA for the treatment of PTSD was completed, which took place in 13 clinics in the US and Israel. In the same year, the US Presidential Administration officially announced preparations for the widespread introduction of MDMA-based prescription drugs in 2023-2024 [25].

In Ukraine, not a single study of PAT has been conducted over the years of independence. Due to the lack of awareness, the legal forms of PAT in Ukraine (such as ketamine-assisted therapy for treatment-resistant depression) are used by only a few specialists [26], [27].

The efficacy of PAT is higher than that of the accepted first-choice methods, at least in the treatment of PTSD, depression and some anxiety disorders. This is confirmed by meta-analyses of clinical trials [28], [29], [30], [31], [32].

For example, after 3 sessions of MDMA-assisted psychotherapy for resistant PTSD, 88% of patients in the experimental group experienced a significant reduction in symptoms. At the same time, 67% were completely cured of PTSD. In the control group, which received psychotherapy alone, only 32% of patients were cured. The positive effect of MDMA-AT was maintained during a follow-up examination 2 months after the study was completed [33].

PAT is also more cost-effective. Even the expensive MDMA-AT protocol used in clinical trials in the US has a 36% lower cost in the long term than the first choice methods. MDMA-AT is also 36% more effective in terms of the number of quality years of life (QALYs) gained [34].

The use of optimised CBT protocols, such as group psychotherapy, will make CBT even more effective. Researchers increasingly insist that the group format also has a higher therapeutic potential [35]. In addition, the group format of therapy is more cost-effective.

A typical PAT protocol includes:

• 1-3 "regular" psychotherapeutic sessions to make a diagnosis, identify contraindications to the use of PAT, formulate therapy goals, and prepare the patient;
• at least one psychotherapeutic session with the use of an auxiliary psychoactive substance;
• another 1-3 "regular" psychotherapy sessions to reflect on and integrate the experience.

PAT uses conventional psychotherapy methods, such as variations of cognitive-behavioural or psychodynamic therapy. The key difference is the auxiliary use of psychoactive drugs to facilitate the psychotherapeutic effect.

PATs use drugs of various classes. These are mainly psychedelics (e.g. psilocybin), empathogens/entactogens (e.g. MDMA) and dissociatives (e.g. ketamine). Due to the ability of these substances to temporarily enhance neuroplasticity, they are sometimes grouped into one class - psychoplastogens [36].

MDMA temporarily increases the concentration of serotonin, dopamine and norepinephrine in the intersynaptic space due to the release and inhibition of reuptake of these neurotransmitters. At the same time, the functional connections between the hippocampus and the amygdala are enhanced, and those between the prefrontal cortex and the hippocampus are weakened. This, among other things, temporarily increases the ability to comprehend and integrate the emotional memory of negative events, i.e., it directly affects the key mechanisms of PTSD [37].

Psilocybin and other psychedelics activate mainly 5-HT2A serotonin receptors. This temporarily weakens the functional connections between the elements of the neural network of the default mode network, which is responsible for modelling a holistic subjective picture of the human world. Psychedelics also modulate the functions of the thalamus and claustrum, which are a kind of information hubs responsible for redirecting, filtering and integrating information flows. Functional connections between all brain regions are enhanced, including those that do not communicate directly with each other in the normal state. Subjectively, a person feels fundamental changes in all mental processes. The therapeutic effect is achieved due to a temporary increase in the plasticity of the psyche. In this state, it becomes generally easier for a person to abandon old unhelpful ways of responding and acquire new useful ones [38].

Ketamine acts mainly as an inhibitor of NMDA glutamate receptors. Ketamine temporarily reduces functional connections within the sensorimotor and visual cortex. Functional connections within the central executive neural network, which is responsible for goal-directed thinking, also decrease, while functional connections between parts of this network and the rest of the brain, on the contrary, increase. Subjectively, a person experiences a temporary state of dissociation - a split in the sensation of the body, the self, and the rest of the thoughts and feelings. The therapeutic effect of ketamine-assisted therapy is associated with the analgesic and anti-anxiety effects of the drug, as well as with a temporary increase in neuroplasticity, somewhat similar to the effect of psilocybin [39].

The use of MDMA, psilocybin and ketamine in a therapeutic context and in appropriate therapeutic doses is generally safe in terms of possible toxicity, addiction potential, etc. Directly during sessions with these substances, they can temporarily cause minor systemic effects, such as changes in systolic and diastolic blood pressure, heart rate, muscle tension, decreased appetite, nausea, and increased sweating [40], [41], [42], [43]. These changes are not dangerous for most people. In addition, the PAT provides for the use of these drugs only in the direct presence of a doctor, which is an additional safety factor.

Contraindications to the use of these drugs include clinical conditions that pose a significant risk of high blood pressure. Other contraindications include schizophrenia spectrum disorders and other psychotic disorders, although the issue of incompatibility between psychotic disorders and antihypertensive drugs is controversial and requires research [42], [43], [44].

It is also worth emphasising that the safety and efficacy of different forms of PAT are still being studied and as of today, no country has approved the widespread implementation of PAT. It is important to remember that there is no one type of psychotherapy, including PAT, that is suitable for everyone. The use of psychotropic drugs in general carries risks, even when used in a clinical context.

In Ukraine, only ketamine-assisted psychotherapy can be legally used in medical practice. Ketamine is a registered medicine and is even produced in Ukraine. Since 2017, it has been possible to use international clinical protocols, and therefore ketamine-assisted psychotherapy [45]. At the same time, this is an off-label use, which is not regulated by law in Ukraine.

PATs using psilocybin, MDMA and other promising drugs are illegal, as they are on the list of substances banned in Ukraine. Even scientific research on these drugs is not possible, although this was stipulated in Ukrainian legislation back in 1995. Since then, and to this day, the procedure for granting relevant permits and licences has not been developed [46].

There are also other psychoactive substances that are not regulated by law in Ukraine (such as ibogaine), and therefore their use has an uncertain legal status.

To ensure that the most promising forms of PAT are already legally available in Ukraine under state supervision, MDMA and psilocybin should be moved from the list of prohibited substances to the list of strictly controlled substances [47]. This would immediately make it possible to legally use PATs in expanded access programmes, provided that it is free of charge for patients [48]. All the necessary regulatory framework for this already exists in Ukraine. In this case, patients will have access to PAT under the supervision of the Ministry of Health and the Ministry of Internal Affairs, and subsequently the Ministry of Health will be able to register the necessary drugs as medicines, which will make PAT available to a wider range of patients. More detailed regulation of PATs can be introduced in the legislation over time, if the need arises. For this purpose, a relevant section can be included in the new law on mental health care, which is currently being prepared [49]. In order to comply with Ukraine's international obligations, the following can be taken as a basis the example of Australia.

An alternative way is to develop a separate law with subsequent amendments to a number of other laws (such as the Law of Ukraine "On Narcotic Drugs, Psychotropic Substances and Precursors") and/or to develop a procedure for regulating the scientific and medical use of prohibited substances, as is done in other countries. At the same time, this way is longer and carries more risks, as it requires significant changes to the current legislation.

1. You can help by sharing this information with your colleagues and friends and signing up for updates on our website to stay informed.

2. You can take free training in the basics of psychedelic assisted therapy, information about which will soon appear on the website.

3. You can join the discussion of standards, curricula, therapy protocols, regulatory mechanisms in the field of PAT and advocacy. Publications of the standards will be published on the website as soon as they are ready. To get involved in advocacy, please send us an email.

4.You can support our mission financially.

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48. The Law of Ukraine "On Amendments to Certain Legislative Acts of Ukraine Regarding the Regulation of Provision of Compassionate Medicines to Patients" No 2054-IX (2022). https://zakon.rada.gov.ua/laws/show/2054-20#Text

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