致幻劑的復興：藥物濫用可能性的篩查

經過幾十年的邊緣化或迴避，儘管挑戰不斷，但對迷幻劑治療潛力的研究仍在增加。

資料來源：Nature research custom / 財團法人台灣紅絲帶基金會編譯

在特定蘑菇中發現的迷幻化合物裸蓋菇素正在作為一種精神治療進行研究，但也需要沒有濫用的可能性。

圖片來源：KATERYNA KON/SCIENCE PHOTO LIBRARY/Getty Images

越來越多的證據顯示，致幻化合物可能在治療創傷性腦損傷 (TBI) 和精神疾病方面具有重要的治療價值。 然而，要實現這一價值，研究人員不僅需要應對藥理學，還需要應對與迷幻劑相關的恐懼：濫用風險和歷史恥辱，這將迷幻劑與自殘和精神錯亂的風險聯繫起來。

藥物濫用是一種化合物的重複非醫療用途的可能性，通常是娛樂性的。「虐待可能導致大腦中的化學變化，從而導致成癮」，芬蘭查爾斯河實驗室的高級客戶經理 Mateusz Dudek 解釋說。

儘管存在這些風險，但對有效心理保健的需求日益增長，這推動了對迷幻藥的研究走向主流。「我們進行了許多研究，研究裸蓋菇素或 N,N-二甲基色胺 (DMT) 等化合物——兩種最常見的致幻劑——如何幫助緩解抑鬱、焦慮、創傷後壓力症候群、創傷性腦損傷 (TBI) 和中風等疾病」，杜德克報告說。「據報導，一些 5-HT 受體的激活和神經元可塑性的誘導是主要驅動因素」。

但由於潛在的缺點，迷幻藥物的開發必然包括篩選潛在的藥物濫用傾向化合物，這不是一項微不足道的任務。

迷幻篩选和神經可塑性

「囓齒類動物無法告訴我們它們的感受，因此我們不得不開發測試，讓它們的行為能夠證明它們對藥物的感受」，查爾斯舊金山河南實驗室體內操作主任邁克爾.吉爾解釋道 .

其中一項測試是頭部抽搐反應。 監測經過藥物處理的囓齒動物的頭部運動——更多的頭部運動與更高的致幻和濫用可能性相關。 然而，僅此測試是不夠的。 像 Gill 這樣的研究人員通常會結合使用非自願給藥、條件性位置偏好和自我給藥測試。 在這裡，囓齒動物通過各種方式給予迷幻劑，然後提供尋找或避免藥物的機會。

「自我管理通常是黃金標準」，吉爾說。「如果一隻動物願意在外圍自我管理藥物，那就是濫用可能性的一個強有力的指標」。

透過這些測試，研究人員能夠更好地研究和開發用於治療應用的迷幻藥。 特別感興趣的是使用迷幻藥來誘導神經可塑性：大腦隨著時間的推移適應和重塑的能力。

迷幻藥可以促進皮質神經元上樹突棘的生長，這是 5-HT 受體集中的地方。 新棘的生長可能有助於形成新的突觸並促進機械性腦損傷的恢復 (Lukasiewicz, Front Mol Neurosci 2021)。

「在機械損傷中，例如 TBI 或中風，腦組織會受到損傷」，Dudek 解釋說，「並且由於迷幻藥具有誘導神經可塑性的能力，它們可能有助於長期康復」。

Dudek 和他在 Charles River 的同事支持藥物開發人員早期發現治療性迷幻藥——測試化合物誘導神經元可塑性、幻覺和成癮行為的能力。 為此，他們通常從軸突生長測試開始，在該測試中，用測試化合物處理離體皮層神經元，然後觀察最大軸突長度、四肢數量、新樹突棘形成等的表型變化。 使用自動分析軟件，該測定可以可靠地預測化合物的神經可塑性潛力。

美好的未來

總的來說，這些測試幫助研究人員篩選大量迷幻化合物以獲得理想的品質，從而有效地開發治療方法。「它正朝著好的方向發展」，杜德克說，「我一直祈禱這些化合物會成功，我們將在臨床環境中看到更多它們」。

了解更多關於在這個先進領域防止藥物濫用的努力，請訪問查爾斯河迷幻研究

The hallucinogenic renaissance: screening for drug abuse potential

After decades of being sidelined or shunned, and despite continued challenges, research into the therapeutic potential of psychedelics is increasing.

Produced by /  Nature research custom / 2022 

Psychedelic compound psilocybin, found in specific mushrooms, is being investigated as a psychiatric treatment, but also needs to have no potential for abuse.Credit: KATERYNA KON/SCIENCE PHOTO LIBRARY/ Getty Images

A growing body of evidence suggests that hallucinogenic compounds may provide significant therapeutic value in treating traumatic brain injuries (TBIs) and psychiatric disorders. However, to realize this value, researchers need to contend not only with the pharmacology, but also the fears associated with psychedelics: risks of abuse and historical stigma, which links psychedelics to the risk of self-harm and insanity.

Drug abuse is the potential for repeated, non-medical uses of a compound, often recreationally. “Abuse may cause chemical changes in the brain that lead to addiction,” explains Mateusz Dudek, a Senior Client Manager at Charles River Laboratories, Finland.

Despite these risks, the growing need for effective mental health care has propelled research into psychedelics towards the mainstream. “We’ve conducted many studies into how compounds like psilocybin or N,N-Dimethyltryptamine (DMT) — two of the most common psychedelics — help with conditions like depression, anxiety, post-traumatic stress disorder, TBI, and stroke,” reports Dudek. “Activation of some of the 5-HT receptors and induction of neuronal plasticity are reported to be primary drivers.”

But because of the potential drawbacks, psychedelic-drug development necessarily includes screening prospective compounds for drug abuse liability, which is not a trivial task.

Psychedelic screening and neuroplasticity

“Rodents can’t tell us what they’re feeling, so we’ve had to develop tests where their behaviour can demonstrate how they feel about the drug,” explains Michael Gill, director of in vivo operations at Charles River’s South San Francisco laboratory.

One such test is the head-twitch response. Drug-treated rodents are monitored for head movements – more head movement correlates to higher hallucinogenic and abuse potential. However, this test alone is not adequate. Researchers like Gill will often use a combination of involuntary administration, conditioned place preference, and self-administration tests. Here, rodents are given the psychedelic through various means, and then presented the opportunity to seek out, or avoid the drug.

“Self-administration is usually the gold standard,” says Gill. “If an animal’s willing to self-administer the drug peripherally, that’s a strong indicator of abuse potential.”

With these tests, researchers are better able to study and develop psychedelics for therapeutic applications. Of particular interest is the use of psychedelics to induce neuroplasticity: the brain’s ability to adapt and remodel over time.

Psychedelics can promote growth of dendritic spines on cortical neurons, which is where 5-HT receptors are concentrated. The growth of new spines may help form new synapses and promote recovery from mechanical brain injuries (Lukasiewicz, Front Mol Neurosci 2021).

“In mechanical injuries, such as in a TBI or stroke, there is damage to the brain tissue,” explains Dudek, “and because of psychedelics’ ability to induce neuroplasticity, they may support long-term recovery.”

Dudek and his colleagues at Charles River support drug developers in early discovery of therapeutic psychedelics – testing a compound’s ability to induce neuronal plasticity, hallucinations, and addictive behaviors. To do this, they usually start with a neurite outgrowth test in which ex vivo cortical neurons are treated with test compounds, and subsequently observed for phenotypic changes in maximum neurite length, number of extremities, formation of new dendritic spines, and more. With automated analytic software, this assay can be a reliable predictor of a compound’s neuroplastic potential.

A promising future

Collectively, these tests help researchers screen large libraries of psychedelic compounds for desirable qualities, enabling efficient development of therapeutics. “It’s going in a good direction,” Dudek says, “I’m keeping my fingers crossed that these compounds will succeed and we’ll see more of them in the clinical setting.”

Learn more about efforts to prevent drug abuse in this advancing field, visit Charles River Psychedelic Research Studies